Objectives: Telemedicine is frequently used to provide remote neurological expertise for acute stroke workup and was associated with better functional outcomes when combined with a stroke unit system-of-care. We investigated whether such system-of-care yields additional benefits when implemented on top of neurological competence already available onsite.

Methods: Quality improvement measures were implemented within a "hub-and-spoke" teleneurology network in 11 hospitals already provided with onsite or telestroke expertise. Measures included dedicated units for neurological emergencies, standardization of procedures, multiprofessional training, and quality-of-care monitoring. Intervention effects were investigated in a controlled study enrolling patients insured at 3 participating statutory health insurances diagnosed with acute stroke or other neurological emergencies. Outcomes during the intervention period between November 2017 and February 2020 were compared with those pre-intervention between October 2014 and March 2017. To control for temporal trends, we compared outcomes of patients with respective diagnoses in 11 hospitals of the same region. Primary outcome was the composite of up-to-90-day death, new disability with the need of ambulatory or nursing home care, expressed by adjusted hazard ratio (aHR).

Results: We included 1,418 patients post-implementation (55% female, mean age 76.7 +/- 12.8 year) and 2,306 patients pre-implementation (56%, 75.8 +/- 13.0 year, respectively). The primary outcome occurred in 479/1,418 (33.8%) patients post-implementation and in 829/2,306 (35.9%) pre-implementation. The aHR for the primary outcome was 0.89 (95% confidence interval [CI]: 0.79-0.99, p = 0.04) with no improvement seen in non-participating hospitals between post- versus pre-implementation periods (aHR 1.04; 95% CI: 0.95-1.15).

Interpretation: Implementation of a multicomponent system-of-care was associated with a lower risk of poor outcomes.

Objective: To determine the effect of additional mobile stroke unit (MSU) dispatch on functional outcomes among the full spectrum of stroke patients, regardless of subtype or potential contraindications to reperfusion therapies.

Methods: We used data from the nonrandomized Berlin-based B_PROUD study (02/2017 to 05/2019), in which MSUs were dispatched based solely on availability, and the linked B-SPATIAL stroke registry. All patients with final stroke or transient ischemic attack (TIA) diagnoses were eligible. The intervention under study was the additional dispatch of an MSU, an emergency physician-staffed ambulance equipped to provide prehospital imaging and thrombolytic treatment, compared to conventional ambulance alone. The primary outcome was the 3-month modified Rankin Scale (mRS) score, and the co-primary outcome was a 3-tiered disability scale. We identified confounders using directed acyclic graphs and obtained adjusted effect estimates using inverse probability of treatment weighting.

Results: MSUs were dispatched to 1,125 patients (mean age: 74 years, 46.5% female), while for 1,141 patients only conventional ambulances were dispatched (75 years, 49.9% female). After confounding adjustment, MSU dispatch was associated with more favorable 3-month mRS scores (common odds ratio [cOR] = 0.82; 95% confidence interval [CI]: 0.71-0.94). No statistically significant association was found with the co-primary outcome (cOR = 0.86; 9% CI: 0.72-1.01) or 7-day mortality (OR = 0.94; 95% CI: 0.59-1.48).

Interpretation: When considering the entire population of stroke/TIA patients, MSU dispatch improved 3-month functional outcomes without evidence of compromised safety. Our results are relevant for decision-makers since stroke subtype and treatment eligibility are unknown at time of dispatch.

Objective: Patients with myelin oligodendrocyte glycoprotein antibody (MOG-IgG)-associated disease (MOGAD) suffer from severe optic neuritis (ON) leading to retinal neuro-axonal loss, which can be quantified by optical coherence tomography (OCT). We assessed whether ON-independent retinal atrophy can be detected in MOGAD.

Methods: Eighty patients with MOGAD and 139 healthy controls (HCs) were included. OCT data was acquired with (1) Spectralis spectral domain OCT (MOGAD: N = 66 and HCs: N = 103) and (2) Cirrus high-definition OCT (MOGAD: N = 14 and HCs: N = 36). Macular combined ganglion cell and inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) were quantified.

Results: At baseline, GCIPL and pRNFL were lower in MOGAD eyes with a history of ON (MOGAD-ON) compared with MOGAD eyes without a history of ON (MOGAD-NON) and HCs (p < 0.001). MOGAD-NON eyes had lower GCIPL volume compared to HCs (p < 0.001) in the Spectralis, but not in the Cirrus cohort. Longitudinally (follow-up up to 3 years), MOGAD-ON with ON within the last 6-12 months before baseline exhibited greater pRNFL thinning than MOGAD-ON with an ON greater than 12 months ago (p < 0.001). The overall MOGAD cohort did not exhibit faster GCIPL thinning compared with the HC cohort.

Interpretation: Our study suggests the absence of attack-independent retinal damage in patients with MOGAD. Yet, ongoing neuroaxonal damage or edema resolution seems to occur for up to 12 months after ON, which is longer than what has been reported with other ON forms. These findings support that the pathomechanisms underlying optic nerve involvement and the evolution of OCT retinal changes after ON is distinct in patients with MOGAD.

Background/aim: Autosomal recessive primary microcephaly (MCPH) is a rare and genetically heterogeneous group of disorders characterized by intellectual disability and microcephaly at birth, classically without further organ involvement. MCPH3 is caused by biallelic variants in the cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2. In the corresponding Cdk5rap2 mutant or Hertwig's anemia mouse model, congenital microcephaly as well as defects in the hematopoietic system, germ cells and eyes have been reported. The reduction in brain volume, particularly affecting gray matter, has been attributed mainly to disturbances in the proliferation and survival of early neuronal progenitors. In addition, defects in dendritic development and synaptogenesis exist that affect the excitation-inhibition balance. Here, we studied proteomic changes in cerebral cortices of Cdk5rap2 mutant mice.

Material and methods: We used large-gel two-dimensional gel (2-DE) electrophoresis to separate cortical proteins. 2-DE gels were visualized by a trained observer on a light box. Spot changes were considered with respect to presence/absence, quantitative variation and altered mobility.

Result: We identified a reduction in more than 30 proteins that play a role in processes such as cell cytoskeleton dynamics, cell cycle progression, ciliary functions and apoptosis. These proteome changes in the MCPH3 model can be associated with various functional and morphological alterations of the developing brain.

Conclusion: Our results shed light on potential protein candidates for the disease-associated phenotype reported in MCPH3.

Objective: With a growing appreciation for interindividual anatomical variability and patient-specific brain connectivity, advanced imaging sequences offer the opportunity to directly visualize anatomical targets for deep brain stimulation (DBS). The lack of quantitative evidence demonstrating their clinical utility, however, has hindered their broad implementation in clinical practice.

Methods: Using fast gray matter acquisition T1 inversion recovery (FGATIR) sequences, the present study identified a thalamic hypointensity that holds promise as a visual marker in DBS. To validate the clinical utility of the identified hypointensity, we retrospectively analyzed 65 patients (26 female, mean age = 69.1 +/- 12.7 years) who underwent DBS in the treatment of essential tremor. We characterized its neuroanatomical substrates and evaluated the hypointensity's ability to predict clinical outcome using stimulation volume modeling and voxelwise mapping. Finally, we determined whether the hypointensity marker could predict symptom improvement on a patient-specific level.

Results: Anatomical characterization suggested that the identified hypointensity constituted the terminal part of the dentatorubrothalamic tract. Overlap between DBS stimulation volumes and the hypointensity in standard space significantly correlated with tremor improvement (R-2 = 0.16, p = 0.017) and distance to hotspots previously reported in the literature (R-2 = 0.49, p = 7.9e-4). In contrast, the amount of variance explained by other anatomical atlas structures was reduced. When accounting for interindividual neuroanatomical variability, the predictive power of the hypointensity increased further (R-2 = 0.37, p = 0.002).

Interpretation: Our findings introduce and validate a novel imaging-based marker attainable from FGATIR sequences that has the potential to personalize and inform targeting and programming in DBS for essential tremor.

Donor age is a major risk factor for allograft outcome in kidney transplantation. The underlying cellular mechanisms and the recipient's immune response within an aged allograft have yet not been analyzed. A comprehensive immunophenotyping of naive and transplanted young versus aged kidneys revealed that naive aged murine kidneys harbor significantly higher frequencies of effector/memory T cells, whereas regulatory T cells were reduced. Aged kidney-derived CD8(+) T cells produced more IFN gamma than their young counterparts. Senescent renal CD8(+) T and NK cells upregulated the cytotoxicity receptor NKG2D and the enrichment of memory-like CD49a(+)CXCR6(+) NK cells was documented in aged naive kidneys. In the C57BL/6 to BALB/c kidney transplantation model, recipient-derived T cells infiltrating an aged graft produced significantly more IFN gamma, granzyme B and perforin on day 7 post-transplantation, indicating an enhanced inflammatory, cytotoxic response towards the graft. Pre-treatment of aged kidney donors with the senolytic drug ABT-263 changed the recipient-derived effector molecule profile to significantly reduced levels of IFN gamma and IL-10 compared to controls. Graft function after ABT-263 pre-treatment was significantly improved 28 days post kidney transplantation. In conclusion, renal senescence also occurs at the immunological level (inflamm-aging) and aged organs provoke an altered recipient-dominated immune response in the graft.

Studies assume that up to 30% of home care recipients are exposed to a possible medication error. For the home care sector, the study situation regarding such errors is limited. The aim of the study was to find out how often medication errors occur and whether they are related to training, quality assurance measures (use of the double-check principle (DCP)), and other structural conditions of home care services. A cross-sectional study was conducted, comprising 485 fully trained nurses of 107 randomly selected home care services. Potential influencing factors were analyzed in a multiple logistic regression model. Of 485 fully qualified nurses, 41.6% reported medication errors within a 12-month period, while 14.8% did not answer this question. Nurses who had attended medication training within the last 2 years compared to a longer period (frequently to rather rarely applied DCP); the odds ratio of not making medication-related errors was 1.79[1.42-3.09] (OR 3.13; [1.88-5.20]). Years of professional experience, amount of patients per shift, and type of work contract (full/part-time) were not statistically significantly associated with reported medication errors. Medication-related errors occur frequently in home care. Regular training and adequate quality management measures increase patient safety. Nursing managers and other responsible individuals of home care institutions have to make sure that nursing staff take part in regular medication training and apply the DCP when they give out medication in home care.

Cell-intrinsic responses mounted in PBMCs during mild and severe COVID-19 differ quantitatively and qualitatively. Whether they are triggered by signals emitted by productively infected cells of the respiratory tract or result from physical interaction with virus particles remains unclear. Here, we analyzed susceptibility and expression profiles of PBMCs from healthy donors upon ex vivo exposure to SARS-CoV and SARS-CoV-2. In line with the absence of detectable ACE2 receptor expression, human PBMCs were refractory to productive infection. RT-PCR experiments and single-cell RNA sequencing revealed JAK/STAT-dependent induction of interferon-stimulated genes (ISGs) but not proinflammatory cytokines. This SARS-CoV-2-specific response was most pronounced in monocytes. SARS-CoV-2-RNA-positive monocytes displayed a lower ISG signature as compared to bystander cells of the identical culture. This suggests a preferential invasion of cells with a low ISG baseline profile or delivery of a SARS-CoV-2-specific sensing antagonist upon efficient particle internalization. Together, nonproductive physical interaction of PBMCs with SARS-CoV-2- and, to a much lesser extent, SARS-CoV particles stimulate JAK/STAT-dependent, monocyte-accentuated innate immune responses that resemble those detected in vivo in patients with mild COVID-19.

Objectives: The paraglottic space is an essential anatomic compartment of the larynx. It is central to the spread of laryngeal cancer and to the choice of conservative laryngeal surgery and many phonosurgical procedures. Since its description, 60 years ago, the surgical anatomy of the paraglottic space was sparsely revisited. Amid the era of endoscopic and transoral microscopic functional surgery of the larynx, we provide here a long-awaited description of the inside-out anatomy of the paraglottic space.

Methodology: Using an endoscope equipped with a 3D camera, we dissected 10 hemilarynges from 5 fresh frozen cadavers from the inside out. Before dissection, we labeled the vessels through injecting them with colored latex. We explored the paraglottic space emphasizing its shape, boundaries, and contents. We documented our findings through endoscopic photography and video recordings.

Results: The paraglottic space is a spacious tetrahedral space located parallel not only to the glottic, but also to the subglottic and the supraglottic compartments of the laryngeal lumen. It has musculo-cartilaginous, musculo-fibrous, and mucosal boundaries. It is separated from the pyriform sinus only by mucosa. A cushion of fat surrounds its vascular and to a lesser extent its neural contents. Harbored intrinsic laryngeal muscles are endoscopically identifiable within the space, namely the thyroarytenoid, the lateral, and posterior cricoarytenoid muscles.

Conclusion: The endoscopic description of the paraglottic space partly fills the knowledge gap on the laryngeal anatomy from the inside out. It opens the door for novel diagnostic methods and for ultraconservative functional laryngeal interventions under endoscopic control.

Background: Inflammatory cardiomyopathy is one of the most common causes of sudden cardiac death in young adults. Diagnosis of inflammatory cardiomyopathy remains challenging, and better monitoring tools are needed. We present magnetocardiography as a method to diagnose myocardial inflammation and monitor treatment response.

Methods and Results: A total of 233 patients were enrolled, with a mean age of 45 (+/- 18) years, and 105 (45%) were women. The primary analysis included 209 adult subjects, of whom 66 (32%) were diagnosed with inflammatory cardiomyopathy, 17 (8%) were diagnosed with cardiac amyloidosis, and 35 (17%) were diagnosed with other types of nonischemic cardiomyopathy; 91 (44%) did not have cardiomyopathy. The second analysis included 13 patients with inflammatory cardiomyopathy who underwent immunosuppressive therapy after baseline magnetocardiography measurement. Finally, diagnostic accuracy of magnetocardiography was tested in 3 independent cohorts (total n=23) and 1 patient, who developed vaccine-related myocarditis.First, we identified a magnetocardiography vector to differentiate between patients with cardiomyopathy versus patients without cardiomyopathy (vector of >= 0.051; sensitivity, 0.59; specificity, 0.95; positive predictive value, 93%; and negative predictive value, 64%). All patients with inflammatory cardiomyopathy, including a patient with mRNA vaccine-related myocarditis, had a magnetocardiography vector >= 0.051. Second, we evaluated the ability of the magnetocardiography vector to reflect treatment response. We observed a decrease of the pathologic magnetocardiography vector toward normal in all 13 patients who were clinically improving under immunosuppressive therapy. Magnetocardiography detected treatment response as early as day 7, whereas echocardiographic detection of treatment response occurred after 1 month. The magnetocardiography vector decreased from 0.10 at baseline to 0.07 within 7 days (P=0.010) and to 0.03 within 30 days (P<0.001). After 30 days, left ventricular ejection fraction improved from 42.2% at baseline to 53.8% (P<0.001).

Conclusions: Magnetocardiography has the potential to be used for diagnostic screening and to monitor early treatment response. The method is valuable in inflammatory cardiomyopathy, where there is a major unmet need for early diagnosis and monitoring response to immunosuppressive therapy.

BACKGROUND: In patients with acute ischemic stroke, little is known regarding the frequency of abnormal ECG findings other than atrial fibrillation and their association with cardiovascular outcomes. We aim to analyze the frequency and type of abnormal ECG findings, subsequent changes in medical treatment, and their association with cardiovascular outcomes in patients with acute ischemic stroke.

METHODS AND RESULTS: In the investigator-initiated multicenter MonDAFIS (impact of standardized monitoring for detection of atrial fibrillation in ischemic stroke) study, 3465 patients with acute ischemic stroke or transient ischemic attack and without known atrial fibrillation were randomized 1:1 to receive Holter- ECG for up to 7 days in-hospital with systematic evaluation in a core cardiology laboratory (intervention group) or standard diagnostic care (control group). Outcomes included predefined abnormal ECG findings (eg, pauses, atrial fibrillation, brady-/tachycardias), medical management in the intervention group, and combined vascular end point (recurrent stroke, myocardial infarction, major bleeds, or all -cause death) and mortality at 24 months in both randomization groups. Predefined abnormal ECG findings were detected in 326 of 1693 (19.3%) patients in the intervention group. Twenty of these 326 patients (6.1%) received a pacemaker, and 62 of 326 (19.0%) patients had newly initiated or discontinued (3- blocker medication. Discontinuation of (3- blockers was associated with a higher death rate in the control group than in the intervention group during 24 months after enrollment (adjusted hazard ratio, 11.0 [95% CI, 2.4- 50.4]; P=0.025 for interaction).

CONCLUSIONS: Systematic in-hospital Holter ECG reveals abnormal findings in 1 of 5 patients with acute stroke, and mortality was lower at 24 months in patients with systematic ECG recording in the hospital. Further studies are needed to determine the potential impact of medical management of abnormal ECG findings.

After ischemic stroke, there is a significant burden of cardiovascular complications, both in the acute and chronic phase. Severe adverse cardiac events occur in 10% to 20% of patients within the first few days after stroke and comprise a continuum of cardiac changes ranging from acute myocardial injury and coronary syndromes to heart failure or arrhythmia. Recently, the term stroke-heart syndrome was introduced to provide an integrated conceptual framework that summarizes neurocardiogenic mechanisms that lead to these cardiac events after stroke. New findings from experimental and clinical studies have further refined our understanding of the clinical manifestations, pathophysiology, and potential long-term consequences of the stroke-heart syndrome. Local cerebral and systemic mediators, which mainly involve autonomic dysfunction and increased inflammation, may lead to altered cardiomyocyte metabolism, dysregulation of (tissue-resident) leukocyte populations, and (micro-) vascular changes. However, at the individual patient level, it remains challenging to differentiate between comorbid cardiovascular conditions and stroke-induced heart injury. Therefore, further research activities led by joint teams of basic and clinical researchers with backgrounds in both cardiology and neurology are needed to identify the most relevant therapeutic targets that can be tested in clinical trials.

Background: Proctoring represents a cornerstone in the acquisition of state-of-the-art cardiovascular interventions. Yet, travel restrictions and containment measures during the COVID-19 pandemic limited on-site proctoring for training and expert support in interventional cardiology.

Methods and Results: We established a teleproctoring setup for training in a novel patent foramen ovale closure device system (NobleStitch EL, HeartStitch Inc, Fountain Valley, CA) at our institution using web-based real-time bidirectional audiovisual communication. A total of 6 patients with prior paradoxical embolic stroke and a right-to-left shunt of grade 2 or 3 were treated under remote proctorship after 3 cases were performed successfully under on-site proctorship. No major device/procedure-related adverse events occurred, and none of the patients had a residual right-to-left shunt of grade 1 or higher after the procedure. Additionally, we sought to provide an overview of current evidence available for teleproctoring in interventional cardiology. Literature review was performed identifying 6 previous reports on teleproctoring for cardiovascular interventions, most of which were related to the current COVID-19 pandemic. In all reports, teleproctoring was carried out in similar settings with comparable setups; no major adverse events were reported.

Conclusions: Teleproctoring may represent a feasible and safe tool for location-independent and cost-effective training in a novel patent foramen ovale closure device system. Future prospective trials comparing teleproctoring with traditional on-site proctoring are warranted.

Background: Gunshot emissions contain toxic elements that can harm those frequently exposed, such as police officers. Several years ago, police indoor firing ranges were closed by the Berlin municipality in response to police officer health complaints, and an investigation was launched into the possible respiratory health risks of frequent gunshot emission exposure. We, therefore, conducted an exploratory cross-sectional study to investigate clinical and functional parameters of respiratory health as well as the burden of trace elements in policemen with long-term high exposure to indoor gunshot emissions, compared to low-exposure and control groups.

Methods: We conducted lung function tests and collected blood and urine samples from Berlin police officers and government employees who were divided into three subject groups based on exposure to gunshot emissions: high exposure (n = 53), low exposure (n = 94) and no exposure (n = 76). Lung function was examined using body plethysmography. Blood and urine samples were tested via inductively coupled plasma mass spectrometry for the presence of common gunshot powder elements (antimony, lead and manganese). Exposure and symptoms were assessed using records as well as questionnaires.

Results: Higher exposure was associated with more respiratory symptoms during gun shooting practice (64% vs. 21%, P < 0.001) compared to the low-exposure group. Headache, cough, discoloured mucous and shortness of breath were also more common as were some other symptoms. The cough symptomatology of the high-exposure group also persisted significantly longer (median: 0.67 vs. 0.01 days, range: 0 to 5 days, P = 0.029) compared to the low-exposure group. They also showed a lower forced expiratory volume in 1 s/forced vital capacity quotient (Tiffeneau index), P = 0.018 between the three groups and P = 0.005 for the high-exposure group, a possible marker of early, subclinical bronchial obstruction. We observed increased blood lead concentrations depending on subject's age (+1.2% per year, 95% confidence interval: 0.5-1.9%, P < 0.001) and cumulative gunshot exposure (+0.34% per 100 000 shots, 0.02-0.66%, P = 0.037).

Conclusions: These first results suggest that long-term exposure to indoor gunshot emissions induces bronchitic reactions due to repeated irritation of the airways. Higher levels of exposure lead to more negatively impacted lung function and higher blood lead levels with the possible reason that more frequent exposure may mean shorter regeneration phases for the respiratory mucous membrane. We recommend a reduction of exposure to gunshot emissions in order to decrease symptoms and avoid any-even small-deterioration in spirometry.

Background: Beta-blockers and selected stereoisomers of beta-blockers, like bisoprolol and S-pindolol (ACM-001), have been shown to be effective in preclinical cancer cachexia models. Here, we tested the efficacy of stereoisomers of oxprenolol in two preclinical models of cancer cachexia-the Yoshida AH-130 rat model and the Lewis lung carcinoma (LLC) mouse model.

Methods and Results: In the Yoshida AH130 hepatoma rat cancer cachexia model and compared with placebo, 50 mg/kg/d S-oxprenolol (HR: 0.49, 95% CI: 0.28-0.85, P = 0.012) was superior to 50 mg/kg/d R-oxprenolol (HR: 0.83, 95% CI 0.38-1.45, P = 0.51) in reducing mortality (= reaching ethical endpoints). Combination of the three doses (12.5, 25 and 50 mg/kg/d) that had a significant effect on body weight loss in the S-oxprenolol groups vs the same combination of the R-oxprenolol groups lead to a significantly improved survival of S-oxprenolol vs R-oxprenolol (HR: 1.61, 95% CI: 1.08-2.39, P = 0.0185). Interestingly, there is a clear dose dependency in S-oxprenolol-treated (5, 12.5, 25 and 50 mg/kg/d) groups, which was not observed in groups treated with R-oxprenolol. A dose-dependent attenuation of weight and lean mass loss by S-oxprenolol was seen in the Yoshida rat model, whereas R-oxprenolol had only had a significant effect on fat mass. S-oxprenolol also non-significantly reduced weight loss in the LLC model and also improved muscle function (grip strength 428 +/- 25 and 539 +/- 37 g/100 g body weight for placebo and S-oxprenolol, respectively). However, there was only a minor effect on quality of life indicators food intake and spontaneous activity in the Yoshida model (25 mg/kg/S-oxprenolol: 11.9 +/- 2.5 g vs placebo: 4.9 +/- 0.8 g, P = 0.013 and also vs 25 mg/kg/d R-oxprenolol: 7.5 +/- 2.6 g, P = 0.025). Both enantiomers had no effects on cardiac dimensions and function at the doses used in this study. Western blotting of proteins involved in the anabolic/catabolic homoeostasis suggest that anabolic signalling is persevered (IGF-1 receptor, Akt) and catabolic signalling is inhibited (FXBO-10, TRAF-6) by S-pindolol, but not he R-enantiomer. Expression of glucose transporters Glut1 and Glut 4 was similar in all groups, as was AMPK.

Conclusions: S-oxprenolol is superior to R-oxprenolol in cancer cachexia animal models and shows promise for a human application in cancer cachexia.

Background: Cancer cachexia (CC) is a severe complication during the last stages of the disease, which is characterized by the substantial loss of muscle and fat mass. Currently, there is no effective treatment of CC. Erythropoietin plays tissue-protective role in different tissues. Based on the structure of erythropoietin, small non-erythropoietic peptides were synthesized, which activate tissue-protective signalling pathways.

Methods: Here, we investigated the influence of the tissue-protective peptide ARA 284 on CC in rats using the Yoshida hepatoma model.

Results: Treatment with ARA 284 (1.7 mu g/kg/day) counteracted the loss of body weight (12.46 +/- 4.82% ARA 284 vs. 26.85 +/- 0.88% placebo, P < 0.01), fat mass (P < 0.01), and lean mass (P < 0.01). It improved spontaneous activity of ARA 284-treated animals. Further, gastrocnemius mass was increased (13.2% ARA 284 vs. placebo, P < 0.01) in association with induced p-Akt (P < 0.01) and decreased in p-p38 MAPK, GSK-3 beta, and myostatin (all P < 0.01), suggesting an induction of anabolic pathways. At the same time, we observed the significant increase in the survival of animals by high-dose ARA 284 treatment (hazard ratio: 0.46, 95% confidence interval: 0.23-0.94, P = 0.0325).

Conclusions: Taken together these results suggest that ARA 284 can be considered beneficial in experimental CC and it remains to be seen, if it can have similar beneficial effects in CC patient.

Background: Iron deficiency (ID) is a common co-morbidity in patients with cardiovascular disease and contributes to impaired functional capacity. The relevance of ID in patients in recovery after acute stroke is not known. We assessed the prevalence of ID and anaemia in relation to functional capacity and to recovery during early rehabilitation after stroke.

Methods: This observational study enrolled consecutively 746 patients with ischaemic or haemorrhagic stroke at in-patient early rehabilitation (age 68 +/- 13 years, female 47%, ischaemic stroke 87%). Functional capacity was assessed before and after rehabilitation using Barthel index (reha-BI), motricity index (MI), trunk control test (TCT), and functional ambulatory category (FAC). ID was defined as ferritin <100 mu g/L or as transferrin saturation (TSAT) 5 mg/L. Anaemia was defined as Hb < 12 g/dL (women) and <13 g/dL (men).

Results: The prevalence of ID and anaemia before rehabilitation were 45% and 46%, respectively, and remained high at discharge (after 27 +/- 17 days) at 40% and 48%, respectively. Patients with ID had lower functional capacity compared with patients without ID (reha-BI 20 [+/- 86] vs. 40 [+/- 80], MI 64 [+/- 66] vs. 77 [+/- 41], TCT 61 [+/- 76] vs. 100 [+/- 39], FAC 1 [+/- 4] vs. 4 [+/- 4]; median [IQR], all P < 0.001). ID was related to inflammation (OR 2.68 [95% CI 1.98-3.63], P < 0.001), female sex (OR 2.13 [95% CI 1.59-2.85], P < 0.001), haemorrhagic stroke (OR 1.70 [95% CI 1.11-2.61], P = 0.015), initial treatment on stroke unit (OR 3.59 [95% CI 1.08-11.89], P < 0.001), and anaemia (OR 2.94 [95% CI 2.18-3.96], P < 0.001), while age, BMI, and renal function were not related to ID. In adjusted analysis, ID was associated with low functional capacity in all functional scores: reha-BI (OR 1.66 [95% CI 1.08-2.54], P = 0.02), motricity index (OR 1.94 [95% CI 1.36-2.76], P < 0.001), trunk control test (OR 2.34 [95% CI] 1.64-3.32, P < 0.001) and functional ambulatory category (OR 1.77 [95% CI 1.2-2.63], P < 0.02). Functional capacity improved during rehabilitation regardless of presence of ID, but functional outcome remained significantly lower in patients with ID at the end of rehabilitation (rehab BI and MI, both P < 0.001).

Conclusions: Iron deficiency and anaemia are common and persistent findings in patients after acute stroke. ID and anaemia are independently related to lower functional capacity after acute stroke and to poor functional outcome after rehabilitation. Regular assessment of iron status may identify patients at risk of low functional recovery.

Nutrient supply via a functional vasculature is essential during regenerative processes, tissue growth, and homeostasis. 3D bioprinting offers the opportunity to engineer vascularized constructs by combining cells and biocompatible materials in specifically designed fashions. However, the complexity of microvascular dynamic networks can hardly be recapitulated yet, even by sophisticated 3D manufacturing. Ideally, the natural organizational competences of endothelial cells will be harnessed such that engineered vascular networks self-assemble to form complex, controllable microvascular patterns. Here, a bioengineering approach is presented to control microvascular structure formation and to steer cellular self-assembly of endothelial and supporting cells within a multi-material stereolithographic 3D bioprinting concept. Bioengineered vascularized constructs are generated by controlled cell deposition in an enzymatically degradable or a non-degradable material. In vitro, the microvascular structures are regulated in distribution, network orientation, vessel length and branching behavior and developed lumen, signs of vascular stabilization and an interconnected vascular network including anastomosis. This novel biofabrication approach demonstrates the capability to control microvascular network formation by using cellular and spatial cues allowing the generation of distinctly yet precisely vascularized constructs. Such novel approach of controlled microvascular formation may play a fundamental role in the development of vascularized implants or in vitro screening models.