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Background (1) Description of clinical and cranial MRI features in the original Pontine Autosomal Dominant Microangiopathy with Leukoencephalopathy (PADMAL) family and correlation with the segregation analysis of the causative collagen 4A1 gene (COL4A1) variant. (2) Sequence analysis of the COL4A1 miRNA-binding site containing the causative variant in two independent cross-sectional samples of sporadic stroke patients. Patients and methods Sanger sequencing of the COL4A1 miRNA-binding site in the PADMAL family and 874 sporadic stroke patients. Results PADMAL shows adult-onset usually between 30 and 50 years of age with initial brainstem-related symptoms most commonly dysarthria, with progression to dementia and tetraparesis. Radiologically pontine lacunes are followed by supratentorial white matter involvement. Radiological onset may precede clinical symptoms. We found no variants in the COL4A1 miRNA-binding site of sporadic stroke patients. Conclusion Our results allow an early diagnosis of PADMAL based on cranial MRI, clinical signs, and confirmatory sequencing of the COL4A1 miRNA-29-binding site. COL4A1 miRNA-29-binding site variants do not contribute to a sizeable proportion of sporadic stroke.

The optimal treatment for patients with asymptomatic carotid artery stenosis is under debate. Since best medical treatment (BMT) has improved over time, the benefit of carotid endarterectomy (CEA) or carotid artery stenting (CAS) is unclear. Randomised data comparing the effect of CEA and CAS versus BMT alone are absent. We aimed to directly compare CEA plus BMT with CAS plus BMT and both with BMT only.SPACE-2 was a multicentre, randomised, controlled trial at 36 study centres in Austria, Germany, and Switzerland. We enrolled participants aged 50-85 years with asymptomatic carotid artery stenosis at the distal common carotid artery or the extracranial internal carotid artery of at least 70%, according to European Carotid Surgery Trial criteria. Initially designed as a three-arm trial including one group for BMT alone (with a randomised allocation ratio of 2·9:2·9:1), the SPACE-2 study design was amended (due to slow recruitment) to become two substudies with two arms each comparing CEA plus BMT with BMT alone (SPACE-2a) and CAS plus BMT with BMT alone (SPACE-2b); in each case in a 1:1 randomisation. Participants and clinicians were not masked to allocation. The primary efficacy endpoint was the cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years. The primary safety endpoint was any stroke or death from any cause within 30 days after CEA or CAS. The primary analysis was by intention-to treat, which included all randomly assigned patients in SPACE-2, SPACE-2a, and SPACE-2b, analysed using meta-analysis of individual patient data. We did two-step hierarchical testing to first show superiority of CEA and CAS to BMT alone then to assess non-inferiority of CAS to CEA. Originally, we planned to recruit 3640 patients; however, the study had to be stopped prematurely due to insufficient recruitment. This report presents the primary analysis at 5-year follow-up. This trial is registered with ISRCTN, number ISRCTN78592017.513 patients across SPACE-2, SPACE-2a, and SPACE-2b were recruited and surveyed between July 9, 2009, and Dec 12, 2019, of whom 203 (40%) were allocated to CEA plus BMT, 197 (38%) to CAS plus BMT, and 113 (22%) to BMT alone. Median follow-up was 59·9 months (IQR 46·6-60·0). The cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years (primary efficacy endpoint) was 2·5% (95% CI 1·0-5·8) with CEA plus BMT, 4·4% (2·2-8·6) with CAS plus BMT, and 3·1% (1·0-9·4) with BMT alone. Cox proportional-hazard testing showed no difference in risk for the primary efficacy endpoint for CEA plus BMT versus BMT alone (hazard ratio [HR] 0·93, 95% CI 0·22-3·91; p=0·93) or for CAS plus BMT versus BMT alone (1·55, 0·41-5·85; p=0·52). Superiority of CEA or CAS to BMT was not shown, therefore non-inferiority testing was not done. In both the CEA group and the CAS group, five strokes and no deaths occurred in the 30-day period after the procedure. During the 5-year follow-up period, three ipsilateral strokes occurred in both the CAS plus BMT and BMT alone group, with none in the CEA plus BMT group.CEA plus BMT or CAS plus BMT were not found to be superior to BMT alone regarding risk of any stroke or death within 30 days or ipsilateral stroke during the 5-year observation period. Because of the small sample size, results should be interpreted with caution.German Federal Ministry of Education and Research (BMBF) and German Research Foundation (DFG).

Despite improved techniques and sophisticated postinterventional care, symptomatic intracranial hemorrhage (sICH) remains the most feared complication of mechanical thrombectomy (MT). Based on peri-interventional parameters, we aimed to discover which patients have a higher risk of sICH.From March 2017 until March 2020 consecutive patients with acute ischemic stroke (AIS) and confirmed large-vessel occlusion who underwent MT were analyzed retrospectively. Demographic, clinical, and radiological variables and parameters specific to thrombectomy were reviewed. A univariate analysis was performed and statistically significant variables were included in a logistic regression model to identify independent factors predictive of sICH.A total of 236 patients with confirmed large-vessel occlusion were included and 22 (9.3%) had sICH. Univariate predictors of sICH included diabetes mellitus, glucose 11.1 mmol/L, creatinine clearance (CrCl) ≤ 30 ml/min/1.73, ASPECTS indicating pretreatment infarct size, acute internal carotid artery (ICA) occlusion, stent implantation, tirofiban use, time from symptom onset to groin puncture 4.5 h and high contrast medium consumption. In the adjusted analysis, ASPECTS 6 (OR 3.673, p = 0.041), and amount of contrast injected ≥ 140 ml (OR 5.412, p = 0.003) were independent predictors of sICH, but not any more baseline glucose 11.1 mmol/L (OR 1.467, p = 0.584), CrCl ≤ 30 ml/min/1.73 (OR 4.177, p = 0.069), acute ICA occlusion (OR 2.079, p = 0.181), stent implantation (OR 0.465, p = 0.512), tirofiban use (OR 5.164, p = 0.167), and time from onset-to-groin puncture (OR 1.453, p = 0.514).The amount of contrast medium used is a modifiable factor associated with sICH. This association is novel and may be related to the neurotoxicity of the contrast medium disrupting the blood-brain barrier.

Determining driver situational awareness is one of the most difficult tasks in driver performance profiling. Perception, being the first level of driver situational awareness, is perhaps the only objectively quantifiable factor for driver inattention detection. In the context of this paper, driver perception is defined as their ability to understand their operating environment and peripheral contextual information. One of the most reliable means of determining driver perception is through eye tracking and gaze concentration. In this study, a set of carefully chosen in-vehicle gaze targets are used to determine driver gaze concentration on/off the road. The time drivers spend looking at these predefined gaze targets has been used to characterise driver visual behaviour at roundabouts during normal driving. In total, 24 drivers completed a 22 km route, including two 5-exit two-lane roundabouts in urban and suburban traffic. This study shows that on the approach to roundabouts, driver gaze direction and gaze concentration was often diverted away from the direction of travel of the vehicle and for some drivers it took a significant amount of time to return their gaze towards the direction of travel of the vehicle. The study is based on the premise that a driver not looking at key regions in a scene cannot perceive the contents of those regions with sufficient detail for safe driving. It is not possible to determine a driver's level of understanding of a scene, unless the parameters of the scene as well as the driver's response is determined in real time.

Polatuzumab (Pola)-based regimens and chimeric antigen receptor T (CAR T) cells provide superior outcome compared to conventional chemoimmunotherapy in patients with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL). Choosing between these strategies remains controversial. The efficacy of CAR T versus Pola-rituximab(R) /Pola-bendamustine(B)-R in R/R DLBCL patients after failing ≥2 lines of treatment was compared in a retrospective, 'real-world' study. Propensity score matching, for age, lymphoma category (de-novo/transformed), number of prior lines, Eastern Cooperative Oncology Group performance status and lactate dehydrogenase level, was applied to control for differences in patients' characteristics. Response rate, progression-free survival (PFS) and overall survival (OS) were analyzed. A total of 82 patients, treated with CAR T (n=41) or Pola-based regimens (n=41), were included. No treatment-related deaths occurred with CAR T vs. 3 (7.3%) with Pola. The overall and complete response rates were 83% and 58% with CAR T vs. 66% and 44% with Pola-based-regimens (p=0.077 and p=0.18, respectively). At a median follow-up of 9 months (range 1-19.2) and 16 months (range 0.7-25.3) for the CAR T and Pola arm respectively, the median PFS has not been reached for CAR T vs. 5.6 months for Pola (95% CI 3.6-7.6, p=0.014). Median OS has not been reached for CAR T vs. 10.8 months (95% CI 2.2-19.4) for Pola (p=0.026). To conclude, in a real-world setting, treatment with CAR T achieved superior PFS and OS compared to Pola-based regimens in patients with R/R DLBCL.

Supplemental material, sj-docx-1-msj-10.1177_13524585231151212 for Cognition in patients with neuromyelitis optica spectrum disorders: A prospective multicentre study of 217 patients (CogniNMO-Study) by Martin W Hümmert, Carlotta Stern, Friedemann Paul, Ankelien Duchow, Judith Bellmann-Strobl, Ilya Ayzenberg, Carolin Schwake, Ingo Kleiter, Kerstin Hellwig, Sven Jarius, Brigitte Wildemann, Makbule Senel, Achim Berthele, Katrin Giglhuber, Felix Luessi, Matthias Grothe, Luisa Klotz, Rasmus Schülke, Stefan Gingele, Jürgen H Faiss, Annette Walter, Clemens Warnke, Florian Then Bergh, Orhan Aktas, Marius Ringelstein, Jan-Patrick Stellmann, Vivien Häußler, Joachim Havla, Hannah Pellkofer, Tania Kümpfel, Bruno Kopp and Corinna Trebst in Multiple Sclerosis Journal

Supplemental material, sj-docx-1-msj-10.1177_13524585231151212 for Cognition in patients with neuromyelitis optica spectrum disorders: A prospective multicentre study of 217 patients (CogniNMO-Study) by Martin W Hümmert, Carlotta Stern, Friedemann Paul, Ankelien Duchow, Judith Bellmann-Strobl, Ilya Ayzenberg, Carolin Schwake, Ingo Kleiter, Kerstin Hellwig, Sven Jarius, Brigitte Wildemann, Makbule Senel, Achim Berthele, Katrin Giglhuber, Felix Luessi, Matthias Grothe, Luisa Klotz, Rasmus Schülke, Stefan Gingele, Jürgen H Faiss, Annette Walter, Clemens Warnke, Florian Then Bergh, Orhan Aktas, Marius Ringelstein, Jan-Patrick Stellmann, Vivien Häußler, Joachim Havla, Hannah Pellkofer, Tania Kümpfel, Bruno Kopp and Corinna Trebst in Multiple Sclerosis Journal

IntroductionGiven the varying severity of coronavirus disease 2019 (COVID-19) and the rapid spread of Severe-Acute-Respiratory-Syndrome-Corona-Virus-2 (SARS-CoV-2), vaccine-mediated protection of particularly vulnerable individuals has gained increasing attention during the course of the pandemic.MethodsWe performed a 1-year follow-up study of 51 ocrelizumab-treated patients with multiple sclerosis (OCR-pwMS) who received COVID-19 vaccination in 2021. We retrospectively identified 37 additional OCR-pwMS, 42 pwMS receiving natalizumab, 27 pwMS receiving sphingosine 1-phosphate receptor modulators, 59 pwMS without a disease-modifying therapy, and 61 controls without MS (HC). In OCR-pwMS, anti-SARS-CoV-2(S)-antibody titers were measured prior to the first and after the second, third, and fourth vaccine doses (pv2/3/4). The SARS-CoV-2-specific T cell response was analyzed pv2. SARS-CoV-2 infection status, COVID-19 disease severity, and vaccination-related adverse events were assessed in all pwMS and HC.ResultsWe found a pronounced and increasing anti-SARS-CoV-2(S)-antibody response after COVID-19 booster vaccinations in OCR-pwMS (pv2: 30.4%, pv3: 56.5%, and pv4 90.0% were antibody positive). More than one third of OCR-pwMS without detectable antibodies pv2 developed positive antibodies pv3. 23.5% of OCR-pwMS had a confirmed SARS-CoV-2 infection, of which 84.2% were symptomatic. Infection rates were comparable between OCR-pwMS and control groups. None of the pwMS had severe COVID-19. An attenuated humoral immune response was not associated with a higher risk of SARS-CoV-2 infection.DiscussionAdditional COVID-19 vaccinations can boost the humoral immune response in OCR-pwMS and improve clinical protection against COVID-19. Vaccines effectively protect even OCR-pwMS without a detectable COVID-19 specific humoral immune response, indicating compensatory, e.g., T cell-mediated immunological mechanisms.

In chronic lymphocytic leukemia (CLL), the immune system is skewed towards a suppressive milieu. Levels of thrombopoietin (TPO), promoting cellular immune regulatory activity in immune thrombocytopenic purpura, were shown to be elevated in CLL patients. This study explored TPO as a potential immunomodulator, supporting CLL progression. We evaluated CLL cell-induced expression of TPO receptor (TPO-R) on T-cells and effects of its activation on T-cell responses. CLL cell involvement in TPO generation was also assessed. Baseline TPO-R expression on CD4+T-cells was found to be higher in CLL patients than in healthy controls (HC). Exposure of HC-T-cells to B-cells, especially to CLL-B-cells stimulated with B-cell activating molecules, resulted in enhanced TPO-R expression on T-cells. CLL-T-cell stimulation with TPO reduced their proliferation and expanded the regulatory T-cell (Treg) population. At baseline, phosphorylation of STAT5, known to impact the Treg phenotype, was elevated in CLL-T-cells relative to those of HC. Exposure to TPO further enhanced STAT5 phosphorylation in CLL-T-cells, possibly driving the observed Treg expansion. The CLL immune milieu is involved in promotion of inhibitory features in T-cells through increased TPO-R levels and TPO-induced intracellular signaling. TPO and its signaling pathway could potentially support immunosuppression in CLL, and may emerge as novel therapeutic targets.

Chimeric antigen receptor T-cells (CAR-T) are widely used for the treatment of relapsed/refractory Diffuse large B cell lymphoma (DLBCL). The data for CAR-T cell therapy in patients with extra-nodal(EN) lymphoma is restricted. We included 126 consecutive patients with DLBCL treated with commercially available CAR-T cells (tisagenlecleucel, n=100, 79.4% and axicabtagene ciloleucel, n=26, 20.6%). At lymphodepletion , 72/126(57%) had EN disease, 42/126(33%) patients had nodal disease (ND)-only and 12/126(10%) showed no disease assessed by PET-CT. There were no significant differences in CAR-T related toxicities and in the median PFS between EN patients and ND [10.76(95% CI: 7.8-13.6) vs 14.1 (95% CI:10-18.1) months, p =0.126)]. Similarly, median OS was not significantly different [15.36 (95% CI 12.5-18.2) vs. 18.4 (95% CI 14.8-22.1) months , p =0.100]. Subgroup analysis according to the number of EN involved sites showed that median PFS and OS were significantly higher in patients with ≤ 2 EN sites [12.3 months (95% CI 9-15.5)] vs 4.28 months (95% CI 0.6-7.9), p=0.010] compared to patients with ≥3 EN sites, respectively[16.5 months (95% CI 13.4-19.6) vs 8.7 months (95% CI 4.6-12.8), p=0.05]. In multivariate cox regression analysis, increased number sites of EN disease and high LDH at lymphodepletion negatively impacted PFS (p=0.021 and

Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, often debilitating neuroinflammatory disease, whose predominant clinical manifestations are longitudinally extensive transverse myelitis and optic neuritis. About 80% of the patients with an NMOSD phenotype have pathogenic autoantibodies against the astrocyte water channel aquaporin-4 (AQP4-IgG). While therapeutic options for NMOSD have greatly expanded in recent years, well-established biomarkers for prognosis or treatment response are still lacking. Glial fibrillary acidic protein (GFAP) is mainly expressed in astrocytes and can be detected in cerebrospinal fluid (CSF) and blood of patients with NMOSD.Here, we comprehensively review the current knowledge on GFAP as a biomarker in NMOSD.In patients with AQP4-IgG

Im Juni 2023 tritt die EU-Verordnung für Wasserwiederverwendung in Kraft. Ein Aachener Netzwerk arbeitet an der Idee, vorhandenes Abwasser innerhalb eines Quartiers so aufzubereiten, dass es für weitere Zwecke in demselbigen wiederverwendet werden kann.

Background and Purpose: Functional outcome after stroke may be related to preexisting brain health. Several imaging markers of brain frailty have been described including brain atrophy and markers of small vessel disease. We investigated the association of these imaging markers with functional outcome after acute ischemic stroke. Methods: We retrospectively studied patients with acute ischemic stroke enrolled in the AXIS-2 trial (AX200 in Ischemic Stroke Trial), a randomized controlled clinical trial of granulocyte colony-stimulating factor versus placebo. We assessed the ratio of brain parenchymal volume to total intracerebral volumes (ie, the brain parenchymal fraction) and total brain volumes from routine baseline magnetic resonance imaging data obtained within 9 hours of symptom onset using the unified segmentation algorithm in SPM12. Enlarged perivascular spaces, white matter hyperintensities, lacunes, as well as a small vessel disease burden, were rated visually. Functional outcomes (modified Rankin Scale score) at day 90 were determined. Logistic regression was used to test associations between brain imaging features and functional outcomes. Results: We enrolled 259 patients with a mean age of 69±12 years and 46 % were female. Increased brain parenchymal fraction was associated with higher odds of excellent outcome (odds ratio per percent increase, 1.078 [95% CI, 1.008–1.153]). Total brain volumes and small vessel disease burden were not associated with functional outcome. An interaction between brain parenchymal fraction and large vessel occlusion on excellent outcome was not observed. Conclusions: Global brain health, as assessed by brain parenchymal fraction on magnetic resonance imaging, is associated with excellent functional outcome after ischemic stroke. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00927836.

BACKGROUND AND PURPOSE Myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) is an inflammatory autoimmune condition of the central nervous system. However, data on pain and depression have remained scarce. The aim of this study was to assess features of chronic pain and depression as well as their impact on health-related quality of life (hr-QoL) in MOGAD. METHODS Patients with MOGAD were identified in the Neuromyelitis Optica Study Group registry. Data were acquired by a questionnaire, including clinical, demographic, pain (PainDetect, Brief Pain Inventory-Short Form, McGill Pain Questionnaire-Short Form), depression (Beck Depression Inventory-II), and hr-QoL (Short Form-36 Health Survey) items. RESULTS Twenty-two of 43 patients suffered from MOGAD-related pain (11 nociceptive, eight definite neuropathic, three possible neuropathic) and 18 from depression. Patients with neuropathic pain had the highest pain intensity and most profound activities of daily living (ADL) impairment. Fifteen patients reported spasticity-associated pain, including four with short-lasting painful tonic spasms. Later disease onset, profound physical impairment, and depression were associated with chronic pain. Physical QoL was more affected in pain sufferers (p

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.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.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.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. ANN NEUROL 2022;92:476-485.

Background Optic neuritis (ON) is the most prevalent manifestation of pediatric multiple sclerosis (MSped) and myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGADped) in children > 6 years. In this study, we investigated retinal atrophy patterns and diagnostic accuracy of optical coherence tomography (OCT) in differentiating between both diseases after the first ON episode. Methods Patients were retrospectively identified in eight tertial referral centers. OCT, VEP and high/low-contrast visual acuity (HCVA/LCVA) have been investigated > 6 months after the first ON. Prevalence of pathological OCT findings was identified based on data of 144 age-matched healthy controls. Results Thirteen MOGADped (10.7 ± 4.2 years, F:M 8:5, 21 ON eyes) and 21 MSped (14.3 ± 2.4 years, F:M 19:2, 24 ON eyes) patients were recruited. We observed a significantly more profound atrophy of both peripapillary and macular retinal nerve fiber layer in MOGADped compared to MSped (pRNFL global: 68.2 ± 16.9 vs. 89.4 ± 12.3 µm, p 3, p ped developed global atrophy affecting all peripapillary segments, while MSped displayed predominantly temporal thinning. Nasal pRNFL allowed differentiation between both diseases with the highest diagnostic accuracy (AUC = 0.902, cutoff ped). OCT was also substantially more sensitive compared to VEP in identification of ON eyes in MOGAD (pathological findings in 90% vs. 14%, p = 0.016). Conclusion First MOGAD-ON results in a more severe global peripapillary atrophy compared to predominantly temporal thinning in MS-ON. Nasal pRNFL allows differentiation between both diseases with the highest accuracy, supporting the additional diagnostic value of OCT in children with ON.

Neurology: Neuroimmunology & Neuroinflammation 9(6), e200034 (2022). doi:10.1212/NXI.0000000000200034, Published by Lippincott Williams & Wilkins, Philadelphia, Pa.

BackgroundPatients with anti-aquaporin-4 antibody seropositive (AQP4-IgG+) neuromyelitis optica spectrum disorders (NMOSDs) frequently suffer from optic neuritis (ON) leading to severe retinal neuroaxonal damage. Further, the relationship of this retinal damage to a primary astrocytopathy in NMOSD is uncertain. Primary astrocytopathy has been suggested to cause ON-independent retinal damage and contribute to changes particularly in the outer plexiform layer (OPL) and outer nuclear layer (ONL), as reported in some earlier studies. However, these were limited in their sample size and contradictory as to the localisation. This study assesses outer retinal layer changes using optical coherence tomography (OCT) in a multicentre cross-sectional cohort.Method197 patients who were AQP4-IgG+ and 32 myelin-oligodendrocyte-glycoprotein antibody seropositive (MOG-IgG+) patients were enrolled in this study along with 75 healthy controls. Participants underwent neurological examination and OCT with central postprocessing conducted at a single site.ResultsNo significant thinning of OPL (25.02±2.03 µm) or ONL (61.63±7.04 µm) were observed in patients who were AQP4-IgG+ compared with patients who were MOG-IgG+ with comparable neuroaxonal damage (OPL: 25.10±2.00 µm; ONL: 64.71±7.87 µm) or healthy controls (OPL: 24.58±1.64 µm; ONL: 63.59±5.78 µm). Eyes of patients who were AQP4-IgG+ (19.84±5.09 µm, p=0.027) and MOG-IgG+ (19.82±4.78 µm, p=0.004) with a history of ON showed parafoveal OPL thinning compared with healthy controls (20.99±5.14 µm); this was not observed elsewhere.ConclusionThe results suggest that outer retinal layer loss is not a consistent component of retinal astrocytic damage in AQP4-IgG+ NMOSD. Longitudinal studies are necessary to determine if OPL and ONL are damaged in late disease due to retrograde trans-synaptic axonal degeneration and whether outer retinal dysfunction occurs despite any measurable structural correlates.

Additional file 1. Table S1. Patient and subgroup characteristics.

BACKGROUND The optimal treatment for patients with asymptomatic carotid artery stenosis is under debate. Since best medical treatment (BMT) has improved over time, the benefit of carotid endarterectomy (CEA) or carotid artery stenting (CAS) is unclear. Randomised data comparing the effect of CEA and CAS versus BMT alone are absent. We aimed to directly compare CEA plus BMT with CAS plus BMT and both with BMT only. METHODS SPACE-2 was a multicentre, randomised, controlled trial at 36 study centres in Austria, Germany, and Switzerland. We enrolled participants aged 50-85 years with asymptomatic carotid artery stenosis at the distal common carotid artery or the extracranial internal carotid artery of at least 70%, according to European Carotid Surgery Trial criteria. Initially designed as a three-arm trial including one group for BMT alone (with a randomised allocation ratio of 2·9:2·9:1), the SPACE-2 study design was amended (due to slow recruitment) to become two substudies with two arms each comparing CEA plus BMT with BMT alone (SPACE-2a) and CAS plus BMT with BMT alone (SPACE-2b); in each case in a 1:1 randomisation. Participants and clinicians were not masked to allocation. The primary efficacy endpoint was the cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years. The primary safety endpoint was any stroke or death from any cause within 30 days after CEA or CAS. The primary analysis was by intention-to treat, which included all randomly assigned patients in SPACE-2, SPACE-2a, and SPACE-2b, analysed using meta-analysis of individual patient data. We did two-step hierarchical testing to first show superiority of CEA and CAS to BMT alone then to assess non-inferiority of CAS to CEA. Originally, we planned to recruit 3640 patients; however, the study had to be stopped prematurely due to insufficient recruitment. This report presents the primary analysis at 5-year follow-up. This trial is registered with ISRCTN, number ISRCTN78592017. FINDINGS 513 patients across SPACE-2, SPACE-2a, and SPACE-2b were recruited and surveyed between July 9, 2009, and Dec 12, 2019, of whom 203 (40%) were allocated to CEA plus BMT, 197 (38%) to CAS plus BMT, and 113 (22%) to BMT alone. Median follow-up was 59·9 months (IQR 46·6-60·0). The cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years (primary efficacy endpoint) was 2·5% (95% CI 1·0-5·8) with CEA plus BMT, 4·4% (2·2-8·6) with CAS plus BMT, and 3·1% (1·0-9·4) with BMT alone. Cox proportional-hazard testing showed no difference in risk for the primary efficacy endpoint for CEA plus BMT versus BMT alone (hazard ratio [HR] 0·93, 95% CI 0·22-3·91; p=0·93) or for CAS plus BMT versus BMT alone (1·55, 0·41-5·85; p=0·52). Superiority of CEA or CAS to BMT was not shown, therefore non-inferiority testing was not done. In both the CEA group and the CAS group, five strokes and no deaths occurred in the 30-day period after the procedure. During the 5-year follow-up period, three ipsilateral strokes occurred in both the CAS plus BMT and BMT alone group, with none in the CEA plus BMT group. INTERPRETATION CEA plus BMT or CAS plus BMT were not found to be superior to BMT alone regarding risk of any stroke or death within 30 days or ipsilateral stroke during the 5-year observation period. Because of the small sample size, results should be interpreted with caution. FUNDING German Federal Ministry of Education and Research (BMBF) and German Research Foundation (DFG).

While natural killer (NK) cells are essential players in detection and elimination of malignant cells, these surveillance properties can be compromised by cancer cells. Since NK cell education primarily occurs in the bone marrow and lymphoid tissue, this process might be particularly affected by their infiltration with lymphoma cells. This study aimed to explore functional properties of diffuse large B-cell lymphoma (DLBCL) patient NK cells, which could potentially promote tumour immune evasion and disease propagation.NK cells isolated from the peripheral blood (PB) of 26 DLBCL patients and 13 age-matched healthy controls (HC) were analysed. The cytotoxic CD56

Introduction Acute kidney injury (AKI) after high dose methotrexate (HD-MTX) is associated with delayed MTX-excretion and life-threatening toxicity. Glucapridase, the recommended therapy, is expensive and not always available. Case series We describe 3 cases (69, 67, 73 years) with diffuse large B-cell lymphoma who developed AKI and early-onset severely delayed MTX elimination after HD-MTX. MTX serum concentrations were 101 and 69 μmol/L at 24 h after administration in two patients and 34 μmol/L at 32 h in the third. Management and outcome Since glucarpidase was unavailable, we performed daily high-flux hemodialysis (HF-HD) or online hemodiafiltration (HDF) sessions (median duration, 6 h). The median serum MTX elimination half-life during HDF/HF-HD sessions was similar in all patients (median, 4.4 h; IQR, 3.8–5.3 h), but serum MTX concentrations rebounded after each dialysis by a median of 40% of the trough concentrations. The three patients underwent multiple dialysis sessions, until MTX serum concentrations remained sufficiently low to be neutralized by leucovorin. Only 1 patient developed severe pancytopenia, and renal function normalized in all patients after 3–6 weeks. Discussion In conclusion, when glucarpidase is unavailable or delayed, early, repeated and prolonged HDF/HF-HD effectively enhance MTX elimination and prevent toxicity in patients with AKI and severely delayed MTX elimination after HD-MTX.

Brain : a journal of neurology (2022). doi:10.1093/brain/awac119, Published by Oxford Univ. Press, Oxford

The pan-European electric grid evolves towards a network with a wide diversity of (micro-)energy systems spread throughout all voltage levels. At the transmission level, this poses new challenges for cross-border energy exchange. At the distribution level small-scale generation, storages, and controllable loads offer flexibility available for provision of ancillary services. Meeting the EU energy supply policy while optimally operating the network under these conditions needs advanced TSO-DSO collaboration schemes. Taking this into account, this paper proposes a methodology which combines application of local flexibility management and control with central grid operation planning in order to meet planning criteria for future network operation. We discuss motivation and methodology process and present results of a proof-of-concept where the methodology was applied to a synthetic benchmark grid model.

Anti-IgLON5 disease is a newly defined clinical entity characterized by a progressive course with high disability and mortality rate. While precise pathogenetic mechanisms remain unclear, features characteristic of both autoimmune and neurodegenerative diseases were reported. Data on immunotherapy are limited, and its efficacy remains controversial. In this study, we retrospectively investigated an anti-IgLON5 disease cohort with special focus on clinical, serological and genetic predictors of the immunotherapy response and long-term outcome. Patients were recruited from the GENERATE (German Network for Research on Autoimmune Encephalitis) registry. Along with clinical parameters, anti-IgLON5 immunoglobulin (Ig)G in serum and CSF, anti-IgLON5 IgG1-4, IgA and IgM in serum, neurofilament light chain and glial fibrillary acidic protein in serum as well as human leukocyte antigen-genotypes were determined. We identified 53 patients (symptom onset 63.8 ± 10.3 years, female:male 1:1.5). The most frequent initial clinical presentations were bulbar syndrome, hyperkinetic syndrome or isolated sleep disorder [at least one symptom present in 38% (20/53)]. At the time of diagnosis, the majority of patients had a generalized multi-systemic phenotype; nevertheless, 21% (11/53) still had an isolated brainstem syndrome and/or a characteristic sleep disorder only. About one third of patients [28% (15/53)] reported subacute disease onset and 51% (27/53) relapse-like exacerbations during the disease course. Inflammatory CSF changes were evident in 37% (19/51) and increased blood-CSF-barrier permeability in 46% (21/46). CSF cell count significantly decreased, while serum anti-IgLON5 IgG titre increased with disease duration. The presence of human leukocyte antigen-DRB1*10:01 [55% (24/44)] was associated with higher serum anti-IgLON5 IgG titres. Neurofilament light chain and glial fibrillary acidic protein in serum were substantially increased (71.1 ± 103.9 pg/ml and 126.7 ± 73.3 pg/ml, respectively). First-line immunotherapy of relapse-like acute-to-subacute exacerbation episodes resulted in improvement in 41% (11/27) of patients and early initiation within the first 6 weeks was a predictor for therapy response. Sixty-eight per cent (36/53) of patients were treated with long-term immunotherapy and 75% (27/36) of these experienced no further disease progression (observation period of 20.2 ± 15.4 months). Long-term immunotherapy initiation during the first year after onset and low pre-treatment neurofilament light chain were significant predictors for a better outcome. In conclusion, subacute disease onset and early inflammatory CSF changes support the primary role of autoimmune mechanisms at least at initial stages of anti-IgLON5 disease. Early immunotherapy, prior to advanced neurodegeneration, is associated with a better long-term clinical outcome. Low serum neurofilament light chain at treatment initiation may serve as a potential biomarker of the immunotherapy response.

BACKGROUND Assessment of motor symptoms in Huntington's disease (HD) is based on the Unified-HD-Rating-Scale-Total-Motor-Score (UHDRS-TMS). Its categorical and rater-dependent nature reduces the ability to detect subtle changes and often placebo effects have been observed in trials. We have previously shown that impairments in isometric force matching can be detected by quantitative motor (Q-Motor) assessments of tongue protrusion forces (glossomotography) in HD. OBJECTIVE We aimed to investigate whether similar impairments in isometric force matching can be detected in tasks assessing hand and foot force coordination and whether correlations with clinical measures and the disease burden score can be found. METHODS Using a pre-calibrated force transducer, the ability of subjects to generate and maintain isometric forces at different target levels displayed on a monitor was assessed. Target forces applied in the hand were 1.5 and 5 Newton [N] and in feet 1, 5, and 10 N. Subjects with HD (n = 31) and age-matched controls (n = 22) were recruited from the HD out-patient clinic. RESULTS All paradigms distinguished controls from HD. The static coefficient of variability (%) was the most robust measure across all matching tasks. Correlations with clinical measures, such as the UHDRS-TMS, TFC, and the DBS were found. CONCLUSIONS Assessment of hand and foot force matching tasks was feasible and provided quantitative objective measures for severity of motor phenotype in HD. Since both upper and lower extremity motor function are relevant for everyday activities, these measures should be further assessed as candidates for developing functionally meaningful quantitative motor tasks.

Autologous stem cell transplantation (ASCT), intensifying anti-leukemic effects without significant treatment-related mortality (TRM), is particularly appealing in AML with favorable genetic/molecular profile. This study retrospectively evaluated the outcomes of post-remission treatment in consecutive favorable-risk AML patients. Sixty-six patients were included: 32 had mutated NPM1/wild-type FLT-ITD, 16 had t(8:21) and 18 - inv(16). Forty patients received chemotherapy alone, 26 underwent ASCT upfront. In time-dependent analysis, the ASCT group demonstrated higher relapse-free (RFS) (

Background and ObjectivesTo evaluate costs and health-related quality of life (HRQoL) of neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD).MethodsIn this multicenter cross-sectional study, data on consumption of medical and nonmedical resources and work ability were assessed via patient questionnaires. Costs were analyzed in Euros for 2018 from the societal perspective. HRQoL was captured by the EuroQoL Group 5 Dimension 5 Level Scale (EQ-5D-5L) questionnaire. Clinical data were retrieved from the Neuromyelitis Optica Study Group (NEMOS) database.ResultsTwo hundred twelve patients (80% women, median age 50 [19–83] years, median disease duration 7 [0–43] years, median Expanded Disability Status Scale [EDSS] score 3.5 [0–8.5], 66% aquaporin-4 immunoglobulin G [IgG] positive, 22% MOG IgG positive, 12% double seronegative) were analyzed. The mean total annual per capita cost of illness accounted for €59,574 (95% CI 51,225–68,293 or US dollars [USD] 70,297, 95% CI 60,445–80,586), and the mean index value of the EQ-5D-5L was 0.693 (95% CI 0.65–0.73). The most important cost drivers were informal care costs (28% of total costs), indirect costs (23%), and drugs (16%), especially immunotherapeutics. Costs showed a positive correlation with disease severity (ρ = 0.56, 95% CI 0.45–0.65); in the EDSS score 6.5 to 8.5 subgroup, the mean annual costs were €129,687 (95% CI 101,946–160,336 or USD 153,031, 95% CI 120,296–189,196). The HRQoL revealed a negative correlation to disease severity (ρ = −0.69, 95% CI −0.76 to −0.61); in the EDSS score 6.5 to 8.5 subgroup, the EQ-5D-5L mean index value was 0.195 (95% CI 0.13–0.28). Neither antibody status nor disease duration influenced the total annual costs or HRQoL.DiscussionThese German data from the era without approved preventive immunotherapies show enormous effects of the diseases on costs and quality of life. An early and cost-effective therapy should be provided to prevent long-term disability and to preserve quality of life.

Patients with lymphoma, especially those treated with anti-CD20 monoclonal antibodies, suffer high COVID-19-associated morbidity and mortality. The goal of this study was to assess the ability of lymphoma patients to generate a sufficient humoral response after two injections of BNT162b2 Pfizer vaccine and to identify factors influencing the response. Antibody titers were measured with the SARS-CoV-2 IgG II Quant (Abbott ) assay in blood samples drawn from lymphoma patients 4 2 weeks after the second dose of vaccine. The cutoff for a positive response was set at 50 AU/mL. Positive serological responses were observed in 51% of the 162 patients enrolled in this cross-sectional study. In a multivariate analysis, an interval of 1 year after this therapy. The latter percentage was equal to that of patients never exposed to monoclonal antibodies. In conclusion, lymphoma patients, especially those recently treated with anti- CD20 monoclonal antibodies, fail to develop sufficient humoral response to BNT162b2 vaccine. While a serological response is not the only predictor of immunity, its low level could make this population more vulnerable to COVID-19, which implies the need for a different vaccination schedule for such patients.

Background and ObjectivesTo determine optic nerve and retinal damage in aquaporin-4 antibody (AQP4-IgG)-seropositive neuromyelitis optica spectrum disorders (NMOSD) in a large international cohort after previous studies have been limited by small and heterogeneous cohorts.MethodsThe cross-sectional Collaborative Retrospective Study on retinal optical coherence tomography (OCT) in neuromyelitis optica collected retrospective data from 22 centers. Of 653 screened participants, we included 283 AQP4-IgG–seropositive patients with NMOSD and 72 healthy controls (HCs). Participants underwent OCT with central reading including quality control and intraretinal segmentation. The primary outcome was thickness of combined ganglion cell and inner plexiform (GCIP) layer; secondary outcomes were thickness of peripapillary retinal nerve fiber layer (pRNFL) and visual acuity (VA).ResultsEyes with ON (NMOSD-ON, N = 260) or without ON (NMOSD-NON, N = 241) were assessed compared with HCs (N = 136). In NMOSD-ON, GCIP layer (57.4 ± 12.2 μm) was reduced compared with HC (GCIP layer: 81.4 ± 5.7 μm, p < 0.001). GCIP layer loss (−22.7 μm) after the first ON was higher than after the next (−3.5 μm) and subsequent episodes. pRNFL observations were similar. NMOSD-NON exhibited reduced GCIP layer but not pRNFL compared with HC. VA was greatly reduced in NMOSD-ON compared with HC eyes, but did not differ between NMOSD-NON and HC.DiscussionOur results emphasize that attack prevention is key to avoid severe neuroaxonal damage and vision loss caused by ON in NMOSD. Therapies ameliorating attack-related damage, especially during a first attack, are an unmet clinical need. Mild signs of neuroaxonal changes without apparent vision loss in ON-unaffected eyes might be solely due to contralateral ON attacks and do not suggest clinically relevant progression but need further investigation.

Objective: The timing of brain atrophy after stroke is not well understood. We investigated the associations between age and imaging features and brain volume change in the first month after stroke. Methods: We retrospectively studied patients with acute ischemic stroke enrolled in the AXIS-2 trial. Total brain volume change from hyperacute MRI data to the first month after stroke was assessed using unified segmentation in SPM12. We hypothesized that age, ischemic brain lesion size and white matter changes were associated with larger brain volume change. Enlarged perivascular spaces (EPVS) and white matter hyperintensities (WMH) were rated visually and the presence of lacunes was assessed. Results: We enrolled 173 patients with a mean age of 67±11 years, 44 % were female. There was a median 6 mL decrease in volume (25th percentile -1mL-75th percentile 21mL) over time, equivalent to a median 0.5% (IQR-0.07% - 1.4%), decrease in brain volume. Age was associated with larger brain volume loss (per 10 years of age, 5 mL 95% CI 2 mL-8 mL). Baseline DWI lesion volume was not associated with greater volume loss (per 10 mL of lesion volume, change by 0 mL (95% CI -0.1 mL-0.1mL). Increasing Fazekas scores of deep white matter hyperintensity were associated with greater tissue loss (5 mL, 95% CI 1 mL-10 mL). Brain volume change was associated with ordinal change on the modified Rankin scale at 90 days (per 10 ml, OR 1.085, 95% CI 1.031-1.141) but the association was not present when adjusting for age, baseline diffusion lesion volume and NIHSS score (OR 1.044, 95% CI 0.990-1.010).Interpretation-Global brain volume loss occurs over 1 month after stroke and is associated with age and deep white matter disease. We did not find evidence that more severe strokes lead to increased early tissue loss.

In ischemic stroke, the study of edema, measurable as fluid attenuated inversion recovery (FLAIR) signal increase, has mainly focused on the ischemic core and less on the surrounding penumbra. To the naked eye, no FLAIR changes are present in the penumbra. However, changes in perfusion status could induce physiological changes resulting in subtle penumbral FLAIR signal alterations. To investigate penumbral FLAIR changes, we included subjects from the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) and Granulocyte Colony-Stimulating Factor in Patients With Acute Ischemic Stroke (AXIS 2) trial with perfusion- and diffusion-weighted imaging (PWI, DWI) and FLAIR at baseline. We used RAPID software to calculate the core and perfusion lesion on DWI and PWI and selected subjects with a minimal mismatch volume (15 ml) and ratio (1.2). We created voxel-based relative FLAIR signal intensity (rFLAIR SI) maps at baseline and follow up (FU) by calculating the ratio of the FLAIR intensity in one voxel and the median FLAIR intensity in a sphere with 15 mm radius around a contralateral homologues voxel. We studied rFLAIR SI in two regions of interest: the baseline penumbra (baseline perfusion lesion - [core lesion + voxels with apparent diffusion coefficient -6 mm 2 /s]) and the non-infarcted penumbra (baseline perfusion lesion - FU FLAIR lesion) at 24 hours (WAKE-UP) or 30 days (AXIS 2). Severity of hypoperfusion was defined as the time to maximum of the residue function. In the baseline penumbra, rFLAIR SI was elevated (ratio=1.04, p=1.7*10 -13 , n=126) and correlated with severity of hypoperfusion (Pearson’s r 0.03, p-4 , n=126). At 24 hours in a subgroup from WAKE-UP, rFLAIR SI in the non-infarcted penumbra further increased (ratio=1.05 at 24h vs 1.03 at baseline, p=7.1*10 -3 , n=43). In a different subgroup from AXIS 2, this increase in rFLAIR SI was reversible (ratio=1.02 at 30d vs 1.04 at baseline, p=1.5*10 -3 n=26) since it was no longer different from 1 at 30 days (ratio=1.01 at 30 days, p=0.099, n=26). Increases in rFLAIR SI, likely representing edema, are not restricted to the ischemic core and correlate with severity of hypoperfusion in the penumbra. They appear early after stroke onset, further increase at 24 hours and are reversible by 30 days.

Background and purpose: Functional outcome after stroke may be related to preexisting brain health. Several imaging markers of brain frailty have been described including brain atrophy and markers of small vessel disease. We investigated the association of these imaging markers with functional outcome after acute ischemic stroke. Methods: We retrospectively studied patients with acute ischemic stroke enrolled in the AXIS-2 trial, an international, multicenter, randomized controlled clinical trial of Granulocyte Colony Stimulating Factor versus placebo. We assessed the ratio of brain parenchymal volume to total intracerebral volumes (i.e., the brain parenchymal fraction [BPF]) and total brain volumes from routine baseline MRI data obtained within 9 hours of symptom onset using the unified segmentation algorithm in SPM12. Enlarged perivascular spaces (EPVS), white matter hyperintensities (WMH), lacunes as well as a small vessel disease (SVD) burden were rated visually. Functional outcomes (modified Rankin Scale [mRS] score) at day 90 were determined. Logistic regression was used to test associations between brain imaging features and functional outcomes. As there was no significant effect of G-CSF on any outcomes in AXIS-2, placebo and active groups were combined for these analyses. Results: We enrolled 259 patients with a mean age of 69±12 years and 46 % were female. Increased BPF was associated with higher odds of excellent outcome (OR per percent increase: 1.081, 95%CI: 1.012-1.155). Total brain volumes and SVD burden were not associated with functional outcome. An interaction between BPF and large vessel occlusion on excellent outcome was not observed. Conclusions: Global brain health, as assessed by brain parenchymal fraction on magnetic resonance imaging, is associated with excellent functional outcome after ischemic stroke. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00927836.

BACKGROUND Asymptomatic carotid artery stenosis (ACS) has a low risk of stroke. To achieve an advantage over noninterventional best medical treatment (BMT), carotid endarterectomy (CEA) or carotid artery stenting (CAS) must be performed with the lowest possible risk of stroke. Therefore, an analysis of risk-elevating factors is essential. Grade of ipsilateral and contralateral stenosis as well as plaque morphology are known risk factors in ACS. METHODS The randomized, controlled, multicenter SPACE-2 trial had to be stopped prematurely after recruiting 513 patients. 203 patients were randomized to CEA, 197 to CAS, and 113 to BMT. Within one year, risk factors such as grade of stenosis and plaque morphology were analyzed. RESULTS Grade of contralateral stenosis (GCS) was higher in patients with any stroke (50%ECST vs. 20%ECST; p=0.012). Echolucent plaque morphology was associated with any stroke on the day of intervention (OR 5.23; p=0.041). In the periprocedural period, any stroke was correlated with GCS in the CEA group (70%ECST vs. 20%ECST; p=0.026) and with echolucent plaque morphology in the CAS group (6% vs. 1%; p=0.048). In multivariate analysis, occlusion of the contralateral carotid artery (CCO) was associated with risk of any stroke (OR 7.00; p=0.006), without heterogeneity between CEA and CAS. CONCLUSION In patients with asymptomatic carotid artery stenosis, GCS, CCO, as well as echolucent plaque morphology were associated with a higher risk of cerebrovascular events. The risk of stroke in the periprocedural period was increased by GCS in CEA and by echolucent plaque in CAS. Due to small sample size, results must be interpreted carefully.