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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 Activation of the kallikrein-kinin system promotes vascular leakage, inflammation, and neurodegeneration in ischemic stroke. Inhibition of plasma kallikrein (PK) – a key component of the KKS – in the acute phase of ischemic stroke has been reported to reduce thrombosis, inflammation, and damage to the blood-brain barrier. However, the role of PK during the recovery phase after cerebral ischemia is unknown. To this end, we evaluated the effect of subacute PK inhibition starting from day 3 on the recovery process after transient middle artery occlusion (tMCAO). Our study demonstrated a protective effect of PK inhibition by reducing infarct volume and improving functional outcome at day 7 after tMCAO. In addition, we observed reduced thrombus formation in cerebral microvessels, fewer infiltrated immune cells, and an improvement in blood-brain barrier integrity. This protective effect was facilitated by promoting tight junction reintegration, reducing detrimental matrix metalloproteinases, and upregulating regenerative angiogenic markers. Our findings suggest that PK inhibition in the subacute phase might be a promising approach to accelerate the post-stroke recovery process.

In this paper, we focus on investigating the potential of advanced Neural Radiance Fields (NeRFs) and 3D Gaussian Splatting for 3D scene reconstruction from aerial imagery obtained via sensor platforms with an almost nadir-looking camera. Such a setting for image acquisition is convenient for capturing large-scale urban scenes, yet it poses particular challenges arising from imagery with large overlap, very short baselines, similar viewing direction and almost the same but large distance to the scene, and it therefore differs from the usual object-centric scene capture. We apply a traditional approach for image-based 3D reconstruction (COLMAP), a modern NeRF-based approach (Nerfacto) and a representative for the recently introduced 3D Gaussian Splatting approaches (Splatfacto), where the latter two are provided in the Nerfstudio framework. We analyze results achieved on the recently released UseGeo dataset both quantitatively and qualitatively. The achieved results reveal that the traditional COLMAP approach still outperforms Nerfacto and Splatfacto approaches for various scene characteristics, such as less-textured areas, areas with high vegetation, shadowed areas and areas observed from only very few views.

Depth estimation and 3D model reconstruction from aerial imagery is an important task in photogrammetry, remote sensing, and computer vision. To compare the performance of different image-based approaches, this study presents a benchmark for UAV-based aerial imagery using the UseGeo dataset. The contributions include the release of various evaluation routines on GitHub, as well as a comprehensive comparison of baseline approaches, such as methods for offline multi-view 3D reconstruction resulting in point clouds and triangle meshes, online multi-view depth estimation, as well as single-image depth estimation using self-supervised deep learning. With the release of our evaluation routines, we aim to provide a universal protocol for the evaluation of depth estimation and 3D reconstruction methods on the UseGeo dataset. The conducted experiments and analyses show that each method excels in a different category: the depth estimation from COLMAP outperforms that of the other approaches, ACMMP achieves the lowest error and highest completeness for point clouds, while OpenMVS produces triangle meshes with the lowest error. Among the online methods for depth estimation, the approach from the Plane-Sweep Library outperforms the FaSS-MVS approach, while the latter achieves the lowest processing time. And even though the particularly challenging nature of the dataset and the small amount of training data leads to a significantly higher error in the results of the self-supervised single-image depth estimation approach, it outperforms all other approaches in terms of processing time and frame rate. In our evaluation, we have also considered modern learning-based approaches that can be used for image-based 3D reconstruction, such as NeRFs. However, due to the significantly lower quality of the resulting 3D models, we have only included a qualitative comparison between NeRF-based and conventional approaches in the scope of this work.

Introduction Patients’ beliefs and attitudes about medications play a role in whether they adhere to their medications or not. Knowledge on how beliefs and attitudes about medications can be influenced is therefore important. Objectives The current study aimed to assess whether patients’ perceived support from their therapists regarding use of medications was associated with their beliefs and attitudes about medications. Because non-adherence in patients with psychosis frequently results in relapses and emergencies, this knowledge may be very useful for therapists and patients. Methods This cross-sectional study included 310 patients diagnosed with psychosis from 31 clinical units in Norwegian mental health specialist care. We assessed beliefs about medications using the Beliefs about Medicines Questionnaire (BMQ). BMQ-specific consists of two subscales, BMQ-necessity and BMQ-concerns. Higher score on the necessity subscale indicates stronger beliefs in the necessity of taking the medicine. Higher score on the concern subscale indicates stronger concerns about taking the medicine. We used a newly developed self-report questionnaire, MedSupport, to assess the patients’ perceived support from therapists in dealing with their medications. Higher score on the MedSupport means that the patient experienced more support with decisions related to medications. Linear mixed effect models were used to investigate possible associations of sociodemographic factors, clinical factors and patients’ perceptions of medication support with BMQ. Results Patients’ perceptions of medication support from therapists were positively associated with positive beliefs towards medications, β = 0.20, 95% CI [0.04 to 0.35], p=0.012, and negatively associated with concerns about taking the medications, β = -0.31, 95% CI [-0.44 to -0.17], p < 0.001, when other relevant variables were taken into consideration. Conclusions The present study shows that therapists may affect patients’ beliefs and concerns about medications. Consequently, medication support may lead to improved adherence to medications prescribed. Disclosure of Interest None Declared

Due to worldwide demographic change, the number of older persons in the population is increasing. Aging is accompanied by changes of sleep structure, deposition of beta-amyloid (Aß) and tau proteins and vascular changes and can turn into mild cognitive impairment (MCI) as well as dementia. Sleep disorders are discussed both as a risk factor for and as a consequence of MCI/dementia. Cross-sectional and longitudinal population-based as well as case–control studies revealed sleep disorders, especially sleep-disorderded breathing (SDB) and excessive or insufficient sleep durations, as risk factors for all-cause MCI/dementia. Regarding different dementia types, SDB was especially associated with vascular dementia while insomnia/insufficient sleep was related to an increased risk of Alzheimer’s disease (AD). Scarce and still inconsistent evidence suggests that therapy of sleep disorders, especially continuous positive airway pressure (CPAP) in SDB, can improve cognition in patients with sleep disorders with and without comorbid dementia and delay onset of MCI/dementia in patients with sleep disorders without previous cognitive impairment. Regarding potential pathomechanisms via which sleep disorders lead to MCI/dementia, disturbed sleep, chronic sleep deficit and SDB can impair glymphatic clearance of beta-amyloid (Aß) and tau which lead to amyloid deposition and tau aggregation resulting in changes of brain structures responsible for cognition. Orexins are discussed to modulate sleep and Aß pathology. Their diurnal fluctuation is suppressed by sleep fragmentation and the expression suppressed at the point of hippocampal atrophy, contributing to the progression of dementia. Additionally, sleep disorders can lead to an increased vascular risk profile and vascular changes such as inflammation, endothelial dysfunction and atherosclerosis which can foster neurodegenerative pathology. There is ample evidence indicating that changes of sleep structure in aging persons can lead to dementia and also evidence that therapy of sleep disorder can improve cognition. Therefore, sleep disorders should be identified and treated early.

CoVID-19 can develop into Post-COVID syndrome of potentially high morbidity, with procoagulation and reactivation of dormant viral infections being hypothesized pathophysiological mechanisms. We report on a patient suffering from fatigue, post exertional malaise, pain and neurological symptoms as a consequence of the second CoVID infection. Using live confocal microscopy on native whole blood samples we detected microaggregates of thrombocytes, leukocytes and plasma proteins in peripheral blood. In addition, there was specific cellular immunological reactivity to EBV. Upon anticoagulatory and virustatic pharmacological therapy we observed dissolution of microaggregates and significant stable clinical remission. We suggest to consider circulating microaggregates as a morphological indicator of chronic post-COVID syndrome.

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 Greenland Ice Sheet is a major contributor to current and projected sea level rise in the warming climate. However, uncertainties in Greenland's contribution to future sea level rise remain, partly due to challenges in constraining the role of ice dynamics. Transient ice accelerations, or ice speed-up events, lasting from 1 d to 1 week, have the potential to indirectly affect the mass budget of the ice sheet. They are triggered by an overload of the subglacial drainage system due to an increase in water supply. In this study, we identify melt-induced ice speed-up events at the Russell Glacier, southwest Greenland, in order to analyse synoptic patterns driving these events. The short-term speed-up events are identified from daily ice velocity time series collected from six GPS stations along the glacier for each summer (May–October) from 2009 to 2012. In total, 45 ice speed-up events are identified, of which we focus on the 36 melt-induced events, where melt is derived from two in situ observational datasets and one regional climate model forced by ERA5 reanalysis. We identify two additional potential water sources, namely lake drainages and extreme rainfall, which occur during 14 and 4 out of the 36 melt-induced events, respectively. The 36 melt-induced speed-up events occur during synoptic patterns that can be grouped into three main clusters: (1) patterns that resemble atmospheric rivers with a landfall in southwest Greenland, (2) patterns with anticyclonic blocking centred over southwest Greenland, and (3) patterns that show low-pressure systems centred either south or southeast of Greenland. Out of these clusters, the one resembling atmospheric river patterns is linked to the strongest speed-up events induced by 2 to 3 d continuously increasing surface melt driven by anomalously high sensible heat flux and incoming longwave radiation. In the other two clusters, the net shortwave radiation dominates the contribution to the melt energy. As the frequency and intensity of these weather patterns may change in the warming climate, so may the frequency and intensity of ice speed-up events, ultimately altering the mass loss of the ice sheet.

Abstract Background Stroke remains one of the leading causes of long-term disability worldwide, and the development of effective restorative therapies is hindered by an incomplete understanding of intrinsic brain recovery mechanisms. Growing evidence indicates that the brain extracellular matrix (ECM) has major implications for neuroplasticity. Here we explored how perineuronal nets (PNNs), the facet-like ECM layers surrounding fast-spiking interneurons, contribute to neurological recovery after focal cerebral ischemia in mice with and without induced stroke tolerance. Methods We investigated the structural remodeling of PNNs after stroke using 3D superresolution stimulated emission depletion (STED) and structured illumination (SR-SIM) microscopy. Superresolution imaging allowed for the precise reconstruction of PNN morphology using graphs, which are mathematical constructs designed for topological analysis. Focal cerebral ischemia was induced by transient occlusion of the middle cerebral artery (tMCAO). PNN-associated synapses and contacts with microglia/macrophages were quantified using high-resolution confocal microscopy. Results PNNs undergo transient structural changes after stroke allowing for the dynamic reorganization of GABAergic input to motor cortical L5 interneurons. The coherent remodeling of PNNs and their perforating inhibitory synapses precedes the recovery of motor coordination after stroke and depends on the severity of the ischemic injury. Morphological alterations in PNNs correlate with the increased surface of contact between activated microglia/macrophages and PNN-coated neurons. Conclusions Our data indicate a novel mechanism of post stroke neuroplasticity involving the tripartite interaction between PNNs, synapses, and microglia/macrophages. We propose that prolonging PNN loosening during the post-acute period can extend the opening neuroplasticity window into the chronic stroke phase. Graphical Abstract

Abstract Polyvinyl alcohol (PVA) is a biodegradable, water-soluble polymer with excellent film forming properties, commonly studied or used as tablet coating, food packaging or controlled release fertilizers. Attract-and-kill (AK) beads are sustainable, microbial alternatives to synthetic soil insecticides, whose onset of lethal effect largely depend on how fast the encapsulated entomopathogenic fungus forms virulent conidia. Therefore, the objective of this study was to develop a water-soluble coating accelerating the kill effect of AK beads by immediately releasing virulent Metarhizium brunneum CB15-III blastospores. We assessed three PVA types (PVA 4-88, 8-88, 10-98) which differed in their degree of hydrolysis or molecular weight for their ability to release viable blastospores from thin films after drying at 60–40 °C, and examined how polyethylene glycol and soy-lecithin impact the blastospore survival. Finally, we evaluated the effectiveness of coated AK beads in a bioassay against Tenebrio molitor larvae. The blastospore release rate quadrupled within the first 5 min with decreasing molecular weight and degree of hydrolysis, with PVA 4-88 releasing 79 ± 19% blastospores. Polyethylene glycol and soy-lecithin significantly increased the blastospore survival to 18–28% for all three PVA types. Coated beads exhibited a uniform, 22.4 ± 7.3 µm thin coating layer, with embedded blastospores, as confirmed by scanning electron microscopy. The blastospore coating increased the mortality rate of T. molitor larvae over uncoated AK beads, decreasing the median lethal time from 10 to 6 days. Consequently, the blastospore coating accelerated the kill effect of regular AK beads. These findings pave the way to enhanced pest control efficacy from coated systems such as beads or seeds. Graphical Abstract

Forest dieback in Europe has recently intensified and has become more extensive. This dieback is strongly influenced by meteorological variations of temperature, T2m, and precipitation, P, and can be monitored with forest greenness. This study quantitatively investigates the 3-year meteorological history preceding events of reduced forest greenness in Europe's temperate and Mediterranean biome with a systematic approach. A specific focus lies in the timing of unusually persistent and unusually strong anomalies of T2m and P, as well as their relation to synoptic weather systems. A pragmatic approach based on remote sensing observations of the normalized difference vegetation index (NDVI) serves to identify low-forest-NDVI events at the 50 km scale in Europe in June to August 2002–2022. We quantify the impact of the hottest summer on record in Europe in 2022, which, according to our criteria, negatively affected 37 % of temperate and Mediterranean forest regions, and thereby reduced forest greenness more extensively than any other summer in 2002–2022. The low-NDVI events occurred in particularly dry and hot summers, but their meteorological histories also featured significant anomalies further in the past, with clear differences between the temperate and Mediterranean biome. A key feature is the anomalous accumulation of dry periods (i.e., periods with a P deficit) over the preceding 26 and 34 months in the temperate and Mediterranean biome, respectively. In the temperate biome only, T2m was anomalously persistent during almost the same 26-month period and featured distinctive peaks late in the past three growing seasons. While anomalously strong hot–dry conditions were characteristic of temperate low-NDVI events already in the previous summer, we find hardly any other systematic meteorological precursor in the Mediterranean prior to the event year. The identified dry periods went along with reduced cyclone activity in the Mediterranean and positive anticyclone frequency in the temperate biome. The occurrence of these two weather systems is locally more nuanced, showing, e.g., consistently increased and decreased cyclone frequency over western and northern Europe, respectively, in all event summers. Finally, the systematic meteorological histories are useful to test whether locally observed meteorological impacts, e.g., structural overshoot, systematically influenced the investigated events. In summary, systematic investigations of the multi-annual meteorological history provided clear evidence of how surface weather and synoptic-scale weather systems over up to 3 years can negatively impact European forest greenness. The observation of the record-extensive low-NDVI event in the summer of 2022 underlines that understanding the forest–meteorology interaction is of particular relevance for forest dieback in a changing climate.

Aim: Stroke is one of the leading causes of death and disability worldwide. Plasma biomarkers have long been used to evaluate physiological or pathological processes and to make predictions about the outcome of stroke patients. The current systematic review is focused on genetic plasma biomarkers as a new potential prognostic indicator for post-stroke recovery. The aim of the present systematic review is to assess the potential of genetic plasma biomarkers associated with stroke to predict post-stroke recovery. Methods: The search strategy used PubMed and Web of Science databases to identified 166 studies that investigated genetic plasma biomarkers in patients with stroke between 2017 and 2021. However, only 21 of them met the inclusion criteria. Results: The identified genetic biomarkers can be divided into: (i) serum/plasma circular RNA (circRNA) associated with stroke onset or recurrence (5; 23.80%), (ii) genetic polymorphisms associated with the atherosclerotic process and stroke recurrence (6; 28.57%), (iii) serum/plasma long non-coding RNA (lncRNA) levels involved in immunity/inflammatory processes (4; 19.04%), (iv) marker of DNA methylation associated with stroke onset and outcome (3; 14.28%), and (v) proteins and pathways of stroke identified by serum/ plasma proteomics/genomics analysis (3; 14.28%). Conclusions: Overall, more than 100 potential biomarkers were found and the data suggest that combinations of plasma genetic biomarkers might be used as a better predictor for stroke.

Both classic epigenetic modifications and microRNAs can impact a range of bodily processes, from metabolism to brain function, and may contribute to the development of diseases such as cancer, cardiovascular disorders, and psychiatric disorders. Numerous studies suggest a connection between epigenetic changes and mood disorders. In this study, we performed a comprehensive search using PubMed and Google for the terms “epigenetics”, “ageing”, “miRNA”, “schizophrenia”, and “mood disorders” in the titles and abstracts of articles. Epigenetic changes during early life may play a crucial role in triggering severe mental disorders and shaping their clinical trajectory. Although these alterations can take place at any age, their impact may not be immediately evident or observable until later in life. Epigenetic modifications play a crucial role in the ageing process and challenge the prevailing belief that mutations are the primary driver of ageing. However, it is plausible that these epigenetic changes are a consequence of the disorder rather than its root cause. Moreover, both the disorder and the epigenetic alterations may be influenced by shared environmental or genetic factors. In the near future, we might be able to replace chronological age with biological age, based on the epigenetic clock, with the promise of providing greater therapeutic benefits. A wide range of epigenetic drugs are currently under development at various stages. Although their full effectiveness is yet to be realized, they show great potential in the treatment of cancer, psychiatric disorders, and other complex diseases.

Background and objectivesEmotional and cognitive deficits are prevalent in strokes involving the thalamus. In contrast to cognitive deficits, emotional deficits have not been studied prospectively in isolated thalamic stroke.MethodsIn 37 ischemic thalamic stroke patients (57.0 [50.0; 69.5] years [median (Q1; Q3)], 21 males, 5 anterior, 12 paramedian, 20 inferolateral vascular territory), and 37 non-stroke control patients matched for age and sex, we prospectively examined depression, anxiety, activities of daily living, and quality of life at 1, 6, 12, and 24 months post-stroke using the Hospital-Anxiety-and-Depression Scale (HADS), Nürnberger-Alters-Alltagsaktivitäten scale (NAA), and Short Form-36 (SF36) questionnaire. Voxel-based lesion-symptom mapping (VLSM) and lesion-subtraction analyzes were performed to determine associations between questionnaire scores and thalamic stroke topography.ResultsAt 1 month post-stroke, anterior thalamic stroke patients had higher depression scores [8.0 (7.5; 10.5)] than paramedian [4.5 (1.0; 5.8)] and inferolateral [4.0 (1.0; 7.0)] thalamic stroke patients. Furthermore, anterior thalamic stroke patients had higher anxiety scores [11.0 (8.0; 14.5)] than their matched controls [2.5 (2.0; 2.5)], paramedian [4.5 (1.0; 5.8)] and inferior [4.0 (1.0; 7.0)] thalamic stroke patients. Depression and anxiety scores in anterior thalamic stroke patients remained high across the follow-up [depression: 9.0 (3.5; 13,8); anxiety:10.05 (2.8, 14.5)].Physical health assessed by SF36 was intact in anterior [1 month post-stroke: T-score = 55.9 (37.0; 57.6)] but reduced in inferolateral [44.5(32.4; 53.1)] thalamic stroke, whereas mental health was reduced in anterior thalamic stroke [32.0 (29.8; 47.3)].VLSM confirmed that voxels in the anterior thalamus around Montreal Neurological Institute (MNI) coordinates X = −8, Y = −12, Z = 2 were more often affected by the stroke in depressed (HADS-score ≥ 8) than non-depressed (HADS-score

Ischemic stroke is a highly prevalent condition that frequently results in life-long disability and death. Considerable efforts have been made to establish treatments that prevent secondary ischemic damage and promote stroke recovery. Until now, the recanalization of occluded blood vessels via thrombolysis and thrombectomy, although highly potent, remains the only treatment in humans that enhances stroke outcome. Small extracellular vesicles are non-replicating, nano-sized (70–150 nm) lipid bilayer-enclosed vesicles, which have shown remarkable biological activities in various physiological and pathophysiological contexts. When administered post-stroke, mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) induce neuroprotection, promote brain remodeling and plasticity, and enhance neurological recovery in rodents and non-human primates via mechanisms that involve immunomodulation and anti-inflammation. In this review, experimental studies on the therapeutic actions of MSC-EVs in animal stroke models are summarized and perspectives for clinical translation are outlined.

The available evidence suggests that affective disorders, such as depression and anxiety, increase risk for accelerated cognitive decline and late-life dementia in aging individuals. Behavioral neuropsychology studies also showed that cognitive decline is a central feature of aging impacting the quality of life. Motor deficits are common after traumatic brain injuries and stroke, affect subjective well-being, and are linked with reduced quality of life. Currently, restorative therapies that target the brain directly to restore cognitive and motor tasks in aging and disease are available. However, the very same drugs used for therapeutic purposes are employed by athletes as stimulants either to increase performance for fame and financial rewards or as recreational drugs. Unfortunately, most of these drugs have severe side effects and pose a serious threat to the health of athletes. The use of performance-enhancing drugs by children and teenagers has increased tremendously due to the decrease in the age of players in competitive sports and the availability of various stimulants in many forms and shapes. Thus, doping may cause serious health-threatening conditions including, infertility, subdural hematomas, liver and kidney dysfunction, peripheral edema, cardiac hypertrophy, myocardial ischemia, thrombosis, and cardiovascular disease. In this review, we focus on the impact of doping on psychopathological disorders, cognition, and depression. Occasionally, we also refer to chronic use of therapeutic drugs to increase physical performance and highlight the underlying mechanisms. We conclude that raising awareness on the health risks of doping in sport for all shall promote an increased awareness for healthy lifestyles across all generations.

We report on the developments that enabled the field deployment of a fully automated aerosol mass spectrometer, especially designed for high-altitude measurements on unpressurized aircraft. The merits of the two main categories of real-time aerosol mass spectrometry, i.e. (a) single-particle laser desorption and ionization and (b) continuous thermal desorption and electron impact ionization of aerosols, have been integrated into one compact apparatus with the aim to perform in situ real-time analysis of aerosol chemical composition. The demonstrated instrument, named the ERICA (European Research Council Instrument for Chemical composition of Aerosols), operated successfully aboard the high-altitude research aircraft M-55 Geophysica at altitudes up to 20 km while being exposed to ambient conditions of very low atmospheric pressure and temperature. A primary goal of those field deployments was the in situ study of the Asian tropopause aerosol layer (ATAL). During 11 research flights, the instrument operated for more than 49 h and collected chemical composition information of more than 150 000 single particles combined with quantitative chemical composition analysis of aerosol particle ensembles. This paper presents in detail the technical characteristics of the main constituent parts of the instrument, as well as the design considerations for its integration into the aircraft and its autonomous operation in the upper troposphere and lower stratosphere (UTLS). Additionally, system performance data from the first field deployments of the instrument are presented and discussed, together with exemplary mass spectrometry data collected during those flights.

Abstract Background Older people often suffer from multimorbidity resulting in polypharmacy. The correct administration of medication is a crucial factor influencing treatment efficacy. However, tools for evaluating the ability to self-administer different dosage forms of medications are lacking. The objectives of the ABLYMED study are to 1) assess the ability to self-administer different dosage forms of medication in older non-demented in-hospital patients who report autonomous management of medication, 2) identify factors influencing the ability to self-administer medication, and 3) develop a standardized tool to validly assess the ability to self-administer different dosage forms of medications based on the final study results. Methods One hundred in-patients from the department of orthopedics and trauma surgery of the University Hospital Düsseldorf ≥ 70 years of age and regularly taking ≥ 5 different drugs autonomously will be prospectively recruited into the observational cross-sectional single-center ABLYMED study. Patients undergo an interview addressing demographic and clinical information, medication history (which medications are taken since when, in which dose and dosage form, and subjective proficiency of taking these medications), medication adherence, and factors possibly influencing adherence including personality traits and perceived quality of the medication regimen. Quality of the medication regimen is also rated by clinicians according to validated lists. Further, patients receive a comprehensive geriatric assessment including measures of cognition, mobility, and functional status. The ability to self-administer medication is assessed by having patients perform different tasks related to medication self-administration, which are video recorded and rated by different experts. The patients’ self-reported ability will be correlated with the observed performance in the self-administration tasks. Further, factors correlating with the reported and observed ability to self-administer medication will be evaluated using correlation and regression models. Based on the final study results, a novel tool to assess the ability of older patients to self-administer medication will be developed. Discussion In addition to guideline-based pharmacotherapy, correct intake of prescribed medication is crucial for optimal therapy of multimorbidity in older people. Tools to validly assess the ability of older patients to self-administer different dosage forms of medications are lacking, but should be included in comprehensive geriatric assessments to secure functional health. Trial registration Development of an assessment instrument to evaluate the ability to manage various dosage forms, DRKS-ID: DRKS00025788 , (date of registration: 07/09/2021).

ACKR3 is a critical regulator of platelet-mediated thrombosis and organ injury following ischemia/reperfusion. Platelet ACKR3 surface expression is independently associated with all-cause mortality in patients with cardiovascular diseases.

BackgroundOlder people often experience medication management problems due to multimorbidity, polypharmacy and medication complexity. There is often a large gap between patients’ self-reported and actual abilities to handle the self-administration of their medication. Here we report on the development and evaluation of a new tool to assess the ability of non-demented hospitalized patients to self-administer medication in different dosage forms. To this end, we video-recorded the patients’ medication management performance and implemented a novel assessment scheme, which was applied by several independent raters.MethodsSixty-seven in-patients ≥70 years of age and regularly taking ≥5 different drugs autonomously of the ABLYMED study agreed to the video recording of their medication management performance with five different dosage forms. All raters underwent a training and applied a standardized assessment form and written guide with rating rules for evaluation. In a pilot phase, video recordings of three patients were rated by 19 raters (15 medical students, two expert raters to determine a reference standard, and two main raters who later rated the total sample). In the rating phase, based on the ratings obtained from the two main raters, we determined interrater (assessed every section of 20 patients as agreement between the raters at one point of time) and intrarater (assessed as consistency within each rater across three points of time) agreement by intraclass correlation analysis.ResultsIn the pilot phase we obtained an overall sufficient agreement pattern, with an adjustment of the rating rules for patches. In the rating phase we achieved satisfactory agreement between the two raters (interrater reliability) and across different points of time (intrarater reliability). For two dosage forms (eye-drops and pen), rater training needed to be repeated to reach satisfactory levels.DiscussionOur novel rating procedure was found to be objective, valid and reproducible, given appropriate training of the raters. Our findings are an important part of a larger research project to implement a novel assessment for the ability to self-administer medication in different dosage forms. Further, they can support the development of patient trainings to improve medication management and secure independent living.

Interventional treatment of restrictive atrial septal defects in complex heart disease is considered state-of-the-art therapy up to date. Nevertheless, dedicated balloons are lacking so far, as several products have been withdrawn from the market. We report on off-label use of a balloon embolectomy catheter used successfully in a preterm patient and discuss whether this device might be used in other patients as well as it seems to be promising due to its shape and versatility.

Coronavirus, also known as COVID-19, was first detected in Wuhan, China, in December 2019. It is a family of viruses ranging from the common cold to severe acute respiratory syndrome (SARS). The symptoms of such a virus are similar to those of a cold or seasonal allergies. Like other respiratory viruses, it is mainly transmitted through airborne droplets when coughing or sneezing. Therefore, the recognition of COVID-19 requires careful laboratory analysis, and the reduction of recognition resources is a major challenge. On 11 March, 2020, the World Health Organization (WHO) declared COVID-19, caused by SARS-CoV-2, a pandemic, as there had been an exponential increase in cases worldwide, and demand for intensive beds and related structures had far exceeded existing capacity. The first examples of this are the regions of Italy. Brazil registered the first case of SARS-CoV-2 on 02/26/2020. Transmission of the virus in this country shifted very quickly from imported cases to local and, finally, community missions, with the Brazilian federal government announcing national community transmission on 03/20/2020. As of March 23, in the state of São Paulo with a population of about 12 million people, where the Israelita Albert Einstein Hospital is located, 477 cases of the disease and 30 related deaths were registered, and on March 27, there were already 1223 cases of COVID-19 with 68 concomitant deaths. To slow the spread of the virus in the state of São Paulo, quarantines and social distancing measures were introduced. One of the motivations for this challenge is the fact that, in the context of an extensive healthcare system with the possible limitation of SARS-CoV-2 testing, it is not practical to test every case, and test results can only be used in testing the target subpopulation. The study objective is to build a model based on machine learning that can predict the detection of SARS-CoV-2 from medical data. For this, various classification models of machine learning are compared, and the best one to predict coronaviruses is determined. The comparison is based on individuals in class 1, i.e., those with a positive test. Therefore, it is required to determine the machine learning model with the best response and F1 score for class 1.Materials and Methods. An open-source data set from the Israelita Albert Einstein Hospital in São Paulo, Brazil, was taken as a basis. The following machine learning models were used for the study: RandomForests (RF), K-Nearest Neighbor (KNN), Support Vector Machine (SVM), Logistic Regression (LR), Decision Tree (DT) and AdaBoost (AB), as well as the 10-time cross-validation technique. Some machine learning performance measures, such as accuracy, recall, and F1 score were evaluated.Results. Out of a total of 5,644 people tested during the COVID-19 pandemic, 5,086 people tested negative and 558 people tested positive. At the same time, support for machine vectors showed the best results in detecting coronavirus with a recall of 75 % and an F1 score of 60 % compared to models: Random drill, KNN, LR, AB, and DT.Discussion and Conclusions. It was found that when using AB algorithms, greater accuracy is achieved, but the stability of the LSVM algorithm is higher. Therefore, it can be recommended as a useful tool for detecting COVID-19.

How ischaemic stroke affects the brain borders is not fully understood. Here the authors show that a stroke-associated myeloid cell population occurs exclusively in brain parenchyma that shares features with neurodegenerative microglia and blockade of proteins on these cells can ameliorate stroke symptoms.

Abstract Systemic transplantation of oxygen−glucose deprivation (OGD)-preconditioned primary microglia enhances neurological recovery in rodent stroke models, albeit the underlying mechanisms have not been sufficiently addressed. Herein, we analyzed whether or not extracellular vesicles (EVs) derived from such microglia are the biological mediators of these observations and which signaling pathways are involved in the process. Exposing bEnd.3 endothelial cells (ECs) and primary cortical neurons to OGD, the impact of EVs from OGD-preconditioned microglia on angiogenesis and neuronal apoptosis by the tube formation assay and TUNEL staining was assessed. Under these conditions, EV treatment stimulated both angiogenesis and tube formation in ECs and repressed neuronal cell injury. Characterizing microglia EVs by means of Western blot analysis and other techniques revealed these EVs to be rich in TGF-β1. The latter turned out to be a key compound for the therapeutic potential of microglia EVs, affecting the Smad2/3 pathway in both ECs and neurons. EV infusion in stroke mice confirmed the aforementioned in vitro results, demonstrating an activation of the TGF-β/Smad2/3 signaling pathway within the ischemic brain. Furthermore, enriched TGF-β1 in EVs secreted from OGD-preconditioned microglia stimulated M2 polarization of residing microglia within the ischemic cerebral environment, which may contribute to a regulation of an early inflammatory response in postischemic hemispheres. These observations are not only interesting from the mechanistic point of view but have an immediate therapeutic implication as well, since stroke mice treated with such EVs displayed a better functional recovery in the behavioral test analyses. Hence, the present findings suggest a new way of action of EVs derived from OGD-preconditioned microglia by regulating the TGF-β/Smad2/3 pathway in order to promote tissue regeneration and neurological recovery in stroke mice.

Spinal cord injury (SCI) induces neurological deficits associated with long-term functional impairments. Since the current treatments remain ineffective, novel therapeutic options are needed. Besides its effect on bipolar mood disorder, lithium was reported to have neuroprotective activity in different neurodegenerative conditions, including SCI. In SCI, the effects of lithium on long-term neurological recovery and neuroplasticity have not been assessed. We herein investigated the effects of intraperitoneally administered lithium chloride (LiCl) on motor coordination recovery, electromyography (EMG) responses, histopathological injury and remodeling, and axonal plasticity in mice exposed to spinal cord transection. At a dose of 0.2, but not 2.0 mmol/kg, LiCl enhanced motor coordination and locomotor activity starting at 28 days post-injury (dpi), as assessed by a set of behavioral tests. Following electrical stimulation proximal to the hemitransection, LiCl at 0.2 mmol/kg decreased the latency and increased the amplitude of EMG responses in the denervated hindlimb at 56 dpi. Functional recovery was associated with reduced gray and white matter atrophy rostral and caudal to the hemitransection, increased neuronal survival and reduced astrogliosis in the dorsal and ventral horns caudal to the hemitransection, and increased regeneration of long-distance axons proximal and distal to the lesion site in mice receiving 0.2 mmol/kg, but not 2 mmol/kg LiCl, as assessed by histochemical and immunohistochemical studies combined with anterograde tract tracing. Our results indicate that LiCl induces long-term neurological recovery and neuroplasticity following SCI.

Stroke is primarily a neurodegenerative disease but can also severely impact the functions of other vital organs and deteriorate disease outcomes. A malfunction of the gastrointestinal tract (GIT), commonly observed in stroke patients, is often characterized by severe bowel obstruction, intestinal microbiota changes and inflammation. Over-activated immune cells after stroke are the major contributors to endorse intestinal inflammation and may induce damage to single-layer epithelial cell barriers. The post-stroke leakage of intestinal barriers may allow the translocation and dissemination of resident microflora to systemic organs and cause sepsis. This overshooting systemic immune reaction fuels ongoing inflammation in the degenerating brain and slows recovery. Currently, the therapeutic options to treat these GIT-associated anomalies are very limited and further research is required to develop novel treatments. In this mini-review, we first discuss the current knowledge from clinical studies and experimental stroke models that provide strong evidence of the existence of post-stroke GIT complications. Then, we review the literature regarding novel therapeutic approaches that might help to maintain GIT homeostasis and improve neurological outcomes in stroke patients.

Platelets are key mediators of thrombus formation and inflammation during the acute phase of ischaemic stroke. Particularly, the platelet glycoprotein (GP) receptors GPIbα and GPVI have been shown to mediate platelet adhesion and activation in the ischaemic brain. GPIbα and GPVI blockade could reduce infarct volumes and improve functional outcome in mouse models of acute ischaemic stroke, without concomitantly increasing intracerebral haemorrhage. However, the functional role of platelets during long-term stroke recovery has not been elucidated so far.Thus, we here examined the impact of platelet depletion on post-stroke recovery after transient middle cerebral artery occlusion (tMCAO) in adult male mice. Platelet depleting antibodies or isotype control were applied from day 3–28 after tMCAO in mice matched for infarct size. Long-term functional recovery was assessed over the course of 28 days by behavioural testing encompassing motor and sensorimotorical functions, as well as anxiety-like or spontaneous behaviour. Whole brain flow cytometry and light sheet fluorescent microscopy were used to identify resident and infiltrated immune cell types, and to determine the effects of platelet depletion on the cerebral vascular architecture, respectively.We found that delayed platelet depletion does not improve long-term functional outcome in the tMCAO stroke model. Immune cell abundance, the extent of thrombosis and the organisation of the cerebral vasculature were also comparable between platelet-depleted and control mice. Our study demonstrates that, despite their critical role in the acute stroke setting, platelets appear to contribute only marginally to tissue reorganisation and functional recovery at later stroke stages.

Abstract Suicide is one of the leading causes of death globally for all ages, and as such presents a very serious problem for clinicians worldwide. However, the underlying neurobiological pathology remains to a large extent unknown. In order to address this gap, we have carried out a genome-wide investigation of the gene expression in the amygdala, hippocampus, prefrontal cortex and thalamus in post-mortem brain samples obtained from 20 suicide completers and 7 control subjects. By KEGG enrichment analysis indicated we identified novel clusters of downregulated pathways involved in antigen neutralization and autoimmune thyroid disease (amygdala, thalamus), decreased axonal plasticity in the hippocampus. Two upregulated pathways were involved in neuronal death in the hippocampus and olfactory transduction in the thalamus and the prefrontal cortex. Autoimmune thyroid disease pathway was downregulated only in females. Metabolic pathways involved in Notch signaling amino acid metabolism and unsaturated lipid synthesis were thalamus-specific. Suicide-associated changes in the expression of several genes and pseudogenes that point to various functional mechanisms possibly implicated in the pathology of suicide. Two genes (SNORA13 and RNU4-2) involved in RNA processing were common to all brain regions analyzed. Most of the identified gene expression changes were related to region-specific dysregulated manifestation of genetic and epigenetic mechanisms underlying neurodevelopmental disorders (SNORD114-10, SUSd1), motivation, addiction and motor disorders (CHRNA6), long-term depression (RAB3B), stress response, major depression and schizophrenia (GFAP), signal transduction at the neurovascular unit (NEXN) and inhibitory neurotransmission in spatial learning, neural plasticity (CALB2; CLIC6, ENPP1). Some of the differentially expressed genes were brain specific non-coding RNAs involved in the regulation of translation (SNORA13). One, (PARM1) is a potential oncogene and prognostic biomarker for colorectal cancer with no known function in the brain. Disturbed gene expression involved in antigen neutralization, autoimmunity, neural plasticity, stress response, signal transduction at the neurovascular unit, dysregulated nuclear RNA processing and translation and epigenetic imprinting signatures is associated with suicide and point to regulatory non-coding RNAs as potential targets of new drugs development.

Ischemic stroke, a significant neurovascular disorder, currently lacks effective restorative medication. However, recently developed nanomedicines bring renewed promise for alleviating ischemia’s effects and facilitating the healing of neurological and physical functions. The aim of this systematic review was to evaluate the efficacy of nanotherapies in animal models of stroke and their potential impact on future stroke therapies. We also assessed the scientific quality of current research focused on nanoparticle-based treatments for ischemic stroke in animal models. We summarized the effectiveness of nanotherapies in these models, considering multiple factors such as their anti-inflammatory, antioxidant, and angiogenetic properties, as well as their safety and biodistribution. We conclude that the application of nanomedicines may reduce infarct size and improve neurological function post-stroke without causing significant organ toxicity.

Real-time 3D reconstruction enables fast dense mapping of the environment which benefits numerous applications, such as navigation or live evaluation of an emergency. In contrast to most real-time capable approaches, our method does not need an explicit depth sensor. Instead, we only rely on a video stream from a camera and its intrinsic calibration. By exploiting the self-motion of the unmanned aerial vehicle (UAV) flying with oblique view around buildings, we estimate both camera trajectory and depth for selected images with enough novel content. To create a 3D model of the scene, we rely on a three-stage processing chain. First, we estimate the rough camera trajectory using a simultaneous localization and mapping (SLAM) algorithm. Once a suitable constellation is found, we estimate depth for local bundles of images using a Multi-View Stereo (MVS) approach and then fuse this depth into a global surfel-based model. For our evaluation, we use 55 video sequences with diverse settings, consisting of both synthetic and real scenes. We evaluate not only the generated reconstruction but also the intermediate products and achieve competitive results both qualitatively and quantitatively. At the same time, our method can keep up with a 30 fps video for a resolution of 768 × 448 pixels.

Infection is a major reason for poor stroke outcomes, and sepsis is a major cause of stroke-elated deaths. We herein examined whether NMDA receptor blockade, which was reported to exert anti-inflammatory actions, protects against the deleterious consequences of lipopolysaccharide (LPS)-induced sepsis-like state in adult male NMRI mice exposed to transient intraluminal middle cerebral artery occlusion (MCAO). At 24 h post-ischemia, vehicle or Escherichia coli LPS (2 or 4 mg/kg) was intraperitoneally administered, whereas 30 min later vehicle or ketamine (10 mg/kg), which is a non-competitive NMDA receptor antagonist, was intraperitoneally applied. Delivery of LPS at a dosage of 4 mg/kg induced a sepsis-like state characterized by a rectal temperature reduction by ∼4.0°C, increased neurological deficits in Clark score, cylinder and open-field tests, increased brain infarct volume and reduced neuronal survival in the previously ischemic tissue. Notably, additional treatment with ketamine (10 mg/kg) significantly attenuated the sepsis-associated rectal temperature reduction by ∼1.5°C, reduced neurological deficits, reduced infarct volume, and promoted neuronal survival. Ketamine alone did not influence infarct volume or neurological deficits. Real-time PCR data analysis showed that GFAP, CD86, CD206, IL-1β, and IL-10 mRNA levels were significantly increased in ischemic brains of LPS-treated compared with vehicle-treated mice. Additional treatment with ketamine significantly decreased IL-1β and IL-10, but not GFAP, CD86, and CD206 mRNA levels. Our data show that ketamine at a dose that on its own does not confer neuroprotection reverses the adverse effects of LPS-induced sepsis-like state post-ischemia, presumably via immunomodulatory actions.