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Neurofilament light chain is part of the neuroaxonal cytoskeleton and upon disease-related neuroaxonal damage, it is released to the extracellular space and, based on modern highly sensitive assays, can also be detected in the peripheral blood. Thus, neurofilament light chain in the blood is an emerging marker of neurological disease, including age-related conditions, such as neurodegenerative but also neurovascular diseases. Recently, blood neurofilament light chain has been shown to serve as a potentially interesting marker of disease burden and prognostication also in cerebral small-vessel disease, a condition that is highly prevalent in elderly subjects. Small-vessel disease is a progressive condition, often related to common vascular risk factors such as arterial hypertension and is an important cause of stroke, vascular cognitive impairment, and dementia. As an age-dependent condition, small-vessel disease may occur concomitantly with neurodegenerative diseases, with both conditions having a potential impact on clinical status or cognitive performance. The aim of the present article is to give an overview on the current knowledge on neurofilament light chain as a disease or progression marker in small-vessel disease.

Contains fulltext : 235277.pdf (Publisher’s version ) (Closed access) BACKGROUND: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. METHODS: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. FINDINGS: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models. INTERPRETATION: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted. FUNDING: British Heart Foundation and Stroke Association.

Background A recent study found serum neurofilament light chain (NfL) levels to be strongly associated with poor neurological outcome in patients after cardiac arrest. Our aim was to confirm these findings in an independent validation study and to investigate whether NfL improves the prognostic value of two cardiac arrest-specific risk scores. Methods This prospective, single-center study included 164 consecutive adult after out-of-hospital cardiac arrest (OHCA) patients upon intensive care unit admission. We calculated two clinical risk scores (OHCA, CAHP) and measured NfL on admission within the first 24 h using the single molecule array NF-light® assay. The primary endpoint was neurological outcome at hospital discharge assessed with the cerebral performance category (CPC) score. Results Poor neurological outcome (CPC > 3) was found in 60% (98/164) of patients, with 55% (91/164) dying within 30 days of hospitalization. Compared to patients with favorable outcome, NfL was 14-times higher in patients with poor neurological outcome (685 ± 1787 vs. 49 ± 111 pg/mL), with an adjusted odds ratio of 3.4 (95% CI 2.1 to 5.6, p p p p p Conclusions Admission NfL was a strong outcome predictor and significantly improved two clinical risk scores regarding prognostication of neurological outcome in patients after cardiac arrest. When confirmed in future outcome studies, admission NfL should be considered as a standard laboratory measures in the evaluation of OHCA patients.

Most case series of patients with ischemic stroke (IS) and COVID-19 are limited to selected centers or lack 3-month outcomes. The aim of this study was to describe the frequency, clinical and radiological features, and 3-month outcomes of patients with IS and COVID-19 in a nationwide stroke registry. From the Swiss Stroke Registry (SSR), we included all consecutive IS patients ≥18 years admitted to Swiss Stroke Centers or Stroke Units during the first wave of COVID-19 (25 February to 8 June 2020). We compared baseline features, etiology, and 3-month outcome of SARS-CoV-2 polymerase chain reaction-positive (PCR+) IS patients to SARS-CoV-2 PCR- and/or asymptomatic non-tested IS patients. Of the 2341 IS patients registered in the SSR during the study period, 36 (1.5%) had confirmed COVID-19 infection, of which 33 were within 1 month before or after stroke onset. In multivariate analysis, COVID+ patients had more lesions in multiple vascular territories (OR 2.35, 95% CI 1.08-5.14, p = 0.032) and fewer cryptogenic strokes (OR 0.37, 95% CI 0.14-0.99, p = 0.049). COVID-19 was judged the likely principal cause of stroke in 8 patients (24%), a contributing/triggering factor in 12 (36%), and likely not contributing to stroke in 13 patients (40%). There was a strong trend towards worse functional outcome in COVID+ patients after propensity score (PS) adjustment for age, stroke severity, and revascularization treatments (PS-adjusted common OR for shift towards higher modified Rankin Scale (mRS) = 1.85, 95% CI 0.96-3.58, p = 0.07). In this nationwide analysis of consecutive ischemic strokes, concomitant COVID-19 was relatively rare. COVID+ patients more often had multi-territory stroke and less often cryptogenic stroke, and their 3-month functional outcome tended to be worse.

Background and Purpose: Data on the effectiveness and safety of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) in patients with stroke attributable to atrial fibrillation (AF) who were dependent on the daily help of others at hospital discharge are scarce. Methods: Based on prospectively obtained data from the observational Novel-Oral-Anticoagulants-in-Ischemic-Stroke-Patients-longterm registry from Basel, Switzerland, we compared the occurrence of the primary outcome—the composite of recurrent ischemic stroke, major bleeding, and all-cause death—among consecutive patients with AF-stroke treated with either VKAs or DOACs between patients dependent (defined as modified Rankin Scale score, 3–5) and patients independent at discharge. We used simple, adjusted, and weighted Cox proportional hazards regression to account for potential confounders. Results: We analyzed 801 patients (median age 80 years, 46% female), of whom 391 (49%) were dependent at discharge and 680 (85%) received DOACs. Over a total follow-up of 1216 patient-years, DOAC- compared to VKA-treated patients had a lower hazard for the composite outcome (hazard ratio [HR], 0.58 [95% CI, 0.42–0.81]), as did independent compared to dependent patients (HR, 0.54 [95% CI, 0.40–0.71]). There was no evidence that the effect of anticoagulant type (DOAC versus VKA) on the hazard for the composite outcome differed between dependent (HR dependent , 0.68 [95% CI, 0.45–1.01]) and independent patients (HR independent , 0.44 [95% CI, 0.26–0.75]) in the simple model ( P interaction =0.212). Adjusted (HR dependent , 0.74 [95% CI, 0.49–1.11] and HR independent , 0.51 [95% CI, 0.30–0.87]; P interaction =0.284) and weighted models (HR dependent , 0.79 [95% CI, 0.48–1.31] and HR independent , 0.46 [95% CI, 0.26–0.81]; P interaction =0.163) yielded concordant results. Secondary analyses focusing on the individual components of the composite outcome were consistent to the primary analyses. Conclusions: The benefits of DOACs in patients with atrial fibrillation with a recent stroke were maintained among patients who were dependent on the help of others at discharge. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03826927.

OBJECTIVE We compared outcomes after treatment with direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and a recent cerebral ischemia. METHODS We conducted an individual patient data analysis of seven prospective cohort studies. We included patients with AF and a recent cerebral ischemia (

Background: Cervical artery dissection is a major cause of stroke in young people (aged

Background: We determined the frequency of different etiologies of non-traumatic intracerebral hemorrhage (ICH) and their association with clinical characteristics and outcomes. Methods: We analyzed data from consecutive ICH patients enrolled in the prospective Swiss Stroke Registry (2014-2019). Etiology of ICH was determined according to prespecified, mutually exclusive categories. We assessed prevalence of ICH etiologies, their association with clinical characteristics, functional independence (modified Rankin Scale 0-2), mortality, recurrent ICH and ischemic stroke at 3 months. Results: We included 2584 patients (median age 72y, IQR 64-82, 46.6% female, median NIHSS 10; IQR 3-15). 2037 patients (80%) had hypertension and 553 (22.3%) were on anticoagulants. Distribution of etiologies was as follows: Hypertension (n=1216 patients; 47.1% of all / 56.3% of patients with hypertension), unknown etiology (n=542, 21.0%), antithrombotic therapy (n=225, 8.7% of all / 38% of patients on anticoagulants), cerebral amyloid angiopathy (CAA, n=211, 8.2%), macro-vascular (n=121, 4.7%), other determined etiologies (n=269, 10.4%). Patients with hypertensive ICH had significantly higher NIHSS (median 9; IQR 4-16) and blood pressure levels (median systolic 176; IQR 156-195) on admission. Patients with CAA had significantly lower NIHSS at baseline (median 5; IQR 2-12). Three month follow-up was available for 2109/2584 patients (81.6%). 820 (38.9%) were functionally independent, 658 have died (31.2%). Hypertensive ICH was associated with an increased rate of functional independence (aOR =1.42, 95%CI 1.06-1.90, p=0.02). 5.2% of patients had a cerebrovascular event within 3 months. CAA was associated with a high risk of recurrent ICH (HR 6.95, 95%CI 3.05-15.84, p Conclusions: In Swiss Stroke Units and Centers, one of two patients has ICH from a different cause than hypertension. The rate of functionally independent patients at 3 months seems higher than mortality. Absolute and relative risks of recurrent ICH and ischemic stroke after recent ICH differ among underlying etiologies.

Objective: The epidemiology of sub-aneurysmal aortic dilatation (SAA) 25 - 29 mm is not fully understood, and the management of SAA is debated. Lack of evidence is particularly problematic in the screening setting. This study aimed to evaluate the long term outcome of men with screen detected SAAs, focusing on progression to an abdominal aortic aneurysm (AAA), and on the AAAs reaching the threshold diameter for surgical repair. Methods: Between 2006 and 2015, all 65 year old men with a screen detected SAA in middle Sweden were re-examined with ultrasound after five and 10 years. The primary outcomes were expansion to AAA >= 30 mm and progression to AAA >= 55 mm. Secondary outcomes were risk factors for progression, repair rate, and mortality. Results: A total of 1 020 65 year old men with a SAA were identified, of whom 940 (92.2%; 95% confidence interval 91.0 - 93.8) had follow up. The Kaplan-Meier estimated incidence of AAA >= 30 mm development after the five year follow up (which was de facto carried out after a mean of 4.9 years) was 65.8% (61.6 - 69.4), all < 55 mm. The corresponding KM-estimated incidence after the 10 year follow up (carried out after a mean of 11.9 years) was 95.1% (90.1 - 97.4), and 29.7% (18.0 - 39.7) reached >= 55 mm. All 41 SAAs eventually expanding to >= 55 mm were >= 30 mm at the five year follow up. Of these, 32 had surgical repair with 100% survival, six have scheduled repairs, and three (7.3%) were unfit for repair. The KM estimated all cause mortality rates at five and 10 years were 7.0% and 17.9%, respectively, with no proven AAA related deaths. Conclusion: A majority of SAAs eventually progress to an AAA, of which 30% are estimated to eventually reach the threshold for repair within 10 years. A follow up policy with an ultrasound examination after five years can safely and effectively identify those SAAs at risk of developing into clinically significant AAAs needing repair and may be considered for anyone with reasonably good life expectancy.

Lung cancer is one of the most common types of cancer and is also a leading cause of cancer mortality. Surgery, considered the gold standard of therapy for early-stage lung cancer, is often not feasible, or desirable, because of comorbidities or the patient’s low-performance status. At the same time, lung metastases from various cancers are very common. With the emerging concept of oligometastasis as an intermediary state of disease, local therapy has frequently come into focus. Previous treatment modalities were often unable to meet the requirements made by local treatment of metastases. Fortunately, new local therapies such as interventional brachytherapy and stereotactic body radiation therapy (SBRT) have been developed, addressing these issues, and have been found successful in a variety of settings. CT-guided interstitial brachytherapy for the treatment of early-stage lung cancer and lung metastases has proven to be effective, safe, and well-tolerated, with promising results from a variety of centers (mostly in Germany); it represents an elegant addition to existing treatment modalities. At present, further insights must be gained regarding the choice of local therapy and the combination of focal with systemic approaches in a multimodal therapy setting. A wider implementation of the method would be expedient and desirable.

Background and Purpose Serum neurofilament light (NfL)-chain is a circulating marker for neuroaxonal injury and is also associated with severity of cerebral small vessel disease (SVD) cross-sectionally. Here we explored the association of serum-NfL with imaging and cognitive measures in SVD longitudinally.Methods From 503 subjects with SVD, baseline and follow-up magnetic resonance imaging (MRI) was available for 264 participants (follow-up 8.7±0.2 years). Baseline serum-NfL was measured by an ultrasensitive single-molecule-assay. SVD-MRI-markers including white matter hyperintensity (WMH)-volume, mean diffusivity (MD), lacunes, and microbleeds were assessed at both timepoints. Cognitive testing was performed in 336 participants, including SVD-related domains as well as global cognition and memory. Associations with NfL were assessed using linear regression analyses and analysis of covariance (ANCOVA).Results Serum-NfL was associated with baseline WMH-volume, MD-values and presence of lacunes and microbleeds. SVD-related MRI- and cognitive measures showed progression during follow-up. NfL-levels were associated with future MRI-markers of SVD, including WMH, MD and lacunes. For the latter, this association was independent of baseline lacunes. Furthermore, NfL was associated with incident lacunes during follow-up (P=0.040). NfL-levels were associated with future SVD-related cognitive impairment (processing speed: β=–0.159; 95% confidence interval [CI], –0.242 to –0.068; P=0.001; executive function β=–0.095; 95% CI, –0.170 to –0.007; P=0.033), adjusted for age, sex, education, and depression. Dementia-risk increased with higher NfL-levels (hazard ratio, 5.0; 95% CI, 2.6 to 9.4; P

Stroke-like migraine attacks after radiation therapy (SMART) is a syndrome observed in a delayed fashion in patients following brain radiation therapy. It is a rare but important differential diagnosis of migraine in these patients, often presenting with migraine-like headache. In addition, there may be focal neurological deficits or seizures. In general, it is regarded as a reversible condition, therefore termed stroke-like. Our case illustrates that there may also be ischemic stroke associated with SMART leading to an unfavorable course, even after prior remission.

ObjectiveTo explore the utility of serum neurofilament light chain (NfL) as a biomarker for primary and secondary neuroaxonal injury after ischemic stroke (IS) and study its value for the prediction of clinical outcome.MethodsWe used an ultrasensitive single-molecule array assay to measure serum NfL levels in healthy controls (n = 30) and 2 independent cohorts of patients with IS: (1) with serial serum sampling at hospital arrival (n = 196), at days 2, 3, and 7 (n = 89), and up to 6 months post stroke; and (2) with standardized MRI at baseline and at 6 months post stroke, and with cross-sectional serum sampling at 6 months (n = 95). We determined the temporal profile of serum NfL levels, their association with imaging markers of neuroaxonal injury, and with clinical outcome.ResultsPatients with IS had higher serum NfL levels compared with healthy controls starting from admission until 6 months post stroke. Serum NfL levels peaked at day 7 (211.2 pg/mL [104.7–442.6], median [IQR]) and correlated with infarct volumes (day 7: partial r = 0.736, p = 1.5 × 10−15). Six months post stroke, patients with recurrent ischemic lesions on MRI (n = 19) had higher serum NfL levels compared to those without new lesions (n = 76, p = 0.002). Serum NfL levels 6 months post stroke further correlated with a quantitative measure of secondary neurodegeneration obtained from diffusion tensor imaging MRI (r = 0.361, p = 0.001). Serum NfL levels 7 days post stroke independently predicted modified Rankin Scale scores 3 months post stroke (cumulative odds ratio [95% confidence interval] = 2.35 [1.60–3.45]; p = 1.24 × 10−05).ConclusionSerum NfL holds promise as a biomarker for monitoring primary and secondary neuroaxonal injury after IS and for predicting functional outcome.

OBJECTIVE: Information about Rivaroxaban plasma levels (RivLev) may guide treatment decisions in patients with acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) taking rivaroxaban. METHODS: In a multicenter registry-based study (Novel-Oral-Anticoagulants-In-Stroke-Patients collaboration;NOACISP;ClinicalTrials.gov:NCT02353585) of patients with stroke while taking rivaroxaban, we compared RivLev in patients with AIS and ICH. We determined how many AIS-patients had RivLev≤100ng/ml, indicating possible eligibility for thrombolysis and how many ICH-patients had RivLev≥75ng/ml, possibly eligible for the use of specific reversal agents. We explored factors associated with RivLev (Spearman correlation; regression models) and studied the sensitivity and specificity of INR-thresholds to substitute RivLevs using cross tables and ROC curves. RESULTS: Among 241 patients (median age 80 years[IQR73-84], median time-from-onset-to-admission 2 hours[IQR1-4.5hours], median RivLev 89ng/ml[31-194]), 190 had AIS and 51 had ICH. RivLev were similar in AIS-patients (82ng/ml[IQR30-202] and ICH-patients (102ng/ml[IQR 51-165]; p=0.24). Trough RivLev(≤137ng/ml) occurred in 126/190 (66.3%) AIS- and 34/51 (66.7%) ICH-patients. Among AIS-patients, 108/190 (56.8%) had RivLev≤100ng/ml. In ICH-patients 33/51(64.7%) had RivLev≥75ng/ml. RivLev were associated with rivaroxaban dosage, inversely with renal function and time-since-last-intake (each p

The hypertensive disorders of pregnancy (HDP) encompass a spectrum of disorders, including new-onset hypertension diagnosed during pregnancy (gestational hypertension), preeclampsia, and chronic hypertension with superimposed preeclampsia. HDP are estimated to occur in ≈2% to 8% of pregnant women globally.1 The precise etiology of preeclampsia is unknown, although it is believed to be a systemic disease with widespread endothelial dysfunction2 that is either unmasked or invoked during pregnancy.

INTRODUCTION: Cerebral small vessel disease is an important cause for both ischaemic stroke and intracranial haemorrhage. To date, knowledge on the impact of small vessel disease on the clinical course in stroke patients treated with oral anticoagulation for atrial fibrillation is limited. PATIENTS AND METHODS: Registry-based prospective observational study of 320 patients (aged 78.2 ± 9.2 years) treated with anticoagulation following atrial fibrillation stroke. Patients underwent standardised magnetic-resonance-imaging assessing measures of small vessel disease, including cerebral microbleeds and white matter hyperintensities. Median follow-up was 754 (interquartile range = [708–828]) days. Using adjusted logistic and Cox regression, we assessed the association of imaging measures with clinical outcome including recurrent ischaemic stroke, intracranial haemorrhage and death and assessed disability (modified Rankin Scale). RESULTS: Overall, recurrent ischaemic stroke was more common than intracranial haemorrhage (22 versus 8, respectively). Cerebral microbleeds were related to an increased risk of the composite endpoint (ischaemic stroke, intracranial haemorrhage, death: odds ratio (OR) 2.05, 95% confidence interval (CI) 1.27–3.31; P = 0.003), as were white matter hyperintensities (OR 2.00, 95%CI 1.23–3.27, P = 0.005). This was also true in time-to-event analysis (cerebral microbleeds: HR 2.31, 95%CI 1.39–3.52; P

Background Prehospital delay reduces the proportion of patients with stroke treated with recanalization therapies. We aimed to identify novel and modifiable risk factors for prehospital delay. Methods and Results We included patients with an ischemic stroke confirmed by diffusion‐weighted magnetic resonance imaging, symptom onset within 24 hours and hospitalized in the Stroke Center of the University Hospital Basel, Switzerland. Trained study nurses interviewed patients and proxies along a standardized questionnaire. Prehospital delay was defined as >4.5 hours between stroke onset—or time point of wake‐up—and admission. Overall, 336 patients were enrolled. Prehospital delay was observed in 140 patients (42%). The first healthcare professionals to be alarmed were family doctors for 29% of patients (97/336), and a quarter of these patients had a baseline National Institute of Health Stroke Scale score of 4 or higher. The main modifiable risk factor for prehospital delay was a face‐to‐face visit to the family doctor (adjusted odds ratio, 4.19; 95% CI , 1.85–9.46). Despite transport by emergency medical services being associated with less prehospital delay (adjusted odds ratio, 0.41; 95% CI , 0.24–0.71), a minority of patients (39%) who first called their family doctor were transported by emergency medical services to the hospital. The second risk factor was lack of awareness of stroke symptoms (adjusted odds ratio, 4.14; 95% CI , 2.36–7.24). Conclusions Almost 1 in 3 patients with a diffusion‐weighted magnetic resonance imaging–confirmed ischemic stroke first called the family doctor practice. Face‐to‐face visits to the family doctor quadrupled the odds of prehospital delay. Efforts to reduce prehospital delay should address family doctors and their staffs as important partners in the prehospital pathway. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 02798770.

Background: : Cerebral small vessel disease (SVD) is an important cause of stroke and vascular cognitive impairment (VCI), leading to subcortical ischemic vascular dementia. As a hereditary form of SVD with early onset, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) represents a pure form of SVD and may thus serve as a model disease for SVD. To date, underlying molecular mechanisms linking vascular pathology and subsequent neuronal damage in SVD are incompletely understood. Objective: : We performed comparative transcriptional profiling microarray and proteomic analyses on post-mortem frontal lobe specimen from 2 CADASIL patients and 5 non neurologically diseased controls in order to identify dysregulated pathways potentially involved in the development of tissue damage in CADASIL. Method: : Transcriptional microarray analysis of material extracted from frontal grey and white matter (WM) identified subsets of up- or down-regulated genes enriched into biological pathways mostly in WM areas. Proteomic analysis of these regions also highlighted cellular processes identified by dysregulated proteins. Result: : Discrepancies between proteomic and transcriptomic data were observed, but a number of pathways were commonly associated with genes and corresponding proteins, such as: “ribosome” identified by upregulated genes and proteins in frontal cortex or “spliceosome” associated with down-regulated genes and proteins in frontal WM. Conclusion:: This latter finding suggests that defective expression of spliceosomal components may alter widespread splicing profile, potentially inducing expression abnormalities that could contribute to cerebral WM damage in CADASIL.

Contains fulltext : 208975.pdf (Publisher’s version ) (Open Access) BACKGROUND: Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke. METHODS: We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602. FINDINGS: Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1.34 years [IQR 0.19-2.44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1.35 (95% CI 1.20-1.50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2.45 (1.82-3.29) for intracranial haemorrhage and 1.23 (1.08-1.40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4.55 [95% CI 3.08-6.72] for intracranial haemorrhage vs 1.47 [1.19-1.80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5.52 [3.36-9.05] vs 1.43 [1.07-1.91]; and for >/=20 cerebral microbleeds, aHR 8.61 [4.69-15.81] vs 1.86 [1.23-1.82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95% CI 48-84] per 1000 patient-years vs 27 intracranial haemorrhages [17-41] per 1000 patient-years; and for >/=20 cerebral microbleeds, 73 ischaemic strokes [46-108] per 1000 patient-years vs 39 intracranial haemorrhages [21-67] per 1000 patient-years). INTERPRETATION: In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden. FUNDING: British Heart Foundation and UK Stroke Association.

Objective:\ud It is not known whether patients with atrial fibrillation (AF) with ischemic stroke despite oral anticoagulant therapy are at increased risk for further recurrent strokes or how ongoing secondary prevention should be managed.\ud \ud Methods:\ud We conducted an individual patient data pooled analysis of 7 prospective cohort studies that recruited patients with AF and recent cerebral ischemia. We compared patients taking oral anticoagulants (vitamin K antagonists [VKA] or direct oral anticoagulants [DOAC]) prior to index event (OACprior ) with those without prior oral anticoagulation (OACnaive ). We further compared those who changed the type (ie, from VKA or DOAC, vice versa, or DOAC to DOAC) of anticoagulation (OACchanged ) with those who continued the same anticoagulation as secondary prevention (OACunchanged ). Time to recurrent acute ischemic stroke (AIS) was analyzed using multivariate competing risk Fine-Gray models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).\ud \ud Results:\ud We included 5,413 patients (median age = 78 years [interquartile range (IQR) = 71-84 years]; 5,136 [96.7%] had ischemic stroke as the index event, median National Institutes of Health Stroke Scale on admission = 6 [IQR = 2-12]). The median CHA2 DS2 -Vasc score (congestive heart failure, hypertension, age≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category) was 5 (IQR = 4-6) and was similar for OACprior (n = 1,195) and OACnaive (n = 4,119, p = 0.103). During 6,128 patient-years of follow-up, 289 patients had AIS (4.7% per year, 95% CI = 4.2-5.3%). OACprior was associated with an increased risk of AIS (HR = 1.6, 95% CI = 1.2-2.3, p = 0.005). OACchanged (n = 307) was not associated with decreased risk of AIS (HR = 1.2, 95% CI = 0.7-2.1, p = 0.415) compared with OACunchanged (n = 585).\ud \ud Interpretation:\ud Patients with AF who have an ischemic stroke despite previous oral anticoagulation are at a higher risk for recurrent ischemic stroke despite a CHA2 DS2 -Vasc score similar to those without prior oral anticoagulation. Better prevention strategies are needed for this high-risk patient group.

Introduction The clinical picture of hypothyroidism, including neurological symptoms, can be multiform, which may delay or hamper the correct diagnosis. Case presentation We present an uncommon clinical presentation of a 38-year-old Caucasian man with mild facial palsy on the left side, uvular deviation to the left with preserved gag reflex, tongue deviation to the left, lingual dysarthria, and xerosis by severe hypothyroidism. Blood tests on admission showed elevated serum creatinine of 151 μmol/L (glomerular filtration rate 47 ml/min/1.7 CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration equation]), increased creatinine phosphokinase activity (1243 U/L), markedly elevated thyroid-stimulating hormone (292.2 mIU/L), low free thyroxine level (1.1 pmol/L), and free triiodothyronine level below the limit of detection (

OBJECTIVE To investigate the genomic features of tertiary pattern 5 (TP5) on radical prostatectomy specimens in an effort to explain the poor clinical outcomes associated with this disease subtype. PATIENTS AND METHODS Data from 159 men with Gleason Grade Group (GGG) 3 or 4 were considered. All patients had Decipher diagnostic testing with transcript profiles and single-channel array normalisation (SCAN)-normalised expression of coding genes. The relationship between Decipher and TP5 was investigated by linear and binary logistic regressions. A differential transcriptomic analysis between patients with and without TP5 was performed. The prognostic role of these genes on progression-free survival (PFS) and overall survival (OS) was evaluated using The Cancer Genome Atlas. RESULTS In all, 52/159 (33%) patients had GGG 3-4 with TP5 disease. TP5 was associated with a higher Decipher score (β 0.07, 95% confidence interval [CI] 0.02-0.13; P = 0.04) and higher likelihood of falling within the intermediate- or high-risk categories (odds ratio 3.34, 95% CI 1.34-8.35; P = 0.01). Analysis of microarray data revealed an 18-gene signature that was differentially expressed in patients with TP5; 13 genes were over- and five under-expressed in the TP5 cohort. The overexpression of cyclin dependent kinase inhibitor 2B (CDKN2B), polo-like kinase 1 (PLK1), or cell division cycle 20 (CDC20) was associated with worse PFS. The group harbouring overexpression of at least one gene had a 5-year PFS rate of 50% vs 74% in the group without overexpression (P

AIMS: To evaluate if ticagrelor, an effective platelet inhibitor without known non-responders, could inhibit growth of small abdominal aortic aneurysms (AAAs). METHODS AND RESULTS: In this multi-centre randomized controlled trial, double-blinded for ticagrelor and placebo, acetylic salicylic acid naive patients with AAA and with a maximum aortic diameter 35-49 mm were included. The primary outcome was mean reduction in log-transformed AAA volume growth rate (%) measured with magnetic resonance imaging (MRI) at 12 months compared with baseline. Secondary outcomes include AAA-diameter growth rate and intraluminal thrombus (ILT) volume enlargement rate. A total of 144 patients from eight Swedish centres were randomized (72 in each group). MRI AAA volume increase was 9.1% for the ticagrelor group and 7.5% for the placebo group (P = 0.205) based on intention-to-treat analysis, and 8.5% vs. 7.4% in a per-protocol analysis (P = 0.372). MRI diameter change was 2.5 mm vs. 1.8 mm (P = 0.113), US diameter change 2.3 mm vs. 2.2 mm (P = 0.778), and ILT volume change 12.9% vs. 10.4% (P = 0.590). CONCLUSION: In this RCT, platelet inhibition with ticagrelor did not reduce growth of small AAAs. Whether the ILT has an important pathophysiological role for AAA growth cannot be determined based on this study due to the observed lack of thrombus modulating effect of ticagrelor. TRIAL REGISTRATION: The TicAAA trial is registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT02070653. (Less)

WOS: 000475733300001, PubMed: 31322116, Background: Tranexamic acid reduces death due to bleeding after trauma and postpartum haemorrhage. Objective: The aim of the study was to assess if tranexamic acid is safe, reduces haematoma expansion and improves outcomes in adults with spontaneous intracerebral haemorrhage (ICH). Design: The TICH-2 (Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage) study was a pragmatic, Phase III, prospective, double-blind, randomised placebo-controlled trial. Setting: Acute stroke services at 124 hospitals in 12 countries (Denmark, Georgia, Hungary, Ireland, Italy, Malaysia, Poland, Spain, Sweden, Switzerland, Turkey and the UK). Participants: Adult patients (aged >= 18 years) with ICH within 8 hours of onset. Exclusion criteria: Exclusion criteria were ICH secondary to anticoagulation, thrombolysis, trauma or a known underlying structural abnormality; patients for whom tranexamic acid was thought to be contraindicated; prestroke dependence (i.e. patients with a modified Rankin Scale [mRS] score > 4); life expectancy < 3 months; and a Glasgow Coma Scale score of < 5. Interventions: Participants, allocated by randomisation, received 1 g of an intravenous tranexamic acid bolus followed by an 8-hour 1-g infusion or matching placebo (i.e. 0.9% saline). Main outcome measure: The primary outcome was functional status (death or dependency) at day 90, which was measured by the shift in the mRS score, using ordinal logistic regression, with adjustment for stratification and minimisation criteria. Results: A total of 2325 participants (tranexamic acid, n = 1161; placebo, n = 1164) were recruited from 124 hospitals in 12 countries between 2013 and 2017. Treatment groups were well balanced at baseline. The primary outcome was determined for 2307 participants (tranexamic acid, n = 1152; placebo, n = 1155). There was no statistically significant difference between the treatment groups for the primary outcome of functional status at day 90 [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.76 to 1.03; p = 0.11]. Although there were fewer deaths by day 7 in the tranexamic acid group (aOR 0.73, 95% CI 0.53 to 0.99; p = 0.041), there was no difference in case fatality at 90 days (adjusted hazard ratio 0.92, 95% CI 0.77 to 1.10; p = 0.37). Fewer patients experienced serious adverse events (SAEs) after treatment with tranexamic acid than with placebo by days 2 (p = 0.027), 7 (p = 0.020) and 90 (p = 0.039). There was no increase in thromboembolic events or seizures. Limitations: Despite attempts to enrol patients rapidly, the majority of participants were enrolled and treated > 4.5 hours after stroke onset. Pragmatic inclusion criteria led to a heterogeneous population of participants, some of whom had very large strokes. Although 12 countries enrolled participants, the majority (82.1%) were from the UK. Conclusions: Tranexamic acid did not affect a patient's functional status at 90 days after ICH, despite there being significant modest reductions in early death (by 7 days), haematoma expansion and SAEs, which is consistent with an antifibrinolytic effect. Tranexamic acid was safe, with no increase in thromboembolic events. Future work: Future work should focus on enrolling and treating patients early after stroke and identify which participants are most likely to benefit from haemostatic therapy. Large randomised trials are needed., National Institute for Health Research Health Technology Assessment programmeNational Institute for Health Research (NIHR); Pragmatic Trials, UK; Swiss Heart Foundation in Switzerland, This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 35. See the NIHR Journals Library website for further project information. The project was also funded by the Pragmatic Trials, UK, funding call and the Swiss Heart Foundation in Switzerland.

Zusammenfassung Ziel der Studie: Das Ziel dieser Untersuchung liegt in der Ermittlung der Akzeptanz der einheitlichen Handlungsempfehlungen des Netzwerks „Gesund ins Leben – Netzwerk Junge Familie“ zu den Themen Säuglingsernährung und Ernährung der stillendenden Mutter bei unterschiedlichen Berufsgruppen. Methodik: Webbasierte Befragung u. a. unter Frauenärzten/-innen, Kinder- und Jugendärzten/-innen und Hebammen/Entbindungspflegern sowie eine zweite webbasierte Befragung unter Kinder- und Jugendärzten/-innen. Die Zustimmung wurde dichotom erfasst. Der prozentuale Zustimmungsgrad wurde als gering ( Ergebnisse: An der ersten Befragung nahmen 1 311 Personen teil (n=908 Hebammen/Entbindungspfleger), wovon 77,6% angaben, die Handlungsempfehlungen zu kennen. Der durchschnittliche Zustimmungsgrad war bei Hebammen/Entbindungspflegern mit 67,5% am geringsten. An der zweiten Befragung nahmen 119 Kinder- und Jugendärzte/-innen teil, wobei 86,5% Kenntnis von der Existenz der Empfehlungen hatten. Geringe Akzeptanz wiesen bei allen Berufsgruppen insbesondere die Empfehlungen zu den Nährstoffsupplementen Iod und Fluorid auf. Als Ablehnungsgründe wurden eine Orientierung an der individuellen Situation der jungen Familie, an anderen Empfehlungen oder an eigenen Erfahrungen angeführt. Schlussfolgerung: Die Übertragung der Handlungsempfehlungen in die Hebammenpraxis scheint noch nicht gelungen. Aufgrund der überproportionalen Beteiligung von Hebammen/Entbindungspflegern sind die Ergebnisse aber nicht auf andere Berufsgruppen übertragbar. Die Integration der Empfehlungen in die Aus-, Fort- und Weiterbildung der Berufsgruppen, die Überarbeitung eventuell missverständlicher Formulierungen sowie die Kommunikation der wissenschaftlichen Hintergründe sind sinnvolle Ansatzpunkte für eine Akzeptanzsteigerung.

Background: A general abdominal aortic aneurysm (AAA) screening program, targeting 65-year-old men, has gradually been introduced in Sweden since 2006 and reached nationwide coverage in 2015. The aim of this study was to determine the outcome of this program. Methods: Data on the number of invited and examined men, screening-detected AAAs, AAAs operated on, and surgical outcome were retrieved from all 21 Swedish counties for the years 2006 through 2014. AAA-specific mortality data were retrieved from the Swedish Cause of Death Registry. A linear regression analysis was used to estimate the effect on AAA-specific mortality among all men ≥65 years of age for the observed time period. The long-term effects were projected by using a validated Markov model. Results: Of 302 957 men aged 65 years invited, 84% attended. The prevalence of screening-detected AAA was 1.5%. After a mean of 4.5 years, 29% of patients with AAA had been operated on, with a 30-day mortality rate of 0.9% (1.3% after open repair and 0.3% after endovascular repair, P P =0.020). The number needed to screen and the number needed to operate on to prevent 1 premature death were 667 and 1.5, respectively. With a total population of 9.5 million, the Swedish national AAA-screening program was predicted to annually prevent 90 premature deaths from AAA and to gain 577 quality-adjusted life-years. The incremental cost-efficiency ratio was estimated to be €7770 per quality-adjusted life-years. Conclusions: Screening 65-year-old men for AAA is an effective preventive health measure and is highly cost-effective in a contemporary setting. These findings confirm the results from earlier randomized controlled trials and model studies in a large population-based setting of the importance for future healthcare decision making.

Objective: In patients with recent acute ischemic stroke (AIS) and atrial fibrillation, we assessed the starting time of direct, non–vitamin K antagonist oral anticoagulants (DOACs) for secondary prevention, the rate of intracranial hemorrhage (ICH), and recurrent ischemic events during follow-up. Methods: We included consecutive patients with nonvalvular atrial fibrillation admitted to our hospital for AIS or TIA (index event) who received secondary prophylaxis with DOAC or vitamin K antagonists (VKAs). Follow-up was at least 3 months. In the primary analysis, we compared rates of ICH and recurrent ischemic events (AIS or TIA) between patients with early (≤7 days since event; DOAC early ) and those with late (>7 days, DOAC late ) start of DOAC. Results: Two hundred four patients were included (median age 79 years, 89% AIS) and total follow-up time was 78.25 patient-years. One hundred fifty-five patients received DOAC with a median delay of 5 days after the index event (interquartile range 3–11) and 49 received VKA. DOAC was started early in 100 patients (65%). We observed one ICH (1.3%/y) and 6 recurrent AIS (7.7%/y). The ICH occurred in a patient taking VKA. No significant difference in the rate of recurrent AIS between DOAC early (5.1%/y) and DOAC late (9.3%/y, p = 0.53) was observed. Conclusions: Even if DOACs are often started early after an index event, the risk of ICH appears to be low. Among all patients receiving anticoagulation, the rate of recurrent events was 6 times higher than the rate of ICH.

Background and Purpose— We compared outcome and complications in patients with stroke treated with intravenous thrombolysis (IVT) who could not live alone without help of another person before stroke (dependent patients) versus independent ones. Methods— In a multicenter IVT-register–based cohort study, we compared previously dependent (prestroke modified Rankin Scale score, 3–5) versus independent (prestroke modified Rankin Scale score, 0–2) patients. Outcome measures were poor 3-month outcome (not reaching at least prestroke modified Rankin Scale [dependent patients]; modified Rankin Scale score of 3–6 [independent patients]), death, and symptomatic intracranial hemorrhage. Unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals (OR [95% confidence interval]) were calculated. Results— Among 7430 IVT-treated patients, 489 (6.6%) were dependent and 6941 (93.4%) were independent. Previous stroke, dementia, heart, and bone diseases were the most common causes of preexisting dependency. Dependent patients were more likely to die (OR unadjusted , 4.55 [3.74–5.53]; OR adjusted , 2.19 [1.70–2.84]). Symptomatic intracranial hemorrhage occurred equally frequent (4.8% versus 4.5%). Poor outcome was more frequent in dependent (60.5%) than in independent (39.6%) patients, but the adjusted ORs were similar (OR adjusted , 0.95 [0.75–1.21]). Among survivors, the proportion of patients with poor outcome did not differ (35.7% versus 31.3%). After adjustment for age and stroke severity, the odds of poor outcome were lower in dependent patients (OR adjusted , 0.64 [0.49–0.84]). Conclusions— IVT-treated stroke patients who were dependent on the daily help of others before stroke carry a higher mortality risk than previously independent patients. The risk of symptomatic intracranial hemorrhage and the likelihood of poor outcome were not independently influenced by previous dependency. Among survivors, poor outcome was avoided at least as effectively in previously dependent patients. Thus, withholding IVT in previously dependent patients might not be justified.

Purpose Differences exist concerning when and how to perform lymph node dissection (LND) during radical prostatectomy due to lack of high-grade evidence to its safety and efficacy. We aimed to compare readmission rates between limited and extended LND during open radical prostatectomy (ORP) and robot-assisted radical prostatectomy (RARP). Materials and methods We conducted a prospective trial of 3,706 eligible patients comparing ORP vs. RARP (LAPPRO). Six hundred and twenty-seven underwent concomitant LND. Data were retrieved for readmissions within 90 days from surgery from the Swedish Patient Registry. Causes for readmissions were classified according to the modified Clavien-Dindo classification system. We estimated risks for readmission stratified by type of LND and surgical approach. Results We recorded 107 readmissions in 90 patients. The overall readmission rate was 14% (90/627). In the open group, extended LND had a higher, but not statistically significant readmission rate of 18% compared to 11% after limited LND (95%CI 0.87–3.01). In the robot-assisted group, readmissions after extended LND did not differ from limited LND (15% vs. 18%, 95%CI 0.49–1.61). RARP with limited LND showed a higher risk for any (RR 1.98, 95%CI [1.02–3.81]) as well as Clavien-Dindo grade 1 to 2 readmissions (RR 2.49, 95%CI [1.10–5.63]) compared to open approach with limited LND. Robot-assisted extended LND reduced the risk for Clavien-Dindo grade 3 to 5 complications leading to readmissions compared to the open approach by 59% (RR 0.41, 95%CI [0.19-0.87]). Conclusions The risk for hospital readmission was similar when performing limited or extended LND during a radical prostatectomy. Robot-assisted technique for performing extended LND may decrease the risk for severe complications.

Robot-assistance is being increasingly used for radical cystectomy (RC). Fifteen years of surgical evolution might be considered a short period for a radical procedure to be established as the treatment of choice, but robot assisted radical cystectomy (RARC) is showing promising results when compared with the current gold standard, open RC (ORC). In this review, we describe the current status of RARC and continue the discussion on the on-going RARC versus ORC debate.

Background and purpose The aim was to assess the feasibility and safety of fast-track hospitalizations in a selected cohort of patients with stroke. Methods Patients hospitalized at the Stroke Center of the University Hospital Basel, Switzerland, with an acute ischaemic stroke confirmed on magnetic resonance diffusion-weighted imaging were included. Neurological deficits of the included patients were non-disabling, i.e. not interfering with activities of daily living and compatible with a direct discharge home. Patients with premorbid disability were excluded. All patients were admitted to the Stroke Center for ≥24 h. Two study groups were compared - fast-track hospitalizations (≤72 h) and long-term hospitalizations (>72 h). The primary end-point was a composite of any unplanned rehospitalization for any reason within 3 months since hospital discharge and a modified Rankin Scale 3-6 at 3 months. Adjustment for confounders was done using the inverse probability of treatment weights (IPTW). Results Amongst the 521 patients who met the inclusion criteria, fast-track hospitalizations were performed in 79 patients (15%). In the fast-track group, seven patients (8.9%) met the primary end-point, compared to 37 (8.4%) in the long-term group [odds ratio (OR) 1.06, 95% confidence interval (CI) 0.42-2.34, P = 0.88]. After weighting for IPTW, the odds of the primary end-point remained similar between the two arms (ORIPTW 1.27, 95% CI 0.51-3.16, P = 0.61). The costs of fast-track hospitalizations were lower, on average, by $4994. Conclusions Fast-track hospitalizations including a full workup proved to be feasible, showed no increased risk and were less expensive than long-term hospitalizations.

Serum neurofilaments are markers of axonal injury. We addressed their diagnostic and prognostic role in acute ischemic stroke (AIS) and transient ischemic attack (TIA).Nested within a prospective cohort study, we compared levels of serum neurofilament light chain (sNfL) drawn within 24 h from symptom onset in patients with AIS or TIA. Patients without magnetic resonance imaging on admission were excluded. We assessed whether sNfL was associated with: (i) clinical severity on admission, (ii) diagnosis of AIS vs. TIA, (iii) infarct size on admission magnetic resonance diffusion-weighted imaging (MR-DWI) and (iv) functional outcome at 3 months.We analyzed 504 patients with AIS and 111 patients with TIA. On admission, higher National Institutes of Health Stroke Scale (NIHSS) scores were associated with higher sNfL: NIHSS score7, 13.1 pg/mL [interquartile range (IQR), 5.3-27.8]; NIHSS score 7-15, 16.7 pg/mL (IQR, 7.4-34.9); and NIHSS score15, 21.0 pg/mL (IQR, 9.3-40.4) (P = 0.01). Compared with AIS, patients with TIA had lower sNfL levels [9.0 pg/mL (95% confidence interval, 4.0-19.0) vs. 16.0 pg/mL (95% confidence interval, 7.3-34.4), P0.001], also after adjusting for age and NIHSS score (P = 0.006). Among patients with AIS, infarct size on admission MR-DWI was not associated with sNfL, either in univariate analysis (P = 0.15) or after adjusting for age and NIHSS score on admission (P = 0.56). Functional outcome 3 months after stroke was not associated with sNfL after adjusting for established predictors.In conclusion, among patients admitted within 24 h of AIS or TIA onset, admission sNfL levels were associated with clinical severity on admission and TIA diagnosis, but not with infarct size on MR-DWI acquired on admission or functional outcome at 3 months.

Background: Data on endovascular therapy (EVT) in patients with stroke attributable to CeAD is scarce. We performed a systematic review and meta-analysis of all studies comparing EVT to intravenous thrombolysis (IVT) in CeAD-patients and compared EVT to IVT with regard to 3-month outcome and complications. Additionally, we included data of IVT-/EVT-treated CeAD-patients from a Swiss multicenter IVT-/EVT registry based cohort study. Methods: We systematically searched the pubmed® database to identify all existing studies comparing IVT to EVT in CeAD-patients. Studies were eligible if IVT-treated CeAD- patients were compared to EVT-treated patients, and 3-month outcomes were reported as modified Rankin Scale (mRS) score. Outcome measures in this study were favorable 3-month outcome (i.e. mRS 0-2), excellent 3-month outcome (i.e. mRS 0-1), symptomatic intracranial hemorrhage (sICH) and death. Additionally, in a Swiss multicenter IVT-/EVT registry based cohort-study (SWISS) we identified all consecutive patients with ischemic stroke attributable to CeAD and included outcome data of these patients in our analyses. In a meta-analysis across all studies, we compared EVT to IVT with regard to primary and secondary outcome measures using a fixed-effect Mantel-Haenszel model. Results: The literature search yielded 388 results. We identified 7 eligible studies for a systematic comparison of EVT versus IVT. Data on 62 patients from the SWISS cohort were included as an additional study. In total, we compared EVT (n=102) versus IVT (n=110) in 212 CeAD-patients. With regard to the occurrence of mRS 0-2, there was no significant difference between both treatment groups (OR 1.04 (95% CI 0.57-1.88)). Separate Data on mRS 0-1 was available in 5 studies (OR 0.88 (95% CI 0.39-2.00)). There was no difference between groups with regard to death at 3 months (OR 0.66 (0.22-1.94)) which was separately reported in 6 studies. For sICH there were too few data (n=5 patients) available for meta-analysis. Conclusion: In this systematic review and meta-analysis of all existing studies comparing EVT to IVT in CeAD patients there was no clear signal of superiority of EVT. Further investigation of EVT with up-to-date devices is warranted.

Background and Purpose Neurofilament light chain (NfL) is a blood marker for neuroaxonal damage. We assessed the association between serum NfL and cerebral small vessel disease (SVD), which is highly prevalent in elderly individuals and a major cause of stroke and vascular cognitive impairment Methods Using a cross-sectional design, we studied 53 and 439 patients with genetically defined SVD (Cerebral Autosomal-Dominant Arteriopathy with Subcortica I Infarcts and Leukoencephalopathy [CADASIL]) and sporadic SVD, respectively, as well as 93 healthy controls. Serum NfL was measured by an ultrasensitive single-molecule array assay. We quantified magnetic resonance imaging (MRI) markers of SVD, i.e., white matter hyperintensity volume, lacune volume, brain volume, microbleed count, and mean diffusivity obtained from diffusion tensor imaging. Clinical characterization included neuropsychological testing in both SVD samples. CADASIL patients were further characterized for focal neurological deficits (National Institutes of Health stroke scale [NIHSS]) and disability (modified Rankin scale [mRS]). Results Serum NfL levels were elevated in both SVD samples (P

Introduction In patients with stroke attributable to cervical artery dissection, we compared endovascular therapy to intravenous thrombolysis regarding three-month outcome, recanalisation and complications. Materials and methods In a multicentre intravenous thrombolysis/endovascular therapy-register-based cohort study, all consecutive cervical artery dissection patients with intracranial artery occlusion treated within 6 h were eligible for analysis. Endovascular therapy patients (with or without prior intravenous thrombolysis) were compared to intravenous thrombolysis patients regarding (i) excellent three-month outcome (modified Rankin Scale score 0–1), (ii) symptomatic intracranial haemorrhage, (iii) recanalisation of the occluded intracranial artery and (iv) death. Upon a systematic literature review, we performed a meta-analysis comparing endovascular therapy to intravenous thrombolysis in cervical artery dissection patients regarding three-month outcome using a random-effects Mantel–Haenszel model. Results Among 62 cervical artery dissection patients (median age 48.8 years), 24 received intravenous thrombolysis and 38 received endovascular therapy. Excellent three-month outcome occurred in 23.7% endovascular therapy and 20.8% with intravenous thrombolysis patients. Symptomatic intracranial haemorrhage occurred solely among endovascular therapy patients (5/38 patients, 13.2%) while four (80%) of these patients had bridging therapy; 6/38 endovascular therapy and 0/24 intravenous thrombolysis patients died. Four of these 6 endovascular therapy patients had bridging therapy. Recanalisation was achieved in 84.2% endovascular therapy patients and 66.7% intravenous thrombolysis patients (odds ratio 3.2, 95% confidence interval [0.9–11.38]). Sensitivity analyses in a subgroup treated within 4.5 h revealed a higher recanalisation rate among endovascular therapy patients (odds ratio 3.87, 95% confidence interval [1.00–14.95]), but no change in the key clinical findings. In a meta-analysis across eight studies (n = 212 patients), cervical artery dissection patients (110 intravenous thrombolysis and 102 endovascular therapy) showed identical odds for favourable outcome (odds ratio 0.97, 95% confidence interval [0.38–2.44]) among endovascular therapy patients and intravenous thrombolysis patients. Discussion and Conclusion In this cohort study, there was no clear signal of superiority of endovascular therapy over intravenous thrombolysis in cervical artery dissection patients, which – given the limitation of our sample size – does not prove that endovascular therapy in these patients cannot be superior in future studies. The observation that symptomatic intracranial haemorrhage and deaths in the endovascular therapy group occurred predominantly in bridging patients requires further investigation.

ObjectiveTo study the effect of platelet count (PC) on bleeding risk and outcome in stroke patients treated with IV thrombolysis (IVT) and to explore whether withholding IVT in PC < 100 × 109/L is supported.MethodsIn this prospective multicenter, IVT register–based study, we compared PC with symptomatic intracranial hemorrhage (sICH; Second European-Australasian Acute Stroke Study [ECASS II] criteria), poor outcome (modified Rankin Scale score 3–6), and mortality at 3 months. PC was used as a continuous and categorical variable distinguishing thrombocytopenia (9/L), thrombocytosis (>450 × 109/L), and normal PC (150–450 × 109/L [reference group]). Moreover, PC < 100 × 109/L was compared to PC ≥ 100 × 109/L. Unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) from the logistic regression models were calculated.ResultsAmong 7,533 IVT-treated stroke patients, 6,830 (90.7%) had normal PC, 595 (7.9%) had thrombocytopenia, and 108 (1.4%) had thrombocytosis. Decreasing PC (every 10 × 109/L) was associated with increasing risk of sICH (ORadjusted 1.03, 95% CI 1.02–1.05) but decreasing risk of poor outcome (ORadjusted 0.99, 95% CI 0.98–0.99) and mortality (ORadjusted 0.98, 95% CI 0.98–0.99). The risk of sICH was higher in patients with thrombocytopenic than in patients with normal PC (ORadjusted 1.73, 95% CI 1.24–2.43). However, the risk of poor outcome (ORadjusted 0.89, 95% CI 0.39–1.97) and mortality (ORadjusted 1.09, 95% CI 0.83–1.44) did not differ significantly. Thrombocytosis was associated with mortality (ORadjusted 2.02, 95% CI 1.21–3.37). Forty-four (0.3%) patients had PC < 100 × 109/L. Their risks of sICH (ORunadjusted 1.56, 95% CI 0.48–5.07), poor outcome (ORadjusted 1.63, 95% CI 0.82–3.24), and mortality (ORadjusted 1.38, 95% CI 0.64–2.98) did not differ significantly from those of patients with PC ≥ 100 × 109/L.ConclusionLower PC was associated with increased risk of sICH, while higher PC indicated increased mortality. Our data suggest that PC modifies outcome and complications in individual patients, while withholding IVT in all patients with PC < 100 × 109/L is challenged.

ABSTRACT Background: Right ventricular remodeling due to pulmonary stenosis increases morbidity in children. Its pathophysiology needs to be clarified. Methods: Six newborn lambs underwent pulmonary arterial banding, seven sham operation. mRNA encoding for cytokines, growth factors and regulators of apoptosis was sequentially measured in myocardium and blood before and up to 12 weeks postoperatively. Results: Experimental animals showed hypertrophy and fibrosis of the right ventricular myocardium, myocardial over-expression of CT-1-mRNA and higher blood concentrations of mRNA encoding for VEGF, TGF-β, Bak and BcL-xL than controls, respectively. Conclusion: Neonatal pulmonary stenosis leads to myocardial hypertrophy that is associated with CT-1 gene expression and with activation of growth- and apoptosis pathways in blood cells.

A ureteral stricture is a rather rare urological event defined as a narrowing of the ureter causing a functional obstruction and renal failure, if left untreated. The aim of this review article is to summarize and discuss current knowledge on the incidence, pathogenesis, management, and follow up of proximal, mid, and distal ureteral strictures.

Lymph node dissection in patients with prostate cancer may increase complications. An association of lymph node dissection with thromboembolic events was suggested. We compared the incidence and investigated predictors of deep venous thrombosis and pulmonary embolism among other complications in patients who did or did not undergo lymph node dissection during open and robot-assisted laparoscopic radical prostatectomy.Included in study were 3,544 patients between 2008 and 2011. The cohort was derived from LAPPRO, a multicenter, prospective, controlled trial. Data on adverse events were extracted from patient completed questionnaires. Our primary study outcome was the prevalence of deep venous thrombosis and/or pulmonary embolism. Secondary outcomes were other types of 90-day adverse events and causes of hospital readmission.Lymph node dissection was performed in 547 patients (15.4%). It was associated with eightfold and sixfold greater risk of deep venous thrombosis and pulmonary embolism events compared to that in patients without lymph node dissection (RR 7.80, 95% CI 3.51-17.32 and 6.29, 95% CI 2.11-18.73, respectively). Factors predictive of thromboembolic events included a history of thrombosis, pT4 stage and Gleason score 8 or greater. Open radical prostatectomy and lymph node dissection carried a higher risk of deep venous thrombosis and/or pulmonary embolism than robot-assisted laparoscopic radical prostatectomy (RR 12.67, 95% CI 5.05-31.77 vs 7.52, 95% CI 2.84-19.88). In patients without lymph node dissection open radical prostatectomy increased the thromboembolic risk 3.8-fold (95% CI 1.42-9.99) compared to robot-assisted laparoscopic radical prostatectomy. Lymph node dissection induced more wound, respiratory, cardiovascular and neuromusculoskeletal events. It also caused more readmissions than no lymph node dissection (14.6% vs 6.3%).Among other adverse events we found that lymph node dissection during radical prostatectomy increased the incidence of deep venous thrombosis and pulmonary embolism. Open surgery increased the risks more than robot-assisted surgery. This was most prominent in patients who were not treated with lymph node dissection.

Background— We explored the safety of intravenous thrombolysis (IVT) or intra-arterial treatment (IAT) in patients with ischemic stroke on non-vitamin K antagonist oral anticoagulants (NOACs, last intake Methods and Results— This is a multicenter cohort pilot study. Primary outcome measures were (1) occurrence of intracranial hemorrhage (ICH) in 3 categories: any ICH (ICH any ), symptomatic ICH according to the criteria of the European Cooperative Acute Stroke Study II (ECASS-II) (sICH ECASS-II ) and the National Institute of Neurological Disorders and Stroke (NINDS) thrombolysis trial (sICH NINDS ); and (2) death (at 3 months). Cohorts were compared by using propensity score matching. Our NOAC cohort comprised 78 patients treated with IVT/IAT and the comparison groups of 441 VKA patients and 8938 no-OAC patients. The median time from last NOAC intake to IVT/IAT was 13 hours (interquartile range, 8–22 hours). In VKA patients, median pre-IVT/IAT international normalized ratio was 1.3 (interquartile range, 1.1–1.6). ICH any was observed in 18.4% NOAC patients versus 26.8% in VKA patients and 17.4% in no-OAC patients. sICH ECASS-II and sICH NINDS occurred in 2.6%/3.9% NOAC patients, in comparison with 6.5%/9.3% of VKA patients and 5.0%/7.2% of no-OAC patients, respectively. At 3 months, 23.0% of NOAC patients in comparison with 26.9% of VKA patients and 13.9% of no-OAC patients had died. Propensity score matching revealed no statistically significant differences. Conclusions— IVT/IAT in selected patients with ischemic stroke under NOAC treatment has a safety profile similar to both IVT/IAT in patients on subtherapeutic VKA treatment or in those without previous anticoagulation. However, further prospective studies are needed, including the impact of specific coagulation tests.

Background: Serum neurofilament light chain (sNfL) levels represent a promising marker of neuroaxonal injury. They are elevated in several neurological conditions, but their importance in cerebrovascular diseases remains unclear. In a proof of concept study, we compared sNfL levels with clinical characteristics and outcome in patients with cervical artery dissection (CeAD). Methods: A total of 49 non-traumatic CeAD patients were included. sNfL levels were measured by high-sensitivity electrochemiluminescence immunoassay. Levels were compared with regard to (i) type of presenting symptoms (local symptoms only (n = 8), transient ischemic attack (TIA; n = 10) or ischemic stroke (n = 31)), (ii) stroke severity quantified by National Institute of Health Stroke Scale (NIHSS), (iii) time interval between onset of symptoms and blood sampling and (iv) 3-month outcome as measured by the modified Rankin Scale score. Analyses were performed using univariate and multivariate linear and ordinal regression models. Results: CeAD patients presenting with stroke had significantly higher sNfL levels (median 108.9 pg/ml, interquartile range (37.8-427.7)) than patients with TIA (16.4 pg/ml (8.7-36.3), p = 0.002) or local symptoms (23.4 pg/ml (17.8-30.8), p = 0.0007). Among stroke patients, sNfL levels were positively associated with both NIHSS (p = 0.0002) and time between stroke onset and serum sampling (p = 1.9 × 10-6). Higher sNfL levels were associated with unfavorable outcome at 3 months (OR 4.67, 95% CI 1.69-12.95, p = 0.003). However, this association lost significance after adjustment for NIHSS. The highest sNfL level was observed in a TIA patient who had ischemic stroke 1 day after serum sampling for sNfL measurement. Conclusion: sNfL levels were increased in CeAD patients presenting with stroke, correlated with clinical severity and were influenced by the time point of blood sampling. The prognostic meaning of sNfL in CeAD deserves further testing.

To test the predictability of miserable outcome amongst ischaemic stroke patients receiving intravenous thrombolysis (IVT) based on a simple variables model (SVM) and to compare the model's predictive performance with that of an existing score which includes imaging and laboratory parameters (DRAGON).; The SVM consists of the parameters age, independence before stroke, normal Glasgow coma verbal score, able to lift arms and able to walk. In a derivation cohort (n = 1346) and a validation cohort (n = 638) of consecutive IVT-treated stroke patients, the probability estimated by SVM and the observed occurrence of miserable 3-month outcome (modified Rankin score 5-6) were compared. The performances of SVM and the DRAGON score were compared. The area under the receiver operating curve (AUC) (95% confidence interval, CI) and the bootstrapping approach were used to compare the predictive performance.; The AUCs to predict miserable outcome in the derivation cohort were 0.807 (95% CI 0.774-0.838) using the SVM and 0.822 (0.790-0.850) using the DRAGON score (P = 0.3). For the validation cohort, AUCs were 0.786 (0.742-0.829) for the SVM and 0.809 (0.774-0.845) for the DRAGON score (P = 0.23). Only one patient with an SVM probability of

Data on long-term outcome after IV thrombolysis (IVT) are sparse. Our goals were to 1) estimate annual survival, and 2) evaluate determinants for an unfavorable long-term outcome after IVT for stroke.This observational study is based on the IVT registry of the University Hospital Basel. A structured telephone interview was used to ascertain information about long-term outcome (1 year to 10 years after IVT). Primary outcome parameters were 1) death and 2) excellent outcome (modified Rankin Scale scores 0 and 1). Kaplan-Meier survival estimates were calculated. Uni- and multivariate logistic regression analyses were performed to identify variables independently determining long-term outcome.Two hundred fifty-seven IVT-treated stroke patients were eligible for analysis. Median time of follow-up was 3.0 years (interquartile range 1.0-5.0). Probability of surviving after IVT was 76% after 1 year, 66% after 3 years, and 53% after 4 years. After a median of 3 years, 37% of patients had an excellent outcome. Independent predictors for unfavorable long-term outcome were advanced age (odds ratio [OR] 1.030, 95% confidence interval [CI] 1.002-1.060, p = 0.036), higher stroke severity (OR 1.100, 95% CI 1.012-1.196, p = 0.026), unfavorable 3-month outcome (OR 6.767, 95% CI 3.391-13.503, p0.001), and occurrence of epileptic seizures (OR 4.899, 95% CI 1.349-17.793, p = 0.016). Intracranial hemorrhage, comorbidity, sex, initial glucose or C-reactive protein levels, and stroke etiology did not independently influence long-term outcome.At 3 years after IVT, approximately 1 of 3 stroke patients had an excellent outcome, and 1 of 3 had died. Epileptic seizures seem to have an unfavorable effect on long-term outcome via a mechanism that remains to be clarified.

A clinical impact of cognitive reserve (CR) has been demonstrated in Alzheimer's disease, whereas its role in vascular cognitive impairment (VCI) is largely unknown. In this study, we investigated the impact of CR in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic variant of pure VCI. A total of 247 NOTCH3 mutation carriers from a two-center study were investigated using detailed neuropsychological and neuroimaging protocols. CR was operationalized as years of formal education. Brain pathology was assessed by MRI using normalized brain volume and lacunar lesion volume as proxies. Multivariate analyses were done for each structural measure with scores of processing speed, executive function, and memory as dependent variables. Additional linear regression models were conducted with interaction terms for education × brain volume and education × lacunar lesion volume. Education had an independent impact on cognitive performance in subjects with mild and moderate degrees of brain pathology, whereas there was no significant influence of education on cognition in patients with severe MRI changes. This interaction was found for processing speed, the cognitive domain most impaired in our patients. Our findings demonstrate an interaction of education and brain pathology in regard to cognitive impairment: the effect of education seems most pronounced in early disease stages but may ultimately be overwhelmed by the pathological changes. The results extend the concept of CR to VCI.

Background/Aims: Cerebral small vessel disease (SVD) is characterized by periventricular white matter (WM) changes and can lead to vascular dementia, the second most common form of age-dependent dementia. The pathogenesis of the disease remains poorly understood, and studies of its molecular basis are limited. By profiling gene expression of dissected postmortem brain tissue in SVD patients and comparisons with tissue of nonneurological controls, we aimed to identify genes and processes that are involved in the pathogenesis of SVD to gain new pathogenetic insights. Methods: We performed genome-wide expression analyses in postmortem brain tissue samples dissected from frontal, temporal, and occipital lobes as well as basal nuclei comprising thalamus, basal ganglia, and hippocampus from 5 SVD cases and 5 nonaffected control cases. Cellular pathways associated with differently expressed genes were identified in each brain region individually. Results: This analysis disclosed regional differences, with frontal lobe and thalamus showing the highest numbers of genes with significantly altered expression. Biological functions and pathways associated with changed gene expression depicted brain area-specific defective pathways. Vessel-associated functions, such as increased extracellular matrix-receptor interactions and cell adhesion molecules, were enhanced in all regions. Inflammation and apoptosis were induced particularly in basal nuclei and temporal and occipital regions. Interestingly, genes associated with the ubiquitin-dependent proteolysis (ubiquitin proteasome system) pathway were downregulated in the frontal lobe and in the thalamus, leading to the formation of protein aggregates. Conclusion: This analysis deciphers brain region-specific molecular processes to increase the present knowledge of SVD pathology and determine new potential therapeutic targets.