Natural variation in response to combined water and nitrogen deficiencies in Arabidopsis.

Understanding plant responses to individual stresses does not mean that we understand real world situations, where stresses usually combine and interact. These interactions arise at different levels, from stress exposure to the molecular networks of the stress response. Here, we built an in-depth multi-omics description of plant responses to mild water (W) and nitrogen (N) limitations, either individually or combined, among five genetically different Arabidopsis (Arabidopsis thaliana) accessions. We highlight the different dynamics in stress response through integrative traits such as rosette growth and the physiological status of the plants. We also used transcriptomics and metabolomics profiling during a stage when the plant response was stabilized to determine the wide diversity in stress-induced changes among accessions, highlighting the limited reality of a 'universal' stress response. The main effect of the WxN interaction was an attenuation of the N-deficiency syndrome when combined with mild drought, but to a variable extent depending on the accession. Other traits subject to WxN interactions are often accession-specific. Multi-omics analyses identified a subset of transcript-metabolite clusters that are critical to stress responses but essentially variable according to the genotype factor. Including intra-specific diversity in our descriptions of plant stress response places our findings in perspective.

Conflict, violence, and warfare among early farmers in Northwestern Europe.

Bioarchaeological evidence of interpersonal violence and early warfare presents important insights into conflict in past societies. This evidence is critical for understanding the motivations for violence and its effects on opposing and competing individuals and groups across time and space. Selecting the Neolithic of northwestern Europe as an area for study, the present paper examines the variation and societal context for the violence recorded in the human skeletal remains from this region as one of the most important elements of human welfare. Compiling data from various sources, it becomes apparent that violence was endemic in Neolithic Europe, sometimes reaching levels of intergroup hostilities that ended in the utter destruction of entire communities. While the precise comparative quantification of healed and unhealed trauma remains a fundamental problem, patterns emerge that see conflict likely fostered by increasing competition between settled and growing communities, e.g., for access to arable land for food production. The further development of contextual information is paramount in order to address hypotheses on the motivations, origins, and evolution of violence as based on the study of human remains, the most direct indicator for actual small- and large-scale violence.

Target of rapamycin signaling couples energy to oxygen sensing to modulate hypoxic gene expression in Arabidopsis.

Plants respond to oxygen deprivation by activating the expression of a set of hypoxia-responsive genes (HRGs). The master regulator of this process is a small group of transcription factors belonging to group VII of the ethylene response factors (ERF-VIIs). ERF-VIIs are highly unstable under aerobic conditions due to the continuous oxidation of their characteristic Cys residue at the N terminus by plant cysteine oxidases (PCOs). Under hypoxia, PCOs are inactive and the ERF-VIIs activate transcription of the HRGs required for surviving hypoxia. However, if the plant exposed to hypoxia has limited sugar reserves, the activity of ERF-VIIs is severely dampened. This suggests that oxygen sensing by PCO/ERF-VII is fine-tuned by another sensing pathway, related to sugar or energy availability. Here, we show that oxygen sensing by PCO/ERF-VII is controlled by the energy sensor target of rapamycin (TOR). Inhibition of TOR by genetic or pharmacological approaches leads to a much lower induction of HRGs. We show that two serine residues at the C terminus of RAP2.12, a major ERF-VII, are phosphorylated by TOR and are needed for TOR-dependent activation of transcriptional activity of RAP2.12. Our results demonstrate that oxygen and energy sensing converge in plants to ensure an appropriate transcription of genes, which is essential for surviving hypoxia. When carbohydrate metabolism is inefficient in producing ATP because of hypoxia, the lower ATP content reduces TOR activity, thus attenuating the efficiency of induction of HRGs by the ERF-VIIs. This homeostatic control of the hypoxia-response is required for the plant to survive submergence.

Sensing and regulation of C and N metabolism - novel features and mechanisms of the TOR and SnRK1 signaling pathways.

Carbon (C) and nitrogen (N) metabolisms are tightly integrated to allow proper plant growth and development. Photosynthesis is dependent on N invested in chlorophylls, enzymes, and structural components of the photosynthetic machinery, while N uptake and assimilation rely on ATP, reducing equivalents, and C-skeletons provided by photosynthesis. The direct connection between N availability and photosynthetic efficiency allows the synthesis of precursors for all metabolites and building blocks in plants. Thus, the capacity to sense and respond to sudden changes in C and N availability is crucial for plant survival and is mediated by complex yet efficient signaling pathways such as TARGET OF RAPAMYCIN (TOR) and SUCROSE-NON-FERMENTING-1-RELATED PROTEIN KINASE 1 (SnRK1). In this review, we present recent advances in mechanisms involved in sensing C and N status as well as identifying current gaps in our understanding. We finally attempt to provide new perspectives and hypotheses on the interconnection of diverse signaling pathways that will allow us to understand the integration and orchestration of the major players governing the regulation of the CN balance.

Formation and function of a highly specialised type of organelle in cardiac valve cells.

Within a cell, vesicles play a crucial role in the transport of membrane material and proteins to a given target membrane, and thus regulate a variety of cellular functions. Vesicular transport occurs by means of, among others, endocytosis, where cargoes are taken up by the cell and are processed further upon vesicular trafficking, i.e. transported back to the plasma membrane via recycling endosomes or the degraded by fusion of the vesicles with lysosomes. During evolution, a variety of vesicles with individual functions arose, with some of them building up highly specialised subcellular compartments. In this study, we have analysed the biosynthesis of a new vesicular compartment present in the valve cells of Drosophila melanogaster. We show that the compartment is formed by invaginations of the plasma membrane and grows via re-routing of the recycling endosomal pathway. This is achieved by inactivation of other membrane-consuming pathways and a plasma membrane-like molecular signature of the compartment in these highly specialised heart cells.

The plant TOR kinase tunes autophagy and meristem activity for nutrient stress-induced developmental plasticity.

Plants, unlike animals, respond to environmental challenges with comprehensive developmental transitions that allow them to cope with these stresses. Here we discovered that antagonistic activation of the Target of Rapamycin (TOR) kinase in Arabidopsis thaliana roots and shoots is essential for the nutrient deprivation-induced increase in the root-to-shoot ratio to improve foraging for mineral ions. We demonstrate that sulfate limitation-induced downregulation of TOR in shoots activates autophagy, resulting in enhanced carbon allocation to the root. The allocation of carbon to the roots is facilitated by the specific upregulation of the sucrose-transporter genes SWEET11/12 in shoots. SWEET11/12 activation is indispensable for enabling sucrose to act as a carbon source for growth and as a signal for tuning root apical meristem activity via glucose-TOR signaling. The sugar-stimulated TOR activity in the root suppresses autophagy and maintains root apical meristem activity to support root growth to enhance mining for new sulfate resources in the soil. We provide direct evidence that the organ-specific regulation of autophagy is essential for the increased root-to-shoot ratio in response to sulfur limitation. These findings uncover how sulfur limitation controls the central sensor kinase TOR to enable nutrient recycling for stress-induced morphological adaptation of the plant body.

The Arabidopsis Target of Rapamycin kinase regulates ammonium assimilation and glutamine metabolism.

In eukaryotes, a target of rapamycin (TOR) is a well-conserved kinase that controls cell metabolism and growth in response to nutrients and environmental factors. Nitrogen (N) is an essential element for plants, and TOR functions as a crucial N and amino acid sensor in animals and yeast. However, knowledge of the connections between TOR and the overall N metabolism and assimilation in plants is still limited. In this study, we investigated the regulation of TOR in Arabidopsis (Arabidopsis thaliana) by the N source as well as the impact of TOR deficiency on N metabolism. Inhibition of TOR globally decreased ammonium uptake while triggering a massive accumulation of amino acids, such as Gln, but also of polyamines. Consistently, TOR complex mutants were hypersensitive to Gln. We also showed that the glutamine synthetase inhibitor glufosinate abolishes Gln accumulation resulting from TOR inhibition and improves the growth of TOR complex mutants. These results suggest that a high level of Gln contributes to the reduction in plant growth resulting from TOR inhibition. Glutamine synthetase activity was reduced by TOR inhibition while the enzyme amount increased. In conclusion, our findings show that the TOR pathway is intimately connected to N metabolism and that a decrease in TOR activity results in glutamine synthetase-dependent Gln and amino acid accumulation.

Effect of SGLT-2 inhibitors on arrhythmia events: insight from an updated secondary analysis of > 80,000 patients (the SGLT2i-Arrhythmias and Sudden Cardiac Death).

OBJECTIVE: We aimed to assess the effect of SGLT2i on arrhythmias by conducting a meta-analysis using data from randomized controlled trials(RCTs). BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have shown cardioprotective effects via multiple mechanisms that may also contribute to decrease arrhythmias risk. METHODS: We searched in databases (PubMed, Embase, Cochrane Library, and clinicaltrials.gov) up to April 2023. RCTs comparing SGLT2i with placebo were included. The effects of SGLT2i on atrial fibrillation(AF), atrial flutter(AFL), composite AF/AFL, ventricular fibrillation(VF), ventricular tachycardia(VT), ventricular extrasystoles(VES), sudden cardiac death(SCD) and composite VF/VT/SCD were evaluated. RESULTS: 33 placebo-controlled RCTs were included, comprising 88,098 patients (48,585 in SGLT2i vs. 39,513 in placebo). The mean age was 64.9 ± 9.4 years, 63.0% were male. The mean follow-up was 1.4 ± 1.1 years. The pooled-results showed that SGLT2i was associated with a significantly lower risk of AF [risk ratio(RR): 0.88, 95% confidence interval(CI) 0.78-1.00, P = 0.04] and composite AF/AFL (RR: 0.86, 95%CI 0.77-0.96, P = 0.01). This favorable effect appeared to be substantially pronounced in patients with HFrEF, male gender, dapagliflozin, and > 1 year follow-up. For SCD, only in heart failure patients, SGLT2i were found to be associated with a borderline lower risk of SCD (RR: 0.67, P = 0.05). No significant effects of SGLT2i on other ventricular arrhythmic outcomes were found. CONCLUSIONS: SGLT2i lowers the risks of AF and AF/AFL, and this favorable effect appeared to be particularly pronounced in patients with HFrEF, male gender, dapagliflozin, and longer follow-up (> 1 year). SGLT2i lowers the risk of SCD only in heart failure patients.

Primary Tumor Resection in Leiomyosarcoma Patients With Synchronous Isolated Lung Metastases: A National Cancer Database Study.

INTRODUCTION: Up to half of patients with leiomyosarcoma (LMS) present with distant metastases, most commonly in the lungs. Despite guidelines around managing metachronous oligometastatic disease, limited evidence exists for synchronous isolated lung metastases (SILMs). Our histology-specific study describes management patterns and outcomes for patients with LMS and SILM across disease sites. METHODS: We used the National Cancer Database to analyze patients with LMS of the retroperitoneum, extremity, trunk/chest/abdominal wall, and pelvis with SILM. Patients with extra-pulmonary metastases were excluded. We identified factors associated with primary tumor resection and receipt of metastasectomy. Outcomes included median, 1-year, and 5-year overall survival (OS) across treatment approaches using log-rank tests, Kaplan-Meier curves, and Cox proportional hazard models. RESULTS: We identified 629 LMS patients with SILM from 2004 to 2017. Patients were more likely to have resection of their primary tumor or lung metastases if treated at an academic center compared to a community cancer center. Five year OS for patients undergoing both primary tumor resection and metastasectomy was 20.9% versus 9.2% for primary tumor resection alone, and 2.6% for nonsurgical patients. Median OS for all-comers was 15.5 mo. Community treatment site, comorbidity score, and larger primary tumors were associated with worse survival. Chemotherapy, primary resection, and curative intent surgery predicted improved survival on multivariate Cox regression. CONCLUSIONS: An aggressive surgical approach to primary LMS with SILM was undertaken for select patients in our population and found to be associated with improved OS. This approach should be considered for suitable patients at high-volume centers.

Uterine MEIS1::NCOA2 Fusion Sarcoma With Lung Metastasis: A Case Report and Review of the Literature.

MEIS1::NCOA1/2 fusion sarcomas are a recently described novel entity arising in a variety of locations with a predilection for the genitourinary tract and gynecologic organs. Despite multiple locoregional recurrences, these tumors are thought to behave in a low-grade malignant manner. Here we report a uterine MEIS1::NCOA2 fusion sarcoma with lung metastasis. The patient was a 47-yr-old woman with a history of abnormal uterine bleeding who was found to have a myometrial mass confirmed by pathology to be uterine sarcoma. The tumor was predominantly composed of monotonous spindle cells with scant cytoplasm, crowded nuclei, and brisk mitotic activity, growing in a fascicular and streaming pattern. The morphologic and immunophenotypic features were nonspecific and a diagnosis of high-grade uterine sarcoma with a differential of leiomyosarcoma versus high-grade endometrial stromal sarcoma was rendered. At the 27-mo follow-up, the patient was found to have a lung metastasis consisting of a monotonous round cell sarcoma. A retrospective RNA-based and DNA-based next-generation sequencing of the primary uterine sarcoma revealed a MEIS1::NCOA2 gene fusion, a c.94G>C/p.D32H mutation in exon 3 of CTNNB1 gene, HMGA2 , and CDK4 gene amplification, and an intermediate/marginal level of MDM2 gene amplification. Polymerase chain reaction-based molecular analysis further demonstrated that the MEIS1::NCOA2 gene fusion and CTNNB1 somatic mutation were also present in the lung metastasis. This case represents the first case of such gynecologic sarcoma with distant (lung) metastasis, and the second metastatic case among all reported MEIS1::NCOA1/2 fusion sarcomas, highlighting the malignant metastatic potential of this emerging entity. Our case also indicates that HMGA2/CDK4/MDM2 region amplification and CTNNB1 somatic mutation might be recurrent genetic events in this rare sarcoma subtype.

Management of patients with an electrical storm or clustered ventricular arrhythmias: a clinical consensus statement of the European Heart Rhythm Association of the ESC-endorsed by the Asia-Pacific Heart Rhythm Society, Heart Rhythm Society, and Latin-American Heart Rhythm Society.

Electrical storm (ES) is a state of electrical instability, manifesting as recurrent ventricular arrhythmias (VAs) over a short period of time (three or more episodes of sustained VA within 24 h, separated by at least 5 min, requiring termination by an intervention). The clinical presentation can vary, but ES is usually a cardiac emergency. Electrical storm mainly affects patients with structural or primary electrical heart disease, often with an implantable cardioverter-defibrillator (ICD). Management of ES requires a multi-faceted approach and the involvement of multi-disciplinary teams, but despite advanced treatment and often invasive procedures, it is associated with high morbidity and mortality. With an ageing population, longer survival of heart failure patients, and an increasing number of patients with ICD, the incidence of ES is expected to increase. This European Heart Rhythm Association clinical consensus statement focuses on pathophysiology, clinical presentation, diagnostic evaluation, and acute and long-term management of patients presenting with ES or clustered VA.

App-Based Addiction Prevention at German Vocational Schools: Implementation and Reach for a Cluster-Randomized Controlled Trial.

This article examines the implementation, participation rates, and potential determinants of participation in the digital addiction prevention program "ready4life." A two-arm cluster-randomized trial recruited German vocational students via class-based strategies. Intervention group received 16 weeks of in-app coaching; the control group received health behavior information, with coaching offered after 12 months. Potential determinants of participation were analyzed based on class and individual characteristics. Out of 525 contacted schools, 35 participated, enrolling 376 classes. Implementation during the pandemic required flexible adjustments, with 49.7% of introductions conducted in person, 43.1% digitally via online streaming, and 7.2% received a video link via email. Despite challenges, 72.3% of the vocational students downloaded the app, and 46.7% gave informed consent. Participation rates were highest among (associate) professionals, vocational grammar school classes, classes introduced by females, younger individuals, members of the project team, and classes introduced face-to-face. Female gender, lower social competencies, lifetime cannabis use, higher problematic internet use, and higher perceived stress were associated with higher individual participation. The study highlights the importance of proactive outreach and personalized interventions for addiction prevention programs in vocational schools. While reached students aligned with the aims of the app, tailored recruitment strategies could enhance engagement among under-represented groups. The trial was registered in the German Clinical Trials Register (DRKS): DRKS00022328; registration date 09.10.2020.

Tailup expression in Drosophila larval and adult cardiac valve cells.

In Drosophila larvae, the direction of blood flow within the heart tube, as well as the diastolic filling of the posterior heart chamber, is regulated by a single cardiac valve. This valve is sufficient to close the heart tube at the junction of the ventricle and the aorta and is formed by only two cells; both are integral parts of the heart tube. The valve cells regulate hemolymph flow by oscillating between a spherical and a flattened cell shape during heartbeats. At the spherical stage, the opposing valve cells close the heart lumen. The dynamic cell shape changes of valve cells are supported by a dense, criss-cross orientation of myofibrils and the presence of the valvosomal compartment, a large intracellular cavity. Both structures are essential for the valve cells' function. In a screen for factors specifically expressed in cardiac valve cells, we identified the transcription factor Tailup. Knockdown of tailup causes abnormal orientation and differentiation of cardiac muscle fibers in the larval aorta and inhibits the formation of the ventral longitudinal muscle layer located underneath the heart tube in the adult fly and affects myofibrillar orientation of valve cells. Furthermore, we have identified regulatory sequences of tup that control the expression of tailup in the larval and adult valve cells.

The small GTPase KlRho5 responds to oxidative stress and affects cytokinesis.

Rho5 is the yeast homolog of the human small GTPase Rac1. We characterized the genes encoding Rho5 and the subunits of its dimeric activating guanine-nucleotide-exchange factor (GEF), Dck1 and Lmo1, in the yeast Kluyveromyces lactis. Rapid translocation of the three GFP-tagged components to mitochondria upon oxidative stress and carbon starvation indicate a similar function of KlRho5 in energy metabolism and mitochondrial dynamics as described for its Saccharomyces cerevisiae homolog. Accordingly, Klrho5 deletion mutants are hyper-resistant towards hydrogen peroxide. Moreover, synthetic lethalities of rho5 deletions with key components in nutrient sensing, such as sch9 and gpr1, are not conserved in K. lactis. Instead, Klrho5 deletion mutants display morphological defects with strengthened lateral cell walls and protruding bud scars. The latter result from aberrant cytokinesis, as observed by following the budding process in vivo and by transmission electron microscopy of the bud neck region. This phenotype can be suppressed by KlCDC42G12V, which encodes a hyper-active variant. Data from live-cell fluorescence microscopy support the notion that KlRho5 interferes with the actin moiety of the contractile actomyosin ring, with consequences different from those previously reported for mutants lacking myosin.

Association of age with 1-year outcome in patients with acute ischaemic stroke treated with thrombectomy: real-world analysis in 18 506 patients.

BACKGROUND: To evaluate the association of age with long-term outcome after thrombectomy. METHODS: In a retrospective cohort study based on routine healthcare data from Germany between 2010 and 2018, we included 18 506 patients with acute ischaemic stroke treated with mechanical thrombectomy. Association between age and mortality, disability, and level of care at 1 year was assessed. RESULTS: The median age was 76 years, 36.3% were aged ≥80 years and 55.8% were women. Patients aged ≥80 compared with those <80 years had a higher mortality (55.4% vs 28.5%; adjusted HR 1.13; 95% CI 1.05 to 1.31), more often had moderate/severe disability (35.5% vs 33.2%, adjusted HR 1.14; 95% CI 1.06 to 1.23) and less frequently had no/slight disability (17.4% vs 41.0%) at 1 year. Older age was associated with a higher likelihood of living in a nursing home (13.4% vs 9.2%, adjusted HR 1.09; 95% CI 0.97 to 1.22) and a lower likelihood of living at home (33.8% vs 62.8%) at 1 year. These associations were also robust when analysed in patients with no disability prior to stroke. Factors most strongly associated with worse 1-year outcomes in elderly patients were chronic limb-threatening ischaemia (67.9% vs 56.4%; HR 1.59, 95% CI 1.38 to 1.82), dementia at baseline (65.2% vs 47.3%; HR 1.29, 95% CI 1.17 to 1.44) and ventilation >48 hours (79.3% vs 52.2%; HR 2.91, 95% CI 2.66 to 3.18). CONCLUSIONS: In this large 'real-world' cohort, outcomes after mechanical thrombectomy were strongly associated with age. Of patients aged ≥80 years more than half were dead and less than one-fifth were functionally independent at 1 year. Certain comorbidities and ventilation >48 hours were associated with even worse outcomes.

Differentiation and function of cardiac valves in the adult Drosophila heart.

Drosophila, like all insects, has an open circulatory system for the distribution of haemolymph and its components. The circulation of the haemolymph is essentially driven by the pumping activity of the linear heart. The heart is constructed as a tube into which the haemolymph is sucked and pumped forward by rhythmic contractions running from the posterior to the anterior, where it leaves the heart tube. The heart harbours cardiac valves to regulate flow directionality, with a single heart valve differentiating during larval development to separate the heart tube into two chambers. During metamorphosis, the heart is partially restructured, with the linear heart tube with one terminal wide-lumen heart chamber being converted into a linear four-chambered heart tube with three valves. As in all metazoan circulatory systems, the cardiac valves play an essential role in regulating the direction of blood flow. We provide evidence that the valves in adult flies arise via transdifferentiation, converting lumen-forming contractile cardiomyocytes into differently structured valve cells. Interestingly, adult cardiac valves exhibit a similar morphology to their larval counterparts, but act differently upon heart beating. Applying calcium imaging in living specimens to analyse activity in valve cells, we show that adult cardiac valves operate owing to muscle contraction. However, valve cell shape dynamics are altered compared with larval valves, which led us to propose our current model of the opening and closing mechanisms in the fly heart.

Testing reciprocal associations between child anxiety and parenting across early interventions for inhibited preschoolers.

BACKGROUND: Given the robust evidence base for the efficacy of evidence-based treatments targeting youth anxiety, researchers have advanced beyond efficacy outcome analysis to identify mechanisms of change and treatment directionality. Grounded in developmental transactional models, interventions for young children at risk for anxiety by virtue of behaviorally inhibited temperament often target parenting and child factors implicated in the early emergence and maintenance of anxiety. In particular, overcontrolling parenting moderates risk for anxiety among highly inhibited children, just as child inhibition has been shown to elicit overcontrolling parenting. Although longitudinal research has elucidated the temporal unfolding of factors that interact to place inhibited children at risk for anxiety, reciprocal transactions between these child and parent factors in the context of early interventions remain unknown. METHOD: This study addresses these gaps by examining mechanisms of change and treatment directionality (i.e., parent-to-child vs. child-to-parent influences) within a randomized controlled trial comparing two interventions for inhibited preschoolers (N = 151): the multicomponent Turtle Program ('Turtle') and the parent-only Cool Little Kids program ('CLK'). Reciprocal relations between parent-reported child anxiety, observed parenting, and parent-reported accommodation of child anxiety were examined across four timepoints: pre-, mid-, and post-treatment, and one-year follow-up (NCT02308826). RESULTS: Hypotheses were tested via latent curve models with structured residuals (LCM-SR) and latent change score (LCS) models. LCM-SR results were consistent with the child-to-parent influences found in previous research on cognitive behavioral therapy (CBT) for older anxious youth, but only emerged in Turtle. LCS analyses revealed bidirectional effects of changes in parent accommodation and child anxiety during and after intervention, but only in Turtle. CONCLUSION: Our findings coincide with developmental transactional models, suggesting that the development of child anxiety may result from child-to-parent influences rather than the reverse, and highlight the importance of targeting parent and child factors simultaneously in early interventions for young, inhibited children.

cAMP Imaging at Ryanodine Receptors Reveals ß2-Adrenoceptor Driven Arrhythmias.

[Figure: see text].

Machine Learned Cellular Phenotypes in Cardiomyopathy Predict Sudden Death.

RATIONALE: Susceptibility to VT/VF (ventricular tachycardia/fibrillation) is difficult to predict in patients with ischemic cardiomyopathy either by clinical tools or by attempting to translate cellular mechanisms to the bedside. OBJECTIVE: To develop computational phenotypes of patients with ischemic cardiomyopathy, by training then interpreting machine learning of ventricular monophasic action potentials (MAPs) to reveal phenotypes that predict long-term outcomes. METHODS AND RESULTS: We recorded 5706 ventricular MAPs in 42 patients with coronary artery disease and left ventricular ejection fraction ≤40% during steady-state pacing. Patients were randomly allocated to independent training and testing cohorts in a 70:30 ratio, repeated K=10-fold. Support vector machines and convolutional neural networks were trained to 2 end points: (1) sustained VT/VF or (2) mortality at 3 years. Support vector machines provided superior classification. For patient-level predictions, we computed personalized MAP scores as the proportion of MAP beats predicting each end point. Patient-level predictions in independent test cohorts yielded c-statistics of 0.90 for sustained VT/VF (95% CI, 0.76-1.00) and 0.91 for mortality (95% CI, 0.83-1.00) and were the most significant multivariate predictors. Interpreting trained support vector machine revealed MAP morphologies that, using in silico modeling, revealed higher L-type calcium current or sodium-calcium exchanger as predominant phenotypes for VT/VF. CONCLUSIONS: Machine learning of action potential recordings in patients revealed novel phenotypes for long-term outcomes in ischemic cardiomyopathy. Such computational phenotypes provide an approach which may reveal cellular mechanisms for clinical outcomes and could be applied to other conditions.

Hospital rating websites play a minor role for uro-oncologic patients when choosing a hospital for major surgery: results of the German multicenter NAVIGATOR-study.

PURPOSE: Hospital rating websites (HRW) offer decision support in hospital choice for patients. To investigate the impact of HRWs of uro-oncological patients undergoing elective surgery in Germany. METHODS: From 01/2020 to 04/2021, patients admitted for radical prostatectomy, radical cystectomy, or renal tumor surgery received a questionnaire on decision-making in hospital choice and the use of HRWs at 10 German urologic clinics. RESULTS: Our study includes n = 812 completed questionnaires (response rate 81.2%). The mean age was 65.2 ± 10.2 years; 16.5% were women. Patients were scheduled for prostatectomy in 49.1%, renal tumor surgery in 20.3%, and cystectomy in 13.5% (other 17.1%). Following sources of information influenced the decision process of hospital choice: urologists' recommendation (52.6%), previous experience in the hospital (20.3%), recommendations from social environment (17.6%), the hospital's website (10.8%) and 8.2% used other sources. Only 4.3% (n = 35) used a HRW for decision making. However, 29% changed their hospital choice due to the information provided HRW. The most frequently used platforms were Weisse-Liste.de (32%), the AOK-Krankenhausnavigator (13%) and Qualitaetskliniken.de (8%). On average, patients rated positively concerning satisfaction with the respective HRW on the Acceptability E-Scale (mean values of the individual items: 1.8-2.1). CONCLUSION: In Germany, HRWs play a minor role for uro-oncologic patients undergoing elective surgery. Instead, personal consultation of the treating urologist seems to be far more important. Although patients predominantly rated the provided information of the HRW as positive, only a quarter of users changed the initial choice of hospital.