Intravenous thrombolysis in patients with recent intake of direct oral anticoagulants: A target trial analysis after the liberalization of institutional guidelines.

INTRODUCTION: This study aimed to report the safety and efficacy of off-label intravenous thrombolysis (IVT) with alteplase after sequentially liberalizing our institutional guidelines allowing IVT for patients under direct oral anticoagulants (DOACs) regardless of plasma levels, time of last intake, and without prior anticoagulation reversal therapy. PATIENTS AND METHODS: We utilized the target-trial methodology to emulate hypothetical criteria of a randomized controlled trial in our prospective stroke registry. Consecutive DOAC patients (06/2021-11/2023) otherwise qualifying for IVT were included. Safety and efficacy outcomes (symptomatic intracranial hemorrhage [ICH], any radiological ICH, major bleeding, 90-day mortality, 90-day good functional outcome [mRS 0-2 or return to baseline]) were assessed using inverse-probability-weighted regression-adjustment comparing patients with versus without IVT. RESULTS: Ninety eight patients fulfilled the target-trial criteria. IVT was given in 49/98 (50%) patients at a median of 178 (interquartile range 134-285) min after symptom onset with median DOAC plasma level of 77 ng/ml (15 patients had plasma levels > 100 ng/ml; 25/49 [51%] were treated within 12 h after last DOAC ingestion). Endovascular therapy was more frequent in patients without IVT (73% vs 33%). Symptomatic ICH occurred in 0/49 patients receiving IVT and 2/49 patients without IVT (adjusted difference -2.5%; 95% CI -5.9 to 0.8). The rates of any radiological ICH were comparable. Patients receiving IVT were more likely to have good functional outcomes. DISCUSSION AND CONCLUSION: After liberalizing our approach for IVT regardless of recent DOAC intake, we did not experience any safety concerns. The association of IVT with better functional outcomes warrants prospective randomized controlled trials.

Baseline characteristics and outcome of stroke patients after endovascular therapy according to previous symptomatic vascular disease and sex.

Aim: The aim of this study was to investigate baseline characteristics and outcome of patients after endovascular therapy (EVT) for acute large vessel occlusion (LVO) in relation to their history of symptomatic vascular disease and sex. Methods: Consecutive EVT-eligible patients with LVO in the anterior circulation admitted to our stroke center between 04/2015 and 04/2020 were included in this observational cohort study. All patients were treated according to a standardized acute ischaemic stroke (AIS) protocol. Baseline characteristics and successful reperfusion, recurrent/progressive in-hospital ischaemic stroke, symptomatic in-hospital intracranial hemorrhage, death at discharge and at 3 months, and functional outcome at 3 months were analyzed according to previous symptomatic vascular disease and sex. Results: 995 patients with LVO in the anterior circulation (49.4% women, median age 76 years, median admission NIHSS score 14) were included. Patients with multiple vs. no previous vascular events showed higher mortality at discharge (20% vs. 9.3%, age/sex - adjustedOR = 1.43, p = 0.030) and less independency at 3 months (28.8% vs. 48.8%, age/sex - adjustedOR = 0.72, p = 0.020). All patients and men alone with one or multiple vs. patients and men with no previous vascular events showed more recurrent/progressive in-hospital ischaemic strokes (19.9% vs. 6.4% in all patients, age/sex - adjustedOR = 1.76, p = 0.028) (16.7% vs. 5.8% in men, age-adjustedOR = 2.20, p = 0.035). Men vs. women showed more in-hospital symptomatic intracranial hemorrhage among patients with one or multiple vs. no previous vascular events (23.7% vs. 6.6% in men and 15.4% vs. 5.5% in women, OR = 2.32, p = 0.035/age - adjustedOR = 2.36, p = 0.035). Conclusions: Previous vascular events increased the risk of in-hospital complications and poorer outcome in the analyzed patients with EVT-eligible LVO-AIS. Our findings may support risk assessment in these stroke patients and could contribute to the design of future studies.

Early Versus Late Initiation of Direct Oral Anticoagulants After Ischemic Stroke in People With Atrial Fibrillation and Hemorrhagic Transformation: Prespecified Subanalysis of the Randomized-controlled ELAN Trial.

BACKGROUND: Whether hemorrhagic transformation (HT) modifies the treatment effect of early versus late initiation of direct oral anticoagulation (DOAC) in people with ischemic stroke and atrial fibrillation is unknown. METHODS: This is a post-hoc analysis of the ELAN trial. The primary outcome was a composite of recurrent ischemic stroke, symptomatic intracranial hemorrhage (sICH), major extracranial bleeding, systemic embolism, or vascular death within 30 days. Secondary outcomes were the individual components, 30- and 90-day functional outcome. We estimated outcomes based on HT, subclassified as hemorrhagic infarction (HI) or parenchymal hemorrhage (PH) on pre-randomization imaging (core-lab rating) using adjusted risk differences (aRD) between treatment arms. RESULTS: Overall, 247/1970 (12.5%) participants had HT (114 HI 1, 77 HI 2, 34 PH 1, 22 PH 2). For the primary outcome, the estimated aRD (early versus late) was -2.2% (-7.8 to 3.5%) in people with HT (HI: -4.7%, -10.8 to 1.4%; PH: 6.1%, -8.4 to 20.7%), and -0.9% (-2.6 to 0.8%) in people without. Numbers of sICH were identical in people with and without HT. With early treatment, the estimated aRD for poor 90-day functional outcome (mRS 3-6) was 11.4% (-0.9 to 23.7%) in participants with HT (HI: 7.2%, -6.6 to 21.0%; PH: 25.1%, 0.2 to 50.0%), and -2.6% (-7.1 to 1.8%) in people without HT. CONCLUSIONS: We found no evidence of major treatment effect heterogeneity or safety concerns with early versus late DOAC initiation in people with and without HT. However, early DOAC initiation may worsen functional outcomes in people with PH.

Intracerebral haemorrhage in patients taking different types of oral anticoagulants: a pooled individual patient data analysis from two national stroke registries.

BACKGROUND: We investigated outcomes in patients with intracerebral haemorrhage (ICH) according to prior anticoagulation treatment with Vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) or no anticoagulation. METHODS: This is an individual patient data study combining two prospective national stroke registries from Switzerland and Norway (2013-2019). We included all consecutive patients with ICH from both registries. The main outcomes were favourable functional outcome (modified Rankin Scale 0-2) and mortality at 3 months. RESULTS: Among 11 349 patients with ICH (mean age 73.6 years; 47.6% women), 1491 (13.1%) were taking VKAs and 1205 (10.6%) DOACs (95.2% factor Xa inhibitors). The median percentage of patients on prior anticoagulation was 23.7 (IQR 22.6-25.1) with VKAs decreasing (from 18.3% to 7.6%) and DOACs increasing (from 3.0% to 18.0%) over time. Prior VKA therapy (n=209 (22.3%); adjusted ORs (aOR), 0.64; 95% CI, 0.49 to 0.84) and prior DOAC therapy (n=184 (25.7%); aOR, 0.64; 95% CI, 0.47 to 0.87) were independently associated with lower odds of favourable outcome compared with patients without anticoagulation (n=2037 (38.8%)). Prior VKA therapy (n=720 (49.4%); aOR, 1.71; 95% CI, 1.41 to 2.08) and prior DOAC therapy (n=460 (39.7%); aOR, 1.28; 95% CI, 1.02 to 1.60) were independently associated with higher odds of mortality compared with patients without anticoagulation (n=2512 (30.2%)). CONCLUSIONS: The spectrum of anticoagulation-associated ICH changed over time. Compared with patients without prior anticoagulation, prior VKA treatment and prior DOAC treatment were independently associated with lower odds of favourable outcome and higher odds of mortality at 3 months. Specific reversal agents unavailable during the study period might improve outcomes of DOAC-associated ICH in the future.

Time for "code ICH"? - Workflow metrics of hyperacute treatments and outcome in patients with intracerebral haemorrhage.

INTRODUCTION: Knowledge about uptake and workflow metrics of hyperacute treatments in patients with non-traumatic intracerebral haemorrhage (ICH) in the emergency department are scarce. METHODS: Single centre retrospective study of consecutive patients with ICH between 01/2018-08/2020. We assessed uptake and workflow metrics of acute therapies overall and according to referral mode (stroke code, transfer from other hospital or other). RESULTS: We enrolled 332 patients (age 73years, IQR 63-81 and GCS 14 points, IQR 11-15, onset-to-admission-time 284 minutes, IQR 111-708minutes) of whom 101 patients (35%) had lobar haematoma. Mode of referral was stroke code in 129 patients (38%), transfer from other hospital in 143 patients (43%) and arrival by other means in 60 patients (18%). Overall, 143 of 216 (66%) patients with systolic blood pressure >150mmHG received IV antihypertensive and 67 of 76 (88%) on therapeutic oral anticoagulation received prothrombin complex concentrate treatment (PCC). Forty-six patients (14%) received any neurosurgical intervention within 3 hours of admission. Median treatment times from admission to first IV-antihypertensive treatment was 38 minutes (IQR 18-72minutes) and 59 minutes (IQR 37-111 minutes) for PCC, with significant differences according to mode of referral (p<0.001) but not early arrival (≤6hours of onset, p=0.92). The median time in the emergency department was 139 minutes (IQR 85-220 minutes) and among patients with elevated blood pressure, only 44% achieved a successful control (<140mmHG) during ED stay. In multivariate analysis, code ICH concordant treatment was associated with significantly lower odds for in-hopsital mortality (aOR 0.30, 95%CI 0.12-0.73, p=0.008) and a non-significant trends towards better functional outcome measured using the modified Rankin scale score at 3 months (aOR for ordinal shift 0.54 95%CI 0.26-1.12, p=0.097). CONCLUSION: Uptake of hyperacute therapies for ICH treatment in the ED is heterogeneous. Treatment delays are short but not all patients achieve treatment targets during ED stay. Code ICH concordant treatment may improve clinical outcomes. Further improvements seem achievable advocating for a "code ICH" to streamline acute treatments.

Andexanet alfa versus non-specific treatments for intracerebral hemorrhage in patients taking factor Xa inhibitors - Individual patient data analysis of ANNEXA-4 and TICH-NOAC.

BACKGROUND: Data comparing the specific reversal agent andexanet alfa with non-specific treatments in patients with non-traumatic intracerebral hemorrhage (ICH) associated with factor-Xa inhibitor (FXaI) use are scarce. AIM: The study aimed to determine the association between the use of andexanet alfa compared with non-specific treatments with the rate of hematoma expansion and thromboembolic complications in patients with FXaI-associated ICH. METHODS: We performed an individual patient data analysis combining two independent, prospective studies: ANNEXA-4 (180 patients receiving andexanet alfa, NCT02329327) and TICH-NOAC (63 patients receiving tranexamic acid or placebo ± prothrombin complex concentrate, NCT02866838). The primary efficacy outcome was hematoma expansion on follow-up imaging. The primary safety outcome was any thromboembolic complication (ischemic stroke, myocardial infarction, pulmonary embolism, or deep vein thrombosis) at 30 days. We used binary logistic regression models adjusted for baseline hematoma volume, age, calibrated anti-Xa activity, times from last intake of FXaI, and symptom onset to treatment, respectively. RESULTS: Among 243 participants included, the median age was 80 (IQR 75-84) years, baseline hematoma volume was 9.1 (IQR 3.4-21) mL and anti-Xa activity 118 (IQR 78-222) ng/mL. Times from last FXaI intake and symptom onset to treatment were 11 (IQR 7-16) and 4.7 (IQR 3.0-7.6) h, respectively. Overall, 50 patients (22%) experienced hematoma expansion (ANNEXA-4: n=24 (14%); TICH-NOAC: n=26 (41%)). After adjusting for pre-specified confounders (baseline hematoma volume, age, calibrated anti-Xa activity, times from last intake of FXaI, and symptom onset to treatment, respectively), treatment with andexanet alfa was independently associated with decreased odds for hematoma expansion (aOR 0.33, 95% CI 0.13-0.80, p = 0.015). Overall, 26 patients (11%) had any thromboembolic complication within 30 days (ANNEXA-4: n=20 (11%); TICH-NOAC: n=6 (10%)). There was no association between any thromboembolic complication and treatment with andexanet alfa (aOR 0.70, 95% CI 0.16-3.12, p = 0.641). CONCLUSION: The use of andexanet alfa compared to any other non-specific treatment strategy was associated with decreased odds for hematoma expansion, without increased odds for thromboembolic complications.

CADMUS: A Novel MRI-Based Classification of Spontaneous Intracerebral Hemorrhage Associated With Cerebral Small Vessel Disease

BACKGROUND AND OBJECTIVES: Cerebral small vessel disease (SVD) is the major cause of intracerebral hemorrhage (ICH). There is no comprehensive, easily applicable classification of ICH subtypes according to the presumed underlying SVD using MRI. We developed an MRI-based classification for SVD-related ICH. METHODS: We performed a retrospective study in the prospectively collected Swiss Stroke Registry (SSR, 2013-2019) and the Stroke InvestiGation in North And central London (SIGNAL) cohort. Patients with nontraumatic, SVD-related ICH and available MRI within 3 months were classified as Cerebral Amyloid angiopathy (CAA), Deep perforator arteriopathy (DPA), Mixed CAA-DPA, or Undetermined SVD using hemorrhagic and nonhemorrhagic MRI markers (CADMUS classification). The primary outcome was inter-rater reliability using Gwet's AC1. Secondary outcomes were recurrent ICH/ischemic stroke at 3 months according to the CADMUS phenotype. We performed Firth penalized logistic regressions and competing risk analyses. RESULTS: The SSR cohort included 1,180 patients (median age [interquartile range] 73 [62-80] years, baseline NIH Stroke Scale 6 [2-12], 45.6% lobar hematoma, systolic blood pressure on admission 166 [145-185] mm Hg). The CADMUS phenotypes were as follows: mixed CAA-DPA (n = 751 patients, 63.6%), undetermined SVD (n = 203, 17.2%), CAA (n = 154, 13.1%), and DPA (n = 72, 6.3%), with a similar distribution in the SIGNAL cohort (n = 313). Inter-rater reliability was good (Gwet's AC1 for SSR/SIGNAL 0.69/0.74). During follow-up, 56 patients had 57 events (28 ICH, 29 ischemic strokes). Three-month event rates were comparable between the CADMUS phenotypes. DISCUSSION: CADMUS, a novel MRI-based classification for SVD-associated ICH, is feasible and reproducible and may improve the classification of ICH subtypes in clinical practice and research.

Clinical Associations and Prognostic Value of MRI-Visible Perivascular Spaces in Patients With Ischemic Stroke or TIA: A Pooled Analysis

BACKGROUND AND OBJECTIVES: Visible perivascular spaces are an MRI marker of cerebral small vessel disease and might predict future stroke. However, results from existing studies vary. We aimed to clarify this through a large collaborative multicenter analysis. METHODS: We pooled individual patient data from a consortium of prospective cohort studies. Participants had recent ischemic stroke or transient ischemic attack (TIA), underwent baseline MRI, and were followed up for ischemic stroke and symptomatic intracranial hemorrhage (ICH). Perivascular spaces in the basal ganglia (BGPVS) and perivascular spaces in the centrum semiovale (CSOPVS) were rated locally using a validated visual scale. We investigated clinical and radiologic associations cross-sectionally using multinomial logistic regression and prospective associations with ischemic stroke and ICH using Cox regression. RESULTS: We included 7,778 participants (mean age 70.6 years; 42.7% female) from 16 studies, followed up for a median of 1.44 years. Eighty ICH and 424 ischemic strokes occurred. BGPVS were associated with increasing age, hypertension, previous ischemic stroke, previous ICH, lacunes, cerebral microbleeds, and white matter hyperintensities. CSOPVS showed consistently weaker associations. Prospectively, after adjusting for potential confounders including cerebral microbleeds, increasing BGPVS burden was independently associated with future ischemic stroke (versus 0-10 BGPVS, 11-20 BGPVS: HR 1.19, 95% CI 0.93-1.53; 21+ BGPVS: HR 1.50, 95% CI 1.10-2.06; p = 0.040). Higher BGPVS burden was associated with increased ICH risk in univariable analysis, but not in adjusted analyses. CSOPVS were not significantly associated with either outcome. DISCUSSION: In patients with ischemic stroke or TIA, increasing BGPVS burden is associated with more severe cerebral small vessel disease and higher ischemic stroke risk. Neither BGPVS nor CSOPVS were independently associated with future ICH.

Geographical Requirements for the Applicability of the Results of the RACECAT Study to Other Stroke Networks.

Background The RACECAT (Transfer to the Closest Local Stroke Center vs Direct Transfer to Endovascular Stroke Center of Acute Stroke Patients With Suspected Large Vessel Occlusion in the Catalan Territory) trial was the first randomized trial addressing the prehospital triage of acute stroke patients based on the distribution of thrombolysis centers and intervention centers in Catalonia, Spain. The study compared the drip-and-ship with the mothership paradigm in regions where a local thrombolysis center can be reached faster than the nearest intervention center (equipoise region). The present study aims to determine the population-based applicability of the results of the RACECAT study to 4 stroke networks with a different degree of clustering of the intervention centers (clustered, dispersed). Methods and Results Stroke networks were compared with regard to transport time saved for thrombolysis (under the drip-and-ship approach) and transport time saved for endovascular therapy (under the mothership approach). Population-based transport times were modeled with a local instance of an openrouteservice server using open data from OpenStreetMap.The fraction of the population in the equipoise region differed substantially between clustered networks (Catalonia, 63.4%; France North, 87.7%) and dispersed networks (Southwest Bavaria, 40.1%; Switzerland, 40.0%). Transport time savings for thrombolysis under the drip-and-ship approach were more marked in clustered networks (Catalonia, 29 minutes; France North, 27 minutes) than in dispersed networks (Southwest Bavaria and Switzerland, both 18 minutes). Conclusions Infrastructure differences between stroke networks may hamper the applicability of the results of the RACECAT study to other stroke networks with a different distribution of intervention centers. Stroke networks should assess the population densities and hospital type/distribution in the temporal domain before applying prehospital triage algorithms to their specific setting.

Immunoliposomes for detection of rupture-prone intracranial aneurysms.

BACKGROUND: It is estimated that significant (3.2%) of population carries intracranial aneurysm (IA). An increasing number of imaging studies have caused that the chance of finding an incidental aneurysm is becoming more common. Since IA rupture causes subarachnoidal hemorrhage (SAH) and have significant mortality and morbidity prophylactic treatment should be considered when IA is detected. The benefit and risk of treatment of IA is based on epidemiological estimate which takes account patient and aneurysm characteristics. However we know that aneurysm rupture is biological process where inflammation of aneurysm wall is actively leading to degeneration of aneurysm wall and finally weakens it until it bursts. Until now, there have not been imaging method to detect inflammatory process of aneurysm wall METHODS: We created targeting immunoliposome for use in the imaging of aneurysm. Immunoliposome comprises antibodies against at least one vascular inflammatory marker associated with aneurysm inflammation and a label and/or a contrast agent. RESULTS: Histological analysis of IAs where immunoliposome comprises antibodies against vascular inflammation with a label shows promising results for selectively detecting aneurysms inflammation. In magnetic resonance imaging (MRI) we were able to detect immunoliposomes carrying gadolinium. CONCLUSION: Our work opens a new avenue for using contrast labeled immunoliposomes for detecting rupture-prone aneurysms. Immunoliposomes can cary gadolinium and selectively bind to inflammatory section of aneurysm that can be detected with MRI. Further research is needed to develop immunoliposomes to be used with MRI in humans to target treatment to those patients who benefit from it the most.

Small vessel disease burden and risk of recurrent cerebrovascular events in patients with lacunar stroke and intracerebral haemorrhage attributable to deep perforator arteriolopathy.

INTRODUCTION: Deep perforator arteriolopathy (DPA) causes intracerebral haemorrhage (ICH) and lacunar strokes (LS). We compare patient characteristics, MRI findings and clinical outcomes among patients with deep ICH and LS. PATIENTS AND METHODS: We included patients with MRI-confirmed LS or ICH in the basal ganglia, thalamus, internal capsule or brainstem from the Bernese Stroke Registry. We assessed MRI small vessel disease (SVD) markers, SVD burden score, modified Rankin Scale (mRS) and ischaemic stroke or ICH at 3 months. RESULTS: We included 716 patients, 117 patients (16.3%) with deep ICH (mean age (SD) 65.1 (±15.2) years, 37.1% female) and 599 patients (83.7%) with LS (mean age (SD) 69.7 (±13.6) years, 39.9% female). Compared to LS, deep ICH was associated with a higher SVD burden score (median (IQR) 2 (1-2) vs 1 (0-2)), aORshift 3.19, 95%CI 2.15-4.75). Deep ICH patients had more often cerebral microbleeds (deep ICH: 71.6% vs LS: 29.2%, p < 0.001, median count (IQR) 4(2-12) vs 2(1-6)) and a higher prevalence of lacunes (deep ICH: 60.5% vs LS: 27.4% p < 0.001). At 3 months, deep ICH was associated with higher mRS (aORshift 2.16, 95%CI 1.21-3.87). Occurrence of ischaemic stroke was numerically but not significantly higher in deep ICH (4.3% vs 2.9%; p = 0.51). One patient (1.1%) with ICH but none with LS suffered ICH recurrence. DISCUSSION/CONCLUSION: DPA manifesting as ICH is associated with more severe MRI SVD burden and worse outcome compared to LS. The short-term risks of subsequent ischaemic stroke and recurrent ICH are similar in ICH and LS patients. This implies potential consequences for future secondary prevention strategies.

Prognostic benefits of early vascular surgical intervention in patients with major peripheral vascular complications following transcatheter aortic valve implantation.

OBJECTIVES: This study aimed to analyze the incidence, surgical management of major vascular complications, and outcomes in patients undergoing transfemoral (TF) transcatheter aortic valve replacement (TAVR) at our center after strict selection of the access route, carefully considering all known major predictors. METHODS: Data of 494 consecutive patients with pre-interventional multi-slice computed tomography (CT) of the aorta who had undergone TF TAVR from 2009 to 2019 were analyzed. RESULTS: In total, 23/494 (4.7%) patients had major vascular and access-related complications of peripheral vessels and/or infrarenal aorta. These included hematomas that met the Valve Academic Research Consortium 3-criteria of major vascular complications (7/494, 1.4%), arterial dissections (3/494, 0.6%), pseudoaneurysm (6/494, 1.2%), thrombus of the external iliac artery leading to acute limb ischemia (1/494, 0.2%), fistula (1/494, 0.2%), and perforation (5/494, 1.0%). In total, 17/23 (73.9%) major vascular complications required immediate endovascular and/or open surgery. In 16/17 (94%) cases, only 1 surgical procedure was performed. The long-term survival of patients with and without major vascular complications of the peripheral vessels was determined after 2 years. CONCLUSIONS: Early vascular surgery intervention reversed the mortality disadvantage in patients with major complications of the peripheral vessels after TAVR. This underscores the importance of immediate vascular surgery stand-by as an indispensable requirement.

Lipoprotein(a) induces caspase-1 activation and IL-1 signaling in human macrophages.

Introduction: Lipoprotein(a) (Lp(a)) is an LDL-like particle with an additional apolipoprotein (apo)(a) covalently attached. Elevated levels of circulating Lp(a) are a risk factor for atherosclerosis. A proinflammatory role for Lp(a) has been proposed, but its molecular details are incompletely defined. Methods and results: To explore the effect of Lp(a) on human macrophages we performed RNA sequencing on THP-1 macrophages treated with Lp(a) or recombinant apo(a), which showed that especially Lp(a) induces potent inflammatory responses. Thus, we stimulated THP-1 macrophages with serum containing various Lp(a) levels to investigate their correlations with cytokines highlighted by the RNAseq, showing significant correlations with caspase-1 activity and secretion of IL-1ß and IL-18. We further isolated both Lp(a) and LDL particles from three donors and then compared their atheroinflammatory potentials together with recombinant apo(a) in primary and THP-1 derived macrophages. Compared with LDL, Lp(a) induced a robust and dose-dependent caspase-1 activation and release of IL-1ß and IL-18 in both macrophage types. Recombinant apo(a) strongly induced caspase-1 activation and IL-1ß release in THP-1 macrophages but yielded weak responses in primary macrophages. Structural analysis of these particles revealed that the Lp(a) proteome was enriched in proteins associated with complement activation and coagulation, and its lipidome was relatively deficient in polyunsaturated fatty acids and had a high n-6/n-3 ratio promoting inflammation. Discussion: Our data show that Lp(a) particles induce the expression of inflammatory genes, and Lp(a) and to a lesser extent apo(a) induce caspase-1 activation and IL-1 signaling. Major differences in the molecular profiles between Lp(a) and LDL contribute to Lp(a) being more atheroinflammatory.

Connecting Women in Neurosciences: A networking project to sustain mutual empowerment in young, female clinical neuroscientists.

Simultaneously acquiring broad clinical knowledge and scientific expertise is a major challenge for young clinical scientists. Female researchers may face additional hurdles in their career, for example, due to unconscious bias. We aimed to address clinical, research, and gender-related challenges among young female clinical neuroscientists. We implemented a peer-led networking group dedicated to increasing clinical and scientific knowledge, improve soft skills, and encourage exchange between fellow residents. In monthly meetings, two participants hold short presentations on a clinical topic or scientific method, followed by a discussion and feedback to the presenter. Afterwards, participants network and discuss challenges they face in their daily experience. Nine neurology residents at a Swiss University Hospital with ≤3 years of training participated in the Connecting Women in Neurosciences project from August 2020 to June 2021. In a qualitative evaluation, participants reported they felt empowered by these meetings and profited from their new network. We identified several challenges in combining clinical and research activities, some of which participants perceived to be gender-related. In addition to women-only meetings, we will promote events addressing all interested researchers. Peer-to-peer networking is an easy and low-budget intervention to encourage female residents to engage in research activities, profit from each other's expertise, and promote interdisciplinary teamwork. It can provide a protected environment to discuss and overcome in particular gender-related challenges. We encourage young colleagues to regularly engage in structured networking activities with their local peers.

Genetic Mapping of Seven Kinds of Locus for Resistance to Asian Soybean Rust.

Asian soybean rust (ASR), caused by Phakopsora pachyrhizi, is one of the most serious soybean (Glycine max) diseases in tropical and subtropical regions. To facilitate the development of resistant varieties using gene pyramiding, DNA markers closely linked to seven resistance genes, namely, Rpp1, Rpp1-b, Rpp2, Rpp3, Rpp4, Rpp5, and Rpp6, were identified. Linkage analysis of resistance-related traits and marker genotypes using 13 segregating populations of ASR resistance, including eight previously published by our group and five newly developed populations, identified the resistance loci with markers at intervals of less than 2.0 cM for all seven resistance genes. Inoculation was conducted of the same population with two P. pachyrhizi isolates of different virulence, and two resistant varieties, 'Kinoshita' and 'Shiranui,' previously thought to only harbor Rpp5, was found to also harbor Rpp3. Markers closely linked to the resistance loci identified in this study will be used for ASR-resistance breeding and the identification of the genes responsible for resistance.

Variations in Biodistribution and Acute Response of Differently Shaped Titania Nanoparticles in Healthy Rodents.

Titanium dioxide nanoparticles (TiO2 NPs) are one of the main sources of the nanoparticulate matter exposure to humans. Although several studies have demonstrated their potential toxic effects, the real nature of the correlation between NP properties and their interaction with biological targets is still far from being fully elucidated. Here, engineered TiO2 NPs with various geometries (bipyramids, plates, and rods) have been prepared, characterized and intravenously administered in healthy mice. Parameters such as biodistribution, accumulation, and toxicity have been assessed in the lungs and liver. Our data show that the organ accumulation of TiO2 NPs, measured by ICP-MS, is quite low, and this is only partially and transiently affected by the NP geometries. The long-lasting permanence is exclusively restricted to the lungs. Here, bipyramids and plates show a higher accumulation, and interestingly, rod-shaped NPs are the most toxic, leading to histopathological pulmonary alterations. In addition, they are also able to induce a transient increase in serum markers related to hepatocellular injury. These results indicate that rods, more than bipyramidal and spherical geometries, lead to a stronger and more severe biological effect. Overall, small physico-chemical differences can dramatically modify both accumulation and safety.

Long-term retention of gold nanoparticles in the liver is not affected by their physicochemical characteristics.

Gold nanoparticles (GNPs) are considered promising candidates for healthcare applications, however, their toxicity after long-term exposure to the material remains uncertain. Since the liver is the main filter organ for nanomaterials, this work was aimed at evaluating hepatic accumulation, internalisation and overall safety of well-characterised and endotoxin-free GNPs in healthy mice from 15 minutes to 7 weeks after a single administration. Our data demonstrate that GNPs were rapidly segregated into lysosomes of endothelial cells (LSEC) or Kupffer cells regardless of coating or shape but with different kinetics. Despite the long-lasting accumulation in tissues, the safety of GNPs was confirmed by liver enzymatic levels, as they were rapidly eliminated from the blood circulation and accumulated in the liver without inducing hepatic toxicity. Our results demonstrate that GNPs have a safe and biocompatibile profile despite their long-term accumulation.

A comparison of urinary bladder weight in male and female mice across five models of diabetes and obesity.

Introduction: Diabetes often leads to lower urinary tract dysfunction. The most frequently assessed parameter of urinary bladder dysfunction in animal models of diabetes is an enlargement of the bladder, which is consistently observed in type 1 and less consistently in type 2 diabetes. The vast majority of studies on bladder weight in animal models of diabetes and obesity has been performed in males, and no studies have directly compared this outcome parameter between sexes. Methods: Therefore, we have compared bladder weight and bladder/body weight ratio in five mouse models of obesity and diabetes (RIP-LCMV, db/db, ob/ob (two studies), insulin receptor substrate 2 (IRS2) knock-out mice and mice on a high-fat diet; pre-specified secondary analysis of a previously reported study). Results: In a pooled analysis of the control groups of all studies, females exhibited slightly lower glucose levels, lower body weight, and lower bladder weight, but bladder/body weight ratio was similar in both sexes (0.957 vs. 0.986 mg/g, mean difference 0.029 [-0.06; 0.118]). Among the six diabetic/obese groups, bladder/body weight ratio was similar in both sexes in three but smaller in female mice in three other groups. The mRNA expression of a panel of genes implied in the pathophysiology of bladder enlargement and/or fibrosis and inflammation did not differ systematically between sexes. Conclusions: We conclude that sex differences in diabetes/obesity-associated bladder enlargement may be model dependent.

Impact of Cerebral Microbleeds in Stroke Patients with Atrial Fibrillation.

OBJECTIVES: Cerebral microbleeds are associated with the risks of ischemic stroke and intracranial hemorrhage, causing clinical dilemmas for antithrombotic treatment decisions. We aimed to evaluate the risks of intracranial hemorrhage and ischemic stroke associated with microbleeds in patients with atrial fibrillation treated with vitamin K antagonists, direct oral anticoagulants, antiplatelets, and combination therapy (i.e. concurrent oral anticoagulant and antiplatelet). METHODS: We included patients with documented atrial fibrillation from the pooled individual patient data analysis by the Microbleeds International Collaborative Network. Risks of subsequent intracranial hemorrhage and ischemic stroke were compared between patients with and without microbleeds, stratified by antithrombotic use. RESULTS: A total of 7,839 patients were included. The presence of microbleeds was associated with an increased relative risk of intracranial hemorrhage (adjusted hazard ratio [aHR] = 2.74, 95% confidence interval = 1.76-4.26) and ischemic stroke (aHR = 1.29, 95% confidence interval = 1.04-1.59). For the entire cohort, the absolute incidence of ischemic stroke was higher than intracranial hemorrhage regardless of microbleed burden. However, for the subgroup of patients taking combination of anticoagulant and antiplatelet therapy, the absolute risk of intracranial hemorrhage exceeded that of ischemic stroke in those with 2 to 4 microbleeds (25 vs 12 per 1,000 patient-years) and ≥ 11 microbleeds (94 vs 48 per 1,000 patient-years). INTERPRETATION: Patients with atrial fibrillation and high burden of microbleeds receiving combination therapy have a tendency of higher rate of intracranial hemorrhage than ischemic stroke, with potential for net harm. Further studies are needed to help optimize stroke preventive strategies in this high-risk group. ANN NEUROL 2023;94:61-74.