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Abstract Acid sphingomyelinase (ASM) inhibitors are widely used for the treatment of post-stroke depression. They promote neurological recovery in animal stroke models via neurorestorative effects. In a previous study, we found that antidepressants including amitriptyline, fluoxetine, and desipramine increase cerebral angiogenesis post-ischemia/reperfusion (I/R) in an ASM-dependent way. To elucidate the underlying mechanisms, we investigated the effects of the functional ASM inhibitor amitriptyline in two models of I/R injury, that is, in human cerebral microvascular endothelial hCMEC/D3 cells exposed to oxygen-glucose deprivation and in mice exposed to middle cerebral artery occlusion (MCAO). In addition to our earlier studies, we now show that amitriptyline increased mitochondrial reactive oxygen species (ROS) formation in hCMEC/D3 cells and increased ROS formation in the vascular compartment of MCAO mice. ROS formation was instrumental for amitriptyline’s angiogenic effects. ROS formation did not result in excessive endothelial injury. Instead, amitriptyline induced a profound metabolic reprogramming of endothelial cells that comprised reduced endothelial proliferation, reduced mitochondrial energy metabolism, reduced endoplasmic reticulum stress, increased autophagy/mitophagy, stimulation of antioxidant responses and inhibition of apoptotic cell death. Specifically, the antioxidant heme oxygenase-1, which was upregulated by amitriptyline, mediated amitriptyline’s angiogenic effects. Thus, heme oxygenase-1 knockdown severely compromised angiogenesis and abolished amitriptyline’s angiogenic responses. Our data demonstrate that ASM inhibition reregulates a complex network of metabolic and mitochondrial responses post-I/R that contribute to cerebral angiogenesis without compromising endothelial survival.

Abstract Heart rate variability (HRV) has been linked to resilience and emotion regulation (ER). How HRV and brain processing interact during ER, however, has remained elusive. Sixty-two subjects completed the acquisition of resting HRV and task HRV while performing an ER functional Magnetic Resonance Imaging (fMRI) paradigm, which included the differential strategies of ER reappraisal and acceptance in the context of viewing aversive pictures. We found high correlations of resting and task HRV across all emotion regulation strategies. Furthermore, individuals with high levels of resting, but not task, HRV showed numerically lower distress during ER with acceptance. Whole-brain fMRI parametrical modulation analyses revealed that higher task HRV covaried with dorso-medial prefrontal activation for reappraisal, and dorso-medial prefrontal, anterior cingulate and temporo-parietal junction activation for acceptance. Subjects with high resting HRV, compared to subjects with low resting HRV, showed higher activation in the pre-supplementary motor area during ER using a region of interest approach. This study demonstrates that while resting and task HRV exhibit a positive correlation, resting HRV seems to be a better predictor of ER capacity. Resting and task HRV were associated with ER brain activation in mid-line frontal cortex (i.e. DMPFC).

BackgroundIncreasing pressure on limited intensive care capacities often requires a subjective assessment of a patient's discharge readiness in the absence of established Admission, Discharge, and Transfer (ADT) guidelines. To avoid suboptimal care transitions, it is important to define clear guidelines for the admission and discharge of intensive care patients and to optimize transfer processes between the intensive care unit (ICU) and lower care levels. To achieve these goals, structured insights into usual ICU discharge and transfer practices are essential. This study aimed to generate these insights by focusing on involved stakeholders, established processes, discharge criteria and tools, relevant performance metrics, and current barriers to a timely and safe discharge.MethodIn 2022, a structured, web-based, anonymous cross-sectional survey was conducted, aimed at practicing ICU physicians, nurses, and bed coordinators. The survey consisted of 29 questions (open, closed, multiple choice, and scales) that were divided into thematic blocks. The study was supported by several national and international societies for intensive care medicine and nursing.ResultsA total of 219 participants from 40 countries (105 from Germany) participated in the survey. An overload of acute care resources with ~90% capacity utilization in the ICU and the general ward (GW) leads to not only premature but also delayed patient transfers due to a lack of available ward and intermediate care (IMC) beds. After multidisciplinary rounds within the intensive care team, the ICU clinician on duty usually makes the final transfer decision, while one-third of the panel coordinates discharge decisions across departmental boundaries. By the end of the COVID-19 pandemic, half of the hospitals had implemented ADT policies. Among these hospitals, nearly one-third of the hospitals had specific transfer criteria established, consisting primarily of vital signs and laboratory data, patient status and autonomy, and organization-specific criteria. Liaison nurses were less common but were ranked right after the required IMC capacities to bridge the care gap between the ICU and normal wards. In this study, 80% of the participants suggested that transfer planning would be easier if there was good transparency regarding the capacity utilization of lower care levels, a standardized transfer process, and improved interdisciplinary communication.ConclusionTo improve care transitions, transfer processes should be managed proactively across departments, and efforts should be made to identify and address care gaps.

Abstract Background The intravenous delivery of adult neural precursor cells (NPC) has shown promising results in enabling cerebroprotection, brain tissue remodeling, and neurological recovery in young, healthy stroke mice. However, the translation of cell-based therapies to clinical settings has encountered challenges. It remained unclear if adult NPCs could induce brain tissue remodeling and recovery in mice with hyperlipidemia, a prevalent vascular risk factor in stroke patients. Methods Male mice on a normal (regular) diet or on cholesterol-rich Western diet were exposed to 30 min intraluminal middle cerebral artery occlusion (MCAO). Vehicle or 106 NPCs were intravenously administered immediately after reperfusion, at 3 day and 7 day post-MCAO. Neurological recovery was evaluated using the Clark score, Rotarod and tight rope tests over up to 56 days. Histochemistry and light sheet microscopy were used to examine ischemic injury and brain tissue remodeling. Immunological responses in peripheral blood and brain were analyzed through flow cytometry. Results NPC administration reduced infarct volume, blood–brain barrier permeability and the brain infiltration of neutrophils, monocytes, T cells and NK cells in the acute stroke phase in both normolipidemic and hyperlipidemic mice, but increased brain hemorrhage formation and neutrophil, monocyte and CD4+ and CD8+ T cell counts and activation in the blood of hyperlipidemic mice. While neurological deficits in hyperlipidemic mice were reduced by NPCs at 3 day post-MCAO, NPCs did not improve neurological deficits at later timepoints. Besides, NPCs did not influence microglia/macrophage abundance and activation (assessed by morphology analysis), astroglial scar formation, microvascular length or branching point density (evaluated using light sheet microscopy), long-term neuronal survival or brain atrophy in hyperlipidemic mice. Conclusions Intravenously administered NPCs did not have persistent effects on post-ischemic neurological recovery and brain remodeling in hyperlipidemic mice. These findings highlight the necessity of rigorous investigations in vascular risk factor models to fully assess the long-term restorative effects of cell-based therapies. Without comprehensive studies in such models, the clinical potential of cell-based therapies cannot be definitely determined.

The measurement of quality indicators supports quality improvement initiatives. The German Interdisciplinary Society of Intensive Care Medicine (DIVI) has published quality indicators for intensive care medicine for the fourth time now. After a scheduled evaluation after three years, changes in several indicators were made. Other indicators were not changed or only minimally. The focus remained strongly on relevant treatment processes like management of analgesia and sedation, mechanical ventilation and weaning, and infections in the ICU. Another focus was communication inside the ICU. The number of 1ndicators remained the same. The development method was more structured and transparency was increased by adding new features like evidence levels or author contribution and potential conflicts of interest. These quality indicators should be used in the peer review in intensive care, a method endorsed by the DIVI. Other forms of measurement and evaluation are also reasonable, for example in quality management. This fourth edition of the quality indicators will be updated in the future to reflect the recently published recommendations on the structure of intensive care units by the DIVI.

Cryo-EM structures of the stress-sensing complex in Listeria innocua reveal conformational changes that initiate the signaling response to environmental stress.

A cryo-electron microscopy reconstruction of a stressosome complex from a Gram-negative bacterium, Vibrio vulnificus, reveals variations in subunit composition and symmetry, which could serve to adjust the activation threshold in the response to low levels of oxygen and starvation.

COVID-19 shocked the world and provided a particular challenge for populist radical right (PRR) forces. We lay out three research questions that this special issue addresses through case studies of the PRR in government in Brazil, Hungary, Turkey and the US and in opposition in France, Italy, Germany and Spain: (1) How have PRR actors responded to the pandemic? (2) How have PRR actors framed the politics of the pandemic? and (3) What have been the effects of the pandemic on the popularity of the PRR? We explain the case selection of this special issue and summarize the main findings of the eight case studies, which show that the pandemic did not severely damage the PRR and that they had very different responses to the challenge. This reinforces the idea that the PRR is not ephemeral but is rather the by-product of structural transformations of contemporary societies and is here for the foreseeable future. [ABSTRACT FROM AUTHOR]