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Background and Purpose: Rapid access to acute stroke treatment improves clinical outcomes in patients with ischemic stroke. We aimed to shorten the time to admission and to acute stroke treatment for patients with acute stroke in the Hamburg metropolitan area by collaborative multilevel measures involving all hospitals with stroke units, the Emergency Medical Services (EMS), and health-care authorities. Methods: In 2007, an area-wide stroke care quality project was initiated. The project included mandatory admission of all stroke patients in Hamburg exclusively to hospitals with stroke units, harmonized acute treatment algorithms among all hospitals, repeated training of the EMS staff, a multimedia educational campaign, and a mandatory stroke care quality monitoring system based on structured data assessment and quality indicators for procedural measures. We analyzed data of all patients with acute stroke who received inhospital treatment in the city of Hamburg during the evaluation period from the quality assurance database data and evaluated trends of key quality indicators over time. Results: From 2007 to 2016, a total of 83,395 patients with acute stroke were registered. During this period, the proportion of patients admitted within ≤3 h from symptom onset increased over time from 27.8% in 2007 to 35.2% in 2016 (p < 0.001). The proportion of patients who received rapid thrombolysis (within ≤30 min after admission) increased from 7.7 to 54.1% (p < 0.001). Conclusions: Collaborative stroke care quality projects are suitable and effective to improve acute stroke care.

Fingolimod-induced lymphopenia is a risk factor for severe monkeypox infection. As monkeypox was recently declared a Public Health Emergency of International Concern, vaccination should be evaluated in patients with MS before immunosuppressive treatment, particularly in patients receiving sphingosine-1-phosphate receptor modulators.(1,2)

Aim: Immune checkpoint inhibitor-induced encephalitis (ICI-iE) is a rare but life-threatening toxicity of immune checkpoint inhibitor treatment. We aim to identify the characteristics of ICI-iE and describe factors that discriminate it from herpes simplex virus (HSV)-1 encephalitis and anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis, as two alternative entities of encephalitis. Methods: In this retrospective multicentre cohort study, we collected patients with ICI-iE reported to the Side Effect Registry Immuno-Oncology from January 2015 to September 2021 and compared their clinical features and outcome with 46 consecutive patients with HSV-1 or anti-LGI1 encephalitis who were treated at a German neurological referral centre. Results: Thirty cases of ICI-iE, 25 cases of HSV-1 encephalitis and 21 cases of anti-LGI1 encephalitis were included. Clinical presentation of ICI-iE was highly variable and resembled that of HSV-1 encephalitis, while impairment of consciousness (66% vs. 5%, p = .007), confusion (83% vs. 43%; p = .02), disorientation (83% vs. 29%; p = .007) and aphasia (43% vs. 0%; p = .007) were more common in ICI-iE than in anti-LGI1 encephalitis. Antineuronal antibodies (17/18, 94%) and MRI (18/30, 60%) were mostly negative in ICI-iE, but cerebrospinal fluid (CSF) showed pleocytosis and/or elevated protein levels in almost all patients (28/29, 97%). Three patients (10%) died of ICI-iE. Early immunosuppressive treatment was associated with better outcome (r = 0.43). Conclusions: ICI-iE is a heterogeneous entity without specific clinical features. CSF analysis has the highest diagnostic value, as it reveals inflammatory changes in most patients and enables the exclusion of infection. Early treatment of ICI-iE is essential to prevent sequelae and death.

Graft-versus-host disease (GvHD) is still the major non-relapse, life-limiting complication after hematopoietic stem cell transplantation. Modern pharmacologic immunosuppression is often insufficient and associated with significant side effects. Novel treatment strategies now include adoptive transfer of ex vivo expanded regulatory T cells (Tregs), but their efficacy in chronic GvHD is unknown. We treated three children suffering from severe, therapy-refractory GvHD with polyclonally expanded Tregs generated from the original stem cell donor. Third-line maintenance immunosuppression was tapered to cyclosporin A and low-dose steroids shortly before cell transfer. Regular follow-up included an assessment of the subjective and objective clinical development, safety parameters, and in-depth immune monitoring. All patients showed marked clinical improvement with substantially decreased GvHD activity. Laboratory follow-up showed a significant enhancement of the immunologic engraftment, including lymphocytes and dendritic cells. Monitoring the fate of Tregs by next-generation sequencing demonstrated clonal expansion. In summary, adoptive transfer of Tregs was well tolerated and able to modulate an established undesired T cell mediated allo-response. Although no signs of overimmunosuppression were detectable, the treatment of patients with invasive opportunistic infections should be undertaken with caution. Further controlled studies are necessary to confirm these encouraging effects and eventually pave the way for adoptive Treg therapy in chronic GvHD.

Facebook started as a platform intended for connecting people but it has developed into a rich information source. Based on the uses-and-gratification approach, we examined to what extent censorship endorsement and personality factors can explain information seeking behavior on Facebook. 1525 German-speaking Facebook users participated in a cross-sectional survey. Censorship endorsement, three personality traits (extraversion, neuroticism, and openness), age, and gender served as predictors in blockwise regression models. Participants’ information seeking behavior on Facebook served as the criterion variable, whereby we examined different behavioral strategies. Overall, the extent of one’s endorsement of censorship was positively and reliably related to different facets of information seeking. Apparently, censorship might be considered a protection measure to establish a decent communication and information space. In contrast, personality traits were inconsistently related to different facets of information seeking. Extraversion and neuroticism were positively related to information seeking in general, but their impact was absent on some subscales. The effects of age and gender differed from what has been found in previous studies. Overall, the results highlight the necessity of a more differentiated perspective on social media use, provide implications for uses-and-gratification research in the context of social media, and indicate interesting venues for future research by incorporating censorship attitude as a hitherto neglected factor.

A previously healthy 42-year-old man had sudden-onset severe headache resolving within days. Two weeks later, he noted acute right-sided hemiparesis. Brain CT, MRI and digital subtraction angiography showed acute left hemispheric ischemic stroke, bilateral middle cerebral artery vasospasms and intracerebral aneurysms (Figure 1 A-E). The following day, cerebrospinal fluid (CSF) was obtained and appeared crystal-clear and without xanthochromia (Figure 2A). CSF cytology proved past subarachnoid hemorrhage (SAH) by demonstrating macrophages with ingested erythrocytes, hemosiderin and hematoidin crystals (Figure 2B). CSF may be clear, but CSF cytology can prove SAH two weeks after aneurysm rupture leading to vasospasm and stroke.1,2

Einleitung: Die chronische Graft-versus-Host-Krankheit (cGVHD) ist eine Komplikation nach allogener Stammzelltransplantation (allo-HSCT), die mit hoher Morbidität und Mortalität einhergeht. Die gegenwärtig verfügbaren Medikamente sind nicht nur mit ausgeprägten Nebenwirkungen verbunden, sondern oftmals unzureichend wirksam. Ein neuer und vielversprechender Behandlungsansatz besteht in dem adoptiven Zelltransfer natürlicher regulatorischer T-Zellen (nTreg-ACT). Durch die Eigenschaft von nTregs, konventionelle T-Zellen (Tconv) zu supprimieren, könnte ihr adoptiver Transfer positive Effekte auf die immunologische Dysregulation der cGVHD erzielen. Erste klinische Studien deuteten bereits einen sicheren und effektiven Einsatz von nTreg-ACTs an, dennoch bestehen weiterhin Herausforderungen in der Produktherstellung und Daten zu pädiatrischen Patienten sind fehlend. Ziel dieser Arbeit war es daher, die weitere Charakterisierung von nTreg-Zellprodukten zu erarbeiten und nTreg-ACTs als adjuvante Therapieoption bei pädiatrischer cGVHD zu evaluieren. Methodik: Zwei Kinder mit schwerer cGVHD wurden im Rahmen eines individuellen Heilversuchs mit 3,0x106 nTregs/kg behandelt. Nach Zelltransfer wurde an definierten Follow-Up-Zeitpunkten der klinische cGVHD-Status erhoben und 71 verschiedene Immunzelltypen im peripheren Blut durchflusszytometrisch analysiert. Zusätzlich wurden nTregs aus unbehandelten und G-CSF mobilisierten Stammzellspendern magnetisoliert und polyklonal expandiert. Neben dem Expansionsverhalten wurde durch Färbung von CD4, CD25, FoxP3, IFN-γ, TNF-α, IL-2, CD154 und CD137 die nTreg-Produktreinheit und CD154/CD137-Expression durchflusszytometrisch bestimmt. Die Suppressionskapazität der nTregs wurde durch Nutzung CFSE-basierter Proliferationsassays ermittelt. Ergebnisse: Die Zellkulturexperimente zeigten, dass sich durch dreiwöchige Expansion mit IL-2, Rapamycin und wiederholter Beadstimulation Expansionsraten von bis zu ~100.000-fach erzielen lassen. Die Zellprodukte zeigten eine hohe Reinheit und eine deutliche Tconv-Suppression in vitro. Der Vergleich von unbehandelten und G-CSF stimulierten nTreg-Linien ergab eine ähnliche Zellexpansion und Produktreinheit. Weitere Experimente zeigten, dass CD137 keinen geeigneten Selektionsmarker für polyklonale nTregs darstellt. Der klinische Einsatz von nTreg-ACTs erwies sich als gut verträglich und führte zu keiner quantitativen Beeinträchtigung der angeborenen Immunität. Nach dem Zelltransfer konnte entweder eine klinische Stabilisierung oder eine deutliche, langfristige Verbesserung der cGVHD erzielt werden. Die immunologischen Begleituntersuchungen zeigten nicht nur einen nTreg-Anstieg in vivo, sondern auch erstmalig eine Zunahme von naiven B- und T-Lymphozyten nach nTreg-ACT. Schlussfolgerung: Diese Arbeit zeigt, dass sich nTreg-Produkte mit hoher Reinheit und suffizienter Funktionalität herstellen lassen. Die klinische Anwendung erwies sich als gut verträglich und zeigte neben einer Reduktion der cGVHD-Aktivität auch eine verbesserte lymphozytäre Rekonstitution sowie einen nachhaltigen Anstieg von nTregs in vivo. Nun sind große systematische Studien nötig, um künftig die breite und evidenzbasierte Anwendung von nTreg-ACTs in der Behandlung der (pädiatrischen) cGVHD zu ermöglichen., Introduction: Chronic Graft-versus-Host-Disease (cGVHD) is a severe complication after allogeneic stem cell transplantation (allo-HSCT) and associated with a high morbidity and mortality rate. The efficacy of currently available drugs is limited and frequently related with significant adverse effects. A new and promising therapeutic approach is the adoptive cell transfer of natural regulatory T cells (nTreg-ACT). Due to the ability of nTregs to suppress activated conventional T cells (Tconv), their adoptive transfer could achieve positive effects on immune dysregulation in cGVHD. First clinical data already implied safety and efficacy of nTreg-therapy, yet challenges remain with respect to cell manufacturing and data from pediatric patients are lacking entirely. Thus, this work aims at establishing an advanced characterization of nTreg-products and evaluating nTreg-ACTs as an adjuvant therapy in pediatric cGVHD. Methods: As a case of compassionate care, two children with severe cGVHD received treatment with 3.0x106 nTregs/kg. After cell transfer the clinical cGVHD status was assessed and 71 different immune cell subsets analyzed via flow cytometry at specific follow-up-timepoints. Additionally, nTregs from untreated and G-CSF-mobilized donors were immunomagnetically isolated and polyclonally expanded. Apart from its cell expansion, the product’s purity and CD154/CD137 phenotype were assessed via staining of CD4, CD25, FoxP3, IFN-γ, TNF-α, IL-2, CD154 and CD137 and flow cytometry. nTregs’ suppressive capacity was obtained via CFSE-based proliferation assays. Results: The experiments showed that three-week cell culture with IL-2, rapamycin and repeated bead stimulation achieved up to ~100.000-fold expansion. The cells showed high purity and distinct Tconv suppression in vitro. Comparing untreated and G-CSF-stimulated nTregs showed equal cell expansion and purity. Further experiments revealed that CD137 represents no feasible selection marker for polyclonal nTregs. The clinical application of nTreg-ACTs was well-tolerated and did not provoke a quantitative impairment of the innate immunity. After nTreg-ACT, either a short-term clinical stabilization or a significant, long-term improvement of cGVHD could be achieved. Immunological follow-ups showed not only an increase of nTregs in vivo, but also, for the first time, an enhanced engraftment of both, the Naïve B- and T-cell compartment, after nTreg-ACT. Conclusion: This work shows that nTreg products of high purity and sufficient function can be manufactured. Clinical application showed good tolerability and revealed, apart from a reduction of cGVHD activity, an improved lymphoid reconstitution as well as a long-term increase of nTregs in vivo. Now systematic studies are required to enable the broad and evidence-based implementation of nTreg-ACTs in the treatment of (pediatric) cGVHD.