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OBJECTIVE: Although oral bisphosphonates are effective treatments for postmenopausal women with osteoporosis, oral dosing may be unsuitable for some patients. An efficacious intravenously administered bisphosphonate could be beneficial for such patients. Ibandronate, a potent nitrogen-containing bisphosphonate, can be administered using extended dosing intervals, either orally or by rapid intravenous injection. The aim of this study was to identify the optimal intravenous dosing regimen for ibandronate in postmenopausal women with osteoporosis. METHODS: In a randomized, double-blind, double-dummy, phase III, noninferiority study, we compared 2 regimens of intermittent intravenous injections of ibandronate (2 mg every 2 months and 3 mg every 3 months) with a regimen of 2.5 mg of oral ibandronate daily, the latter of which has proven antifracture efficacy. The study group comprised 1,395 women (ages 55-80 years) who were at least 5 years postmenopausal. All patients had osteoporosis (lumbar spine [L2-L4] bone mineral density [BMD] T score less than -2.5). Participants also received daily calcium (500 mg) and vitamin D (400 IU). The primary end point was change from baseline in lumbar spine BMD at 1 year. Changes in hip BMD and in the level of serum C-telopeptide of type I collagen (CTX) were also measured, as were safety and tolerability. RESULTS: At 1 year, mean lumbar spine BMD increases were as follows: 5.1% among 353 patients receiving 2 mg of ibandronate every 2 months, 4.8% among 365 patients receiving 3 mg of ibandronate every 3 months, and 3.8% among 377 patients receiving 2.5 mg of oral ibandronate daily. Both of the intravenous regimens not only were noninferior, but also were superior (P < 0.001) to the oral regimen. Hip BMD increases (at all sites) were also greater in the groups receiving medication intravenously than in the group receiving ibandronate orally. Robust decreases in the serum CTX level were observed in all arms of the study. Both of the intravenous regimens were well tolerated and did not compromise renal function. CONCLUSION: As assessed by BMD, intravenous injections of ibandronate (2 mg every 2 months or 3 mg every 3 months) are at least as effective as the regimen of 2.5 mg orally daily, which has proven antifracture efficacy, and are well tolerated. [ABSTRACT FROM AUTHOR]

This study evaluated the efficacy and tolerability of risedronate once a week (35 mg and 50 mg) compared with risedronate 5 mg once daily in women with osteoporosis. We conducted a randomized, double-blind, active-controlled, 2-year study; the primary efficacy assessment was performed after 1 year. Subjects were women aged 50 years or older who had been postmenopausal for at least 5 years, with either a bone mineral density (BMD) T-score of ?2.5 or lower (lumbar spine or proximal femur) or a T-score lower than ?2 and at least one prevalent vertebral fracture. Subjects received risedronate 5 mg once daily, 35 mg once a week or 50 mg once a week. All subjects also received 1 g daily of elemental calcium supplementation and supplemental vitamin D if the baseline serum levels were low. The primary efficacy measure was percent change in lumbar spine BMD at 12 months. A total of 1456 women were randomized and received medication; 1209 (83%) women completed 12 months. The mean percent change (SE) in lumbar spine BMD after 12 months was 4.0% (0.2%) in the 5 mg daily group, 3.9% (0.2%) in the 35 mg group, and 4.2% (0.2%) in the 50 mg group; each once-a-week treatment was determined to be as effective as the daily treatment. Outcomes of the secondary efficacy measurements and safety assessments were also similar in all 3 groups after 12 months. Risedronate 35 mg and 50 mg once a week provide the same efficacy and safety as the daily 5 mg regimen; therefore, the lower dose, 35 mg once a week, is considered optimal for women with postmenopausal osteoporosis who desire a once-a-week regimen. [ABSTRACT FROM AUTHOR]

The article focuses on the clinical trial that investigates the effect of desonumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting therapy. It states that the women with a spine T-score of -1.8 to -3.5 were randomized to the human monoclonal antibody denosumab, to placebo, and to open-label oral alendronate every week. Details on the findings of the trial are also provided.

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., Competing Interests: Competing interests: MBo: personal fees from AstraZeneca, a company that produces Andexanet alfa (a specific reversal agent for factor Xa-inhibitor-associated ICH, discussed in this study). SW: consultancy fees from Bayer, a company that produces Rivaroxaban (a DOAC discussed in this study). BV: personal fees from Pfizer AG/Bristol-Myers Squibb SA and Bayer AG, producesr of Apixaban and Rivaroxaban, two drugs discussed in this study. DJS: grants from Alexion/AstraZeneca, producer of andexanet alfa discussed in this study. Personal fees from Bayer, producer of Rivaroxaban, discussed in this study. Consultancy fees from VarmX (producer of VarmX, a compound under development for the treatment of FXaI-associated bleeding). All other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Introduction: Ischemic stroke in patients with a systemic tumor disease or cancer not in remission (active tumors) is less well understood. Some aspects of such paraneoplastic strokes remind on a generalized cerebrovascular disorder. We hypothesized that cerebrovascular regulation in active tumor patients with a stroke is different from other patients with stroke who have no active tumor disease., Methods: Within the first 72 h after the acute ischemic stroke, cerebral blood flow regulation was analyzed by means of transfer function analysis between middle cerebral artery blood flow velocity and blood pressure with estimation of coherence, gain and phase in the very low (0.02-0.07 Hz), low (0.07-0.20 Hz) and high frequencies (0.20-0.5 Hz) in four stroke groups: active tumors, inactive tumors (untreated and in remission), hypertensive lacunar stroke (LS), and non-hypertensive embolic stroke (NHES)., Results: The 4 groups did not differ regarding age, sex distribution, and brain infarct size on magnet resonance imaging Between the four stroke groups, phase was not different in any frequency range in both hemispheres. Gain was highest (either significant or by trend) in the active tumor group in the HF range in comparison to all other stroke subgroups, it was also higher in the LF range in the stroke affected hemisphere when compared to the LS group. The HF gain findings were independent of end-tidal CO2 levels but exhibited some dependency of coherence., Discussion: The high gain can be interpreted as a generalized high vascular resistance. The cerebrovascular regulation in active tumor patients seems to exhibit some analogy to hypertensive patients with lacunar stroke., Clinical Trial Registration: clinicaltrials.gov, identifier NCT04611672., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lakatos, Bolognese, Oesterreich, Müller and Karwacki.)

Background: The rising prevalence of acute ischemic stroke (AIS) in young adults, particularly with undetermined pathogenesis, is a growing concern. This study assessed risk factors, treatments, and outcomes between young AIS patients with undetermined and determined pathogeneses., Methods and Results: This was a retrospective cohort study including AIS patients aged 18 to 55 years in Switzerland, treated between 2014 and 2022. Stroke pathogeneses were classified using a modified TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification, with undetermined pathogenesis defined as no identified cause (including patent foramen ovale and cervical artery dissection). We examined vascular risk factors, acute treatments, 3-month functional outcomes, and AIS recurrence within 3 months using logistic regression and Fine-Gray proportional hazards models. Of 3995 patients, 863 (22%) had undetermined pathogenesis. Compared with patients with determined pathogenesis, those with undetermined pathogenesis had a higher prevalence of dyslipidemia (54% versus 59%, P =0.007) and smoking (37% versus 43%, P =0.001), and were more likely to receive intravenous thrombolysis (27% versus 31%, P =0.046). Despite higher 3-month AIS recurrence risk for the undetermined group (adjusted hazard ratio, 1.72 [95% CI, 1.01-2.94]), favorable functional outcomes at 3 months were more frequent (modified Rankin Scale score, 0-2: 90% versus 87%, P =0.033). Patients aged 46 to 55 years with undetermined pathogenesis had better outcomes than those with determined pathogenesis (modified Rankin Scale score, 0-1: 70% versus 64%, P =0.013; modified Rankin Scale score, 0-2: 89% versus 85%, P =0.023), while those aged 18 to 45 years showed higher recurrence rates (4.5% versus 1.8%, P <0.05) but similar functional outcomes., Conclusions: Young adults with AIS exhibit a considerable vascular risk burden. Those with undetermined pathogenesis displayed age-related outcome disparities, with better short-term outcomes in older and higher recurrence rates in younger patients.

Objectives: To determine the prevalence and distribution of intracranial vessel occlusion identified on computed tomography (CT) or magnet resonance (MR) angiography and to explore its association with functional outcome in patients with atrial fibrillation (AF) and ischemic stroke., Methods: Multicenter cohort study enrolling consecutive patients with AF with imaging-confirmed ischemic stroke who underwent CT- or MR-angiography on admission (2014-2022). Multivariable regression was used to explore the association between intracranial vessel occlusion and poor functional outcome (modified Rankin Scale score 3-6) at 90 days., Results: The analysis included 10,164 patients (median age 81.5 years, 47.8% female, median National Institutes of Health Stroke Scale score on admission 6; 14.7% on a vitamin K antagonist [VKA], 27.5% on a direct oral anticoagulant [DOAC], 57.8% not receiving oral anticoagulation). Angiography showed intracranial vessel occlusion in 5,190 patients (51.1%), affecting the anterior cerebral circulation in 87.4%. Overall, 29.2% and 29.4% of patients received thrombolysis and mechanical thrombectomy, respectively. The proportion of patients with poor functional outcome at 90 days was 60.6% and 42.7% in those with and without vessel occlusion, respectively. In multivariable analyses, vessel occlusion was associated with poor functional outcome (adjusted odds ratio [aOR]: 1.95, 95% confidence interval [CI]: 1.71-2.22) with consistent results in subgroups according to oral anticoagulation use (VKA, aOR: 1.98, 95% CI: 1.40-2.80; DOAC, aOR: 2.35, 95% CI: 1.83-3.03; none, aOR: 1.76, 95% CI: 1.49-2.09)., Interpretation: Intracranial vessel occlusion is common in patients with AF with ischemic stroke, mainly affects the anterior circulation and is associated with poor functional outcome. ANN NEUROL 2024;96:1115-1123., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Cardiac high-sensitivity troponin T (hs-cTnT) is linked to the cardioembolic origin, severity, and outcome of acute ischemic stroke. Furthermore, larger brain infarctions are often accompanied by impaired dynamic cerebral autoregulation (dCA), which is also indicative of a poor prognosis., Objectives: This study aimed to investigate whether hs-cTnT levels can serve as a predictor of dCA impairment., Design: Retrospective cohort study., Methods: In 330 consecutive patients with stroke (age 71 years [IQR 59-78]; 100 women; 229 territorial and 111 non-territorial brain infarcts) with successful dCA assessment, hs-cTnT levels were measured within 24 hours of stroke onset. These measurements were analyzed in relation to cerebrovascular risk factors, stroke origin, stroke severity (National Institute of Health Stroke Scale, NIHSS at entry), modified Rankin scale (mRs) at 3 months, and stroke volume determined by cranial computed tomography perfusion (CTP). dCA was assessed using transfer function analysis, which assessed the relationship between middle cerebral artery blood flow velocity and blood pressure. Coherence, gain, and phase were estimated across 3 frequency ranges: very low (0.02-0.07 Hz), low (0.07-0.15 Hz), and high (0.15-0.5 Hz)., Results: In univariate analysis, hs-cTnT was associated with cardioembolism and territorial infarction. In the multinomial logistic regression analysis, independent risk factors for the presence of a territorial infarction included atrial fibrillation, the NIHSS score, the infarct core on CTP, cardioembolism, and large vessel disease, but not hs-cTnT levels. Risk factors for a poor outcome (mRs >2) included age, hs-cTnT, and NIHSS score. Overall, the coherence, gain, and phase were not predicted by hs-cTnT levels., Conclusions: Hs-cTnT levels are associated with poor stroke outcomes. However, they do not predict dCA impairment., Registration: ClinicalTrials.gov NCT04611672, 11.10.2020., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Objectives: Blood pressure (BP) management is challenging in patients with acute ischemic supratentorial stroke undergoing recanalization therapy due to the lack of established guidelines. Assessing dynamic cerebral autoregulation (dCA) may address this need, as it is a bedside technique that evaluates the transfer function phase in the very low-frequency (VLF) range (0.02-0.07 Hz) between BP and cerebral blood flow velocity (CBFV) in the middle cerebral artery. This phase is a prognostically relevant parameter, with lower values associated with poorer outcomes. This study aimed to evaluate whether early cranial computed tomography perfusion (CTP) can predict this parameter., Methods: In this retrospective study, 165 consecutive patients with hemispheric strokes who underwent recanalizing therapy were included (median age: 73 years; interquartile range (IQR) 60-80; women: 43 (26%)). The cohort comprised 91 patients treated with intravenous thrombolysis (IV-lysis) alone (median National Institute of Health Stroke Scale (NIHSS) score: 5; IQR 3-7) and 74 patients treated with mechanical thrombectomy (median NIHSS: 15; IQR 9-18). Regression analysis was performed to assess the relationship between pretreatment CTP-derived ischemic penumbra and core stroke volumes and the dCA VLF phase, as well as CBFV assessed within the first 72 h post-stroke event., Results: Pretreatment penumbra volume was a significant predictor of the VLF phase (adjusted r 2 = 0.040; β = -0.001, 95% confidence interval (CI): -0.0018 to -0.0002, p = 0.02). Core infarct volume was a stronger predictor of CBFV (adjusted r 2 = 0.082; β = 0.205, 95% CI: 0.0968-0.3198; p = 0.0003) compared to penumbra volume ( p = 0.01). Additionally, in the low-frequency range (0.07-0.20 Hz), CBFV and BP were inversely related to the gain, an index of vascular tone., Conclusion: CTP metrics appear to correlate with the outcome-relevant VLF phase and reactive hyperemic CBFV, which interact with BP to influence vascular tone and gain. These aspects of dCA could potentially guide BP management in patients with acute stroke undergoing recanalization therapy. However, further validation is required.

Background and Aims: Since the beginning of the war in Ukraine on February 24, 2022, many pediatric oncology centers welcomed evacuated patients. To better understanding the needs of patients and families arriving at two Lombardy hospitals in the period March to November 2022, an anonymous questionnaire investigated the families' backgrounds, feelings, and impressions about hospitality and care., Methods: Twenty questions investigated how patients had reached Italy, from whom they had received help (logistically/financially); the emotions regarding their status as war refugees; the knowledge, expectations, and opinions about Italy and Italians; the quality of medical care received and the relationships with the healthcare staff; lastly, suggestions to improve assistance., Results: The questionnaires were completed by 19/32 patients/parents in November 2022 in two different pediatric-oncology centers. Most families had reached Italy (58%) and received medical care (95%) with the help of charities and the Italian Public Health Care System. A significant majority (69%) expressed satisfaction with the assistance provided. The Italian population demonstrated remarkable warmth, for 95% exhibiting friendliness and for 58% generosity. An improvement in their stay could be linked with the positive outcome of their children's cancer (15%), achieving complete family reunification (15%), the cessation of the conflict (10%), and the overcoming of language barriers (10%)., Conclusions: Providing care for children from another country, not only grappling with the trauma of fleeing their homeland but also battling cancer, is an immense undertaking. It demands a diverse range of efforts and resources to ensure a positive and fulfilling outcome for this experience., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Acoustic cameras (ACs) have become very popular in the last decade as an increasing number of applications in environmental acoustics are observed, which are mainly used to display the points of greatest noise emission of one or more sound sources. The results obtained are not yet certifiable because the beamforming algorithms or hardware behave differently under different measurement conditions, but at present, not enough studies have been dedicated to clarify the issues. The present study aims to provide a methodology to extract analytical features from sound maps obtained with ACs, which are generally only visual information. Based on the inputs obtained through a specific measurement campaign carried out with an AC and a known sound source in free field conditions, the present work elaborated a methodology for gathering the coordinates of the maximum emission point on screen, its distance from the real position of the source and the uncertainty associated with this position. The results obtained with the proposed method can be compared, thus acting as a basis for future comparison studies among calculations made with different beamforming algorithms or data gathered with different ACs in all real case scenarios. The method can be applicable to any other sector interested in gathering data from intensity maps not related to sound.

We present a rare case of Listeria monocytogenes (LM) rhombencephalitis with the formation of multifocal abscesses in a young immunocompetent patient. His initial symptoms of dizziness, headache, and feeling generally unwell were put down to a coincidental coinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The unfortunate rapid progression to trigeminal, hypoglossal, vagal, facial, and abducens nuclei palsies, and then an acquired central hypoventilation syndrome, known as Ondine's curse, required a prolonged intensive care unit (ICU) stay, and prolonged mechanical ventilation. As they continued to deteriorate despite targeted antibiotic treatment, surgical drainage of the abscesses was seen as the only meaningful available treatment option left to contain the disease. Postoperatively, the patient's strength rapidly improved as well as the severity of the cranial nerve palsies. After prolonged rehabilitation, at 3 months of follow-up, the patient was weaned off mechanical ventilation, independently mobile, and was left with only minor residual neurologic deficits. This case highlights a number of interesting findings only touched upon in current literature including the route of entry of LM into the central nervous system, the rare entity of acquired central hypoventilation syndrome, and finally the use of surgical intervention in cerebral LM infections., Competing Interests: None declared., (Thieme. All rights reserved.)

Objectives: Whether different antihypertensive drug classes in high blood pressure (HBP) pre-stroke treatment affect dynamic cerebral autoregulation (dCA), stroke severity, and outcome., Methods: Among 337 consecutive ischemic stroke patients (female 102; median age 71 years [interquartile range, [IQR 60; 78]; NIHSS median 3 [IQR 1; 6]) with assessment of dCA, 183 exhibited the diagnosis of HBP. dCA parameters' gain and phase were determined by transfer function analysis of spontaneous oscillations of blood pressure and cerebral blood flow velocity., Results: Patients used beta-blockers ( n = 76), calcium channel blockers (60), diuretics (77), angiotensin-converting enzyme inhibitors (59), or angiotensin-1 receptor blockers (79), mostly in various combinations of two or three drug classes. dCA parameters did not differ between the non-HBP and the different HBP medication groups. Multinomial ordinal logistic regression models revealed that the use of diuretics decreased the likelihood of a less severe stroke (odds ratio 0.691, 95% CI 0.493; 0.972; p = 0.01) and that beta-blockers decreased the likelihood of a better modified Rankin score at 3 months (odds ratio 0.981, 95% CI 0.970; 0.992; p = 0.009). Other independent factors associated with stroke outcome were penumbra and infarct volume, treatment with mechanical thrombectomy, and the initial National Institute of Health Stroke Scale score., Interpretation: In this cohort of ischemic minor to moderate stroke patients, pre-stroke antihypertensive treatment with diuretics was associated with a more severe neurological deficit on admission and pre-stroke treatment with beta-blockers with a poorer 3-month outcome. The antihypertensive drug class used pre-stroke did not impact dCA.

Objectives: To assess whether vertebrobasilar artery ischemia (VBI) affects cortical cerebral blood flow (CBF) regulation., Material and Methods: 107 consecutive patients (mean age 65 ± 15 years; women 21) with VBI underwent structured stroke care with assessment of dynamic cerebral autoregulation (dCA) in both middle cerebral arteries (MCAs) by transfer function analysis using spontaneous oscillations of blood pressure (BP) and CBF velocity that yields by extraction of phase and gain information in the very low (0.02-0.07 Hz), low (0.07-0.15 Hz) and high frequency (0.15-0.5 Hz) ranges. Additionally, power spectrum analysis of BP and heart rate variability (HRV) was performed. The control group consists of 29 age- and sex-matched healthy persons., Results: Compared to controls, phase in the VBI patients was significantly reduced and gain increased in the very low frequencies (VLF), in the low (LF), phase was significantly reduced only ipsilaterally. In the high frequencies (HF), phase reduction was only marginally significant. BP power spectral density (PSD) was much higher in the patients than in the controls across all frequencies. In the PSD of heart rate variability the controls but not the patients exhibited a strong peak around 0.11Hz, while the patients, but not the controls, exhibit a strong peak around 0.36 Hz. In regression analysis, patient's phase and gain results were not related to age, sex, arterial hypertension, diabetes mellitus, renal dysfunction, heart failure as indicated by left ventricular ejection fraction, stroke subtype, presence or absence of cerebral small vessel disease., Conclusion: Patients with VBI exhibit bilateral cortical autoregulation impairment in association with an autonomic nervous system disbalance., Gov Identifier: NCT04611672., Competing Interests: Declaration of Competing Interest No author declares a conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Ischaemic stroke may occur despite antiplatelet therapy (APT). We aimed to investigate frequency, potential causes and outcomes in patients with ischaemic stroke despite APT., Methods: In this cohort study, we enrolled patients with imaging-confirmed ischaemic stroke from the Swiss Stroke Registry (01/2014-07/2022). We determined the frequency of prior APT, assessed stroke aetiology (modified TOAST classification) and determined the association of prior APT with unfavourable functional outcome (modified Rankin Scale score 3-6) and recurrent ischaemic stroke at 3 months using regression models., Results: Among 53,352 patients, 27,484 (51.5%) had no prior antithrombotic treatment, 17,760 (33.3%) were on APT, 7039 (13.2%) on anticoagulation and 1069 (2.0%) were on APT + anticoagulation. In patients with a history of ischaemic stroke/TIA ( n  = 11,948; 22.4%), 2401 (20.1%) had no prior antithrombotic therapy, 6594 (55.2%) were on APT, 2489 (20.8%) on anticoagulation and 464 (3.9%) on APT + anticoagulation. Amongst patients with ischaemic stroke despite APT, aetiology was large artery atherosclerosis in 19.8% ( n  = 3416), cardiac embolism in 23.6% ( n  = 4059), small vessel disease in 11.7% ( n  = 2011), other causes in 7.4% ( n  = 1267), more than one cause in 6.3% ( n  = 1078) and unknown cause in 31.3% ( n  = 5388). Prior APT was not independently associated with unfavourable outcome (aOR = 1.06; 95% CI: 0.98-1.14; p  = 0.135) or death (aOR = 1.10; 95% CI: 0.99-1.21; p  = 0.059) at 3-months but with increased odds of recurrent stroke (6.0% vs 4.3%; aOR 1.26; 95% CI: 1.11-1.44; p  < 0.001)., Conclusions: One-third of ischaemic strokes occurred despite APT and 20% of patients with a history of ischaemic stroke had no antithrombotic therapy when having stroke recurrence. Aetiology of breakthrough strokes despite APT is heterogeneous and these patients are at increased risk of recurrent stroke.

Objective: The aim of this study was to ascertain whether dynamic cerebral autoregulation (CA) in the middle cerebral artery (MCA) is disturbed by cerebral infarctions outside the MCA territory., Methods: We estimated transfer function parameters gain and phase from simultaneous recordings of spontaneous oscillation in blood pressure and MCA cerebral blood flow velocity in 10 consecutive patients with isolated anterior cerebral artery (ACA) infarctions and in 22 consecutive patients with isolated posterior cerebral artery (PCA) infarctions. All ACA infarctions were in the motor, premotor, or supplementary motor cortex areas and presented with pronounced leg hemiparesis. Twenty-eight age- and sex-matched healthy subjects served as controls., Results: Compared to controls, phase was significantly reduced in the MCA ipsilateral to the lesion site and in the contralateral MCA (unaffected hemisphere) in the very low (0.02-0.07 Hz) and low (0.07-0.15 Hz) frequency ranges in the ACA infarctions but not in the PCA infarctions. Gain was reduced only in the very low frequency range in the MCA contralateral to the ACA lesion site. Systemic factors were unrelated to phase and gain results., Conclusion: Bilateral impairment of MCA dynamic CA in patients with a unilateral ACA infarction is frequent., Competing Interests: Conflict of interest: Authors state no conflict of interest., (© 2023 the author(s), published by De Gruyter.)

Objective: To examine rates of intravenous thrombolysis (IVT), mechanical thrombectomy (MT), door-to-needle (DTN) time, door-to-puncture (DTP) time, and functional outcome between patients with admission magnetic resonance imaging (MRI) versus computed tomography (CT)., Methods: An observational cohort study of consecutive patients using a target trial design within the nationwide Swiss-Stroke-Registry from January 2014 to August 2020 was carried out. Exclusion criteria included MRI contraindications, transferred patients, and unstable or frail patients. Multilevel mixed-effects logistic regression with multiple imputation was used to calculate adjusted odds ratios with 95% confidence intervals for IVT, MT, DTN, DTP, and good functional outcome (mRS 0-2) at 90 days., Results: Of the 11,049 patients included (mean [SD] age, 71 [15] years; 4,811 [44%] women; 69% ischemic stroke, 16% transient ischemic attack, 8% stroke mimics, 6% intracranial hemorrhage), 3,741 (34%) received MRI and 7,308 (66%) CT. Patients undergoing MRI had lower National Institutes of Health Stroke Scale (median [interquartile range] 2 [0-6] vs 4 [1-11]), and presented later after symptom onset (150 vs 123 min, p < 0.001). Admission MRI was associated with: lower adjusted odds of IVT (aOR 0.83, 0.73-0.96), but not with MT (aOR 1.11, 0.93-1.34); longer adjusted DTN (+22 min [13-30]), but not with longer DTP times; and higher adjusted odds of favorable outcome (aOR 1.54, 1.30-1.81)., Interpretation: We found an association of MRI with lower rates of IVT and a significant delay in DTN, but not in DTP and rates of MT. Given the delays in workflow metrics, prospective trials are required to show that tissue-based benefits of baseline MRI compensate for the temporal benefits of CT. ANN NEUROL 2022;92:184-194., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose: The present computerized techniques have limits to estimate the ischemic lesion volume especially in vertebrobasilar ischemia (VBI) automatically. We investigated the ability of the RAPID AI (RAPID) software on diffusion-weighted imaging (DWI) to estimate the infarct size in VBI in comparison to supratentorial ischemia (STI)., Methods: Among 123 stroke patients (39 women, 84 men, mean age 66 ± 11 years) having undergone DWI, 41 had had a VBI and 82 a STI. The infarct volume calculation by RAPID was compared to volume calculations by 2 neurologists using the ABC/2 method. For inter-reader and between-method analysis intraclass correlation coefficient (ICC), area under the curve (AUC) estimations, and Bland-Altman plots were used., Results: ICC between the two neurologists and each neurologist and RAPID were >0.946 (largest 95% CI boundaries 0.917-0.988) in the STI group, and > 0.757 (95% CI boundaries between 0.544 and 0.982) in the VBI group. In the STI group, AUC values ranged between 0.982 and 0.999 (95% CI 0.971-1) between the 2 neurologists and between 0.875 and 1 (95% CI 0.787-1) between the neurologists and RAPID; in the VBI group, they ranged between 0.925 and 0.965 (95% CI 0.801-1) between the neurologists, and between 0.788 and 0.931 (95% CI 0.663-1) between RAPID and the neurologists. Compared to the visual DWI interpretation by the neurologists, RAPID did not recognize a substantial number of infarct volumes of ≤ 2 ml., Conclusion: The ability of the RAPID software to depict strokes in the vertebrobasilar artery system seems close to its ability in the supratentorial brain tissue. However, small lesion volumes ≤ 2 ml remain still undetected in both brain areas., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lakatos, Bolognese, Müller, Österreich and von Hessling.)

Introduction: Rapid treatment of acute ischemic stroke (AIS) depends on sufficient staffing which differs between Stroke Centers and Stroke Units in Switzerland. We studied the effect of admission time on performance measures of AIS treatment and related temporal trends over time., Patients and Methods: We compared treatment rates, door-to-image-time, door-to-needle-time, and door-to-groin-puncture-time in stroke patients admitted during office hours (Monday-Friday 8:00-17:59) and non-office hours at all certified Stroke Centers and Stroke Units in Switzerland, as well as secular trends thereof between 2014 and 2019, using data from the Swiss Stroke Registry. Secondary outcomes were modified Rankin Scale and mortality at 3 months., Results: Data were eligible for analysis in 31,788 (90.2%) of 35,261 patients. Treatment rates for IVT/EVT were higher during non-office hours compared with office hours in Stroke Centers (40.8 vs 36.5%) and Stroke Units (21.8 vs 18.5%). Door-to-image-time and door-to-needle-time increased significantly during non-office hours. Median (IQR) door-to-groin-puncture-time at Stroke Centers was longer during non-office hours compared to office hours (84 (59-116) vs 95 (66-130) minutes). Admission during non-office hours was independently associated with worse functional outcome (1.11 [95%CI: 1.04-1.18]) and increased mortality (1.13 [95%CI: 1.01-1.27]). From 2014 to 2019, median door-to-groin-puncture-time improved and the treatment rate for wake-up strokes increased., Discussion and Conclusion: Despite differences in staffing, patient admission during non-office hours delayed IVT to a similar, modest degree at Stroke Centers and Stroke Units. A larger delay of EVT was observed during non-office hours, but Stroke Centers sped up delivery of EVT over time. Patients admitted during non-office hours had worse functional outcomes, which was not explained by treatment delays., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: VLA, SAS, PRW, MP, TK, AvH, TM, EC, SS, RS, JV, JN, LS, SR, MS, MLM, BR, GS report no conflicting interests. GMDM has received support from the Swiss National Science Foundation; Spezialprogramm Nachwuchsförderung Klinische Forschung, University of Basel; Science Funds of the University Hospital Basel; Swiss Heart Foundation; Bangerter-Rhyner-Stiftung; Swisslife Jubiläumsstiftung for Medical Research; Swiss Neurological Society; Fondazione Dr Ettore Balli; De Quervain research grant; Thermo-Fisher-GmbH; consultant honoraria by Bayer; speaker honoraria by Medtronic and BMS/Pfizer. HG has received research support from the Swiss National Science Foundation, advisory board honoraria from Daiichi-Sankyo and funding for travel from BMS/Pfizer. STE has received funding for travel or speaker honoraria from Bayer Boehringer-Ingelheim, and Daiichi-Sankyo. He has served on scientific advisory boards for Bayer, Boehringer-Ingelheim, BMS/Pfizer, MindMaze, the editorial board of Stroke. He has received an educational grant from Pfizer and research support from the Science Funds of the University Hospital Basel, the University Basel, the Swiss Heart Foundation and the Swiss National Science Foundation. KN received speaker’s fees from Abbott. MA received Speaker honoraria from Bayer, Boehringer-Ingelheim, and Covidien; Scientific advisory board honoraria from Amgen, Bayer, Boehringer-Ingelheim, BMS, Pfizer, Covidien, Daichy Sankyo and Nestlé Health Science. Research grants from the Swiss Heart Foundation and the Swiss National Science Foundation. UF has received research support from the Swiss National Science Foundation, the Swiss Heart Foundation and Medtronic; he is a consultant for Medtronic, Stryker, and CSL-Behring. PM received speaker honoraria from Medtronic, Stryker. Consultant for Medtronic, Cerenovus, Phenox, Microvention, research grants from the Swiss Heart Foundation, Siemens and iSchemview. MG reports grants from Bangerter-Rhyner-Foundation. JK reports grants from the Swiss Stroke Society and the Swiss Academy of Medical Sciences/Bangerter Foundation. PM has received has received through his institution research grants from the Swiss National Science Foundation, the Swiss Heart Foundation and the ERISTA program (Pfizer/BMS); consulting fees from Medtronic. All this support goes to his institution for stroke education and research. CWC has received modest honoraria for scientific advisory board from Bayer, Boehringer-Ingelheim and iSchemaview; Research grants from the Swiss Heart Foundation. MB has received honoraria for travel from Bayer and for participation in advisory board from AstraZeneca. GK has received modest honoraria for travel and advisory board from Bayer, Medtronic, Alexion, Bial, Boehringer-Ingelheim and Zambon, a research grant from the Swiss Heart Foundation, Swiss Parkinson Foundation, Swiss National Science Foundation. ARL has received modest honoraria for travel and advisory board from Bayer, Moleac and Amgen and research grants from the P&K Pühringer-Foundation. SW received research funds by the Swiss National Science Foundation, the UZH Clinical research priority program (CRPP) stroke, the Swiss Heart foundation, Boehringer-Ingelheim, speakers honorarium from Amgen and a consultancy fee from Bayer. NP has received research funding from the Swiss Heart Foundation and the Swiss National Science Foundation, speaker honoraria from Vifor; served on advisory boards for Bayer, Boehringer-Ingelheim, BMS/Pfizer, Daiichi-Sankyo and AstraZeneca. FM has received research support from the Swiss Heart Foundation and has not received any honoria from industry 2017. CBe received modest honoraria for travel and advisory board from Novartis and Bayer. CBo reports travel and speaker honoraria from Amgen, Bayer, Biogen, Boehringer-Ingelheim, Bristol-Myers-Squibb, Lilly, Merck, Novartis, Pfizer, Roche, Servier, Sanofi, TEVA. LHB has received grants from the Swiss National Science Foundation, the University of Basel, the Swiss Heart Foundation, and the “Stiftung zur Förderung der gastroenterologischen und allgemeinen klinischen Forschung sowie der medizinischen Bildauswertung.” Unrestricted research grant from AstraZeneca, consultancy or advisory board fees or speaker’s honoraria from Amgen, Bayer, Bristol-Myers-Squibb, Claret Medical, and InnovHeart, and travel grants from AstraZeneca and Bayer., (© European Stroke Organisation 2022.)

Background and Purpose: Central retinal artery occlusion (CRAO) often leads to permanent monocular blindness. Hence, early recognition and rapid re-perfusion is of paramount importance. This study aims to describe prehospital pathways in CRAO compared to stroke and study the knowledge about CRAO., Methods: (1) Description of baseline characteristics, prehospital pathways/delays, and acute treatment (thrombolysis/thrombectomy vs. standard of care) of patients with CRAO and ischemic stroke registered in the Swiss Stroke Registry. (2) Online survey about CRAO knowledge amongst population, general practitioners (GPs) and ophthalmologists in Eastern Switzerland., Results: Three hundred and ninety seven CRAO and 32,816 ischemic stroke cases were registered from 2014 until 2019 in 20 Stroke Centers/Units in Switzerland. In CRAO, 25.6% arrived at the hospital within 4 h of symptom onset and had a lower rate of emergency referrals. Hence, the symptom-to-door time was significantly longer in CRAO compared to stroke (852 min. vs. 300 min). The thrombolysis/thrombectomy rate was 13.2% in CRAO and 30.9% in stroke. 28.6% of the surveyed population recognized CRAO-symptoms, 55.4% of which would present directly to the emergency department in contrast to 90.0% with stroke symptoms. Almost 100% of the ophthalmologist and general practitioners recognized CRAO as a medical emergency and 1/3 of them considered IV thrombolysis a potentially beneficial therapy., Conclusions: CRAO awareness of the general population and physician awareness about the treatment options as well as the non-standardized prehospital organization, seems to be the main reason for the prehospital delays and impedes treating CRAO patients. Educational efforts should be undertaken to improve awareness about CRAO., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ardila Jurado, Sturm, Brugger, Nedeltchev, Arnold, Bonati, Carrera, Michel, Cereda, Bolognese, Albert, Medlin, Berger, Schelosky, Renaud, Niederhauser, Bonvin, Mono, Rodic, Tarnutzer, Schwegler, Salmen, Luft, Peters, Vehoff, Kägi and the Swiss Stroke Registry Investigators.)

Background and Purpose: Knowledge about different etiologies of non-traumatic intracerebral hemorrhage (ICH) and their outcomes is scarce., Methods: We assessed prevalence of pre-specified ICH etiologies and their association with outcomes in consecutive ICH patients enrolled in the prospective Swiss Stroke Registry (2014 to 2019)., Results: We included 2,650 patients (mean±standard deviation age 72±14 years, 46.5% female, median National Institutes of Health Stroke Scale 8 [interquartile range, 3 to 15]). Etiology was as follows: hypertension, 1,238 (46.7%); unknown, 566 (21.4%); antithrombotic therapy, 227 (8.6%); cerebral amyloid angiopathy (CAA), 217 (8.2%); macrovascular cause, 128 (4.8%); other determined etiology, 274 patients (10.3%). At 3 months, 880 patients (33.2%) were functionally independent and 664 had died (25.1%). ICH due to hypertension had a higher odds of functional independence (adjusted odds ratio [aOR], 1.33; 95% confidence interval [CI], 1.00 to 1.77; P=0.05) and lower mortality (aOR, 0.64; 95% CI, 0.47 to 0.86; P=0.003). ICH due to antithrombotic therapy had higher mortality (aOR, 1.62; 95% CI, 1.01 to 2.61; P=0.045). Within 3 months, 4.2% of patients had cerebrovascular events. The rate of ischemic stroke was higher than that of recurrent ICH in all etiologies but CAA and unknown etiology. CAA had high odds of recurrent ICH (aOR, 3.38; 95% CI, 1.48 to 7.69; P=0.004) while the odds was lower in ICH due to hypertension (aOR, 0.42; 95% CI, 0.19 to 0.93; P=0.031)., Conclusions: Although hypertension is the leading etiology of ICH, other etiologies are frequent. One-third of ICH patients are functionally independent at 3 months. Except for patients with presumed CAA, the risk of ischemic stroke within 3 months of ICH was higher than the risk of recurrent hemorrhage.

Background and Purpose: Recent studies suggested an increased incidence of cerebral venous thrombosis (CVT) during the coronavirus disease 2019 (COVID-19) pandemic. We evaluated the volume of CVT hospitalization and in-hospital mortality during the 1st year of the COVID-19 pandemic compared to the preceding year., Methods: We conducted a cross-sectional retrospective study of 171 stroke centers from 49 countries. We recorded COVID-19 admission volumes, CVT hospitalization, and CVT in-hospital mortality from January 1, 2019, to May 31, 2021. CVT diagnoses were identified by International Classification of Disease-10 (ICD-10) codes or stroke databases. We additionally sought to compare the same metrics in the first 5 months of 2021 compared to the corresponding months in 2019 and 2020 (ClinicalTrials.gov Identifier: NCT04934020)., Results: There were 2,313 CVT admissions across the 1-year pre-pandemic (2019) and pandemic year (2020); no differences in CVT volume or CVT mortality were observed. During the first 5 months of 2021, there was an increase in CVT volumes compared to 2019 (27.5%; 95% confidence interval [CI], 24.2 to 32.0; P<0.0001) and 2020 (41.4%; 95% CI, 37.0 to 46.0; P<0.0001). A COVID-19 diagnosis was present in 7.6% (132/1,738) of CVT hospitalizations. CVT was present in 0.04% (103/292,080) of COVID-19 hospitalizations. During the first pandemic year, CVT mortality was higher in patients who were COVID positive compared to COVID negative patients (8/53 [15.0%] vs. 41/910 [4.5%], P=0.004). There was an increase in CVT mortality during the first 5 months of pandemic years 2020 and 2021 compared to the first 5 months of the pre-pandemic year 2019 (2019 vs. 2020: 2.26% vs. 4.74%, P=0.05; 2019 vs. 2021: 2.26% vs. 4.99%, P=0.03). In the first 5 months of 2021, there were 26 cases of vaccine-induced immune thrombotic thrombocytopenia (VITT), resulting in six deaths., Conclusions: During the 1st year of the COVID-19 pandemic, CVT hospitalization volume and CVT in-hospital mortality did not change compared to the prior year. COVID-19 diagnosis was associated with higher CVT in-hospital mortality. During the first 5 months of 2021, there was an increase in CVT hospitalization volume and increase in CVT-related mortality, partially attributable to VITT.

Maritime transport for both passengers and freight is continuously increasing and, consequently, the global attention toward its sustainability is growing. Ships offer advantages in terms of environmental impact compared to other transportation systems but the increasing traffic volume is expected to increase pollutants. Noise produced in port areas has been neglected for too long, until the INTERREG Maritime programme Italy-France 2014-2020 has brought to light how citizen complaints are emerging for some of the main ports in the Mediterranean. However, port noise prevention and management is difficult as knowledge on specific sources is very limited in the literature. Furthermore, on field measurements are difficult to be performed given the complexity of the port area, where multiple types of sound emitters mix and confuse each other. Noise maps represent the first important step in order to align ports to the requirements set by the Environmental Noise Directive to the transportation infrastructures. Once computed, they are an excellent tool supporting port management towards the reduction of citizens' noise exposure while ensuring traffic growth. The present paper reports a guideline for the characterization of noise sources needed as inputs for the noise maps, as developed in the framework of the INTERREG Maritime programme Italy-France 2014-2020. On the basis of the current state of the art, a procedure has been elaborated for different categories of noise sources acting in port, ranging from stationary to moving ships, from mooring operations to loading/unloading operations, from industrial activities to road and railway traffic., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Background: 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., Methods: 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., Results: 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)., Conclusions: 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., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: In Switzerland, the COVID-19 incidence during the first pandemic wave was high. Our aim was to assess the association of the outbreak with acute stroke care in Switzerland in spring 2020., Methods: This was a retrospective analysis based on the Swiss Stroke Registry, which includes consecutive patients with acute cerebrovascular events admitted to Swiss Stroke Units and Stroke Centers. A linear model was fitted to the weekly admission from 2018 and 2019 and was used to quantify deviations from the expected weekly admissions from 13 March to 26 April 2020 (the "lockdown period"). Characteristics and 3-month outcome of patients admitted during the lockdown period were compared with patients admitted during the same calendar period of 2018 and 2019., Results: In all, 28,310 patients admitted between 1 January 2018 and 26 April 2020 were included. Of these, 4491 (15.9%) were admitted in the periods March 13-April 26 of the years 2018-2020. During the lockdown in 2020, the weekly admissions dropped by up to 22% compared to rates expected from 2018 and 2019. During three consecutive weeks, weekly admissions fell below the 5% quantile (likelihood 0.38%). The proportion of intracerebral hemorrhage amongst all registered admissions increased from 7.1% to 9.3% (p = 0.006), and numerically less severe strokes were observed (median National Institutes of Health Stroke Scale from 3 to 2, p = 0.07)., Conclusions: Admissions and clinical severity of acute cerebrovascular events decreased substantially during the lockdown in Switzerland. Delivery and quality of acute stroke care were maintained., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Objectives: There is a worldwide increase in the incidence of stroke in young adults, with major regional and ethnic differences. Advancing knowledge of ethnic and regional variation in causes and outcomes will be beneficial in implementation of regional health care services. We studied the global distribution of risk factors, causes, and 3-month mortality of young patients with ischemic stroke, by performing a patient data meta-analysis from different cohorts worldwide., Methods: We performed a pooled analysis of individual patient data from cohort studies that included consecutive patients with ischemic stroke aged 18-50 years. We studied differences in prevalence of risk factors and causes of ischemic stroke between different ethnic and racial groups, geographic regions, and countries with different income levels. We investigated differences in 3-month mortality by mixed-effects multivariable logistic regression., Results: We included 17,663 patients from 32 cohorts in 29 countries. Hypertension and diabetes were most prevalent in Black (hypertension, 52.1%; diabetes, 20.7%) and Asian patients (hypertension 46.1%, diabetes, 20.9%). Large vessel atherosclerosis and small vessel disease were more often the cause of stroke in high-income countries (HICs; both p < 0.001), whereas "other determined stroke" and "undetermined stroke" were higher in low and middle-income countries (LMICs; both p < 0.001). Patients in LMICs were younger, had less vascular risk factors, and despite this, more often died within 3 months than those from HICs (odds ratio 2.49; 95% confidence interval 1.42-4.36)., Discussion: Ethnoracial and regional differences in risk factors and causes of stroke at young age provide an understanding of ethnic and racial and regional differences in incidence of ischemic stroke. Our results also highlight the dissimilarities in outcome after stroke in young adults that exist between LMICs and HICs, which should serve as call to action to improve health care facilities in LMICs., (© 2021 American Academy of Neurology.)

Objective: The aim was to evaluate, in patients with atrial fibrillation (AF) and acute ischemic stroke, the association of prior anticoagulation with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) with stroke severity, utilization of intravenous thrombolysis (IVT), safety of IVT, and 3-month outcomes., Methods: This was a cohort study of consecutive patients (2014-2019) on anticoagulation versus those without (controls) with regard to stroke severity, rates of IVT/mechanical thrombectomy, symptomatic intracranial hemorrhage (sICH), and favorable outcome (modified Rankin Scale score 0-2) at 3 months., Results: Of 8,179 patients (mean [SD] age, 79.8 [9.6] years; 49% women), 1,486 (18%) were on VKA treatment, 1,634 (20%) on DOAC treatment at stroke onset, and 5,059 controls. Stroke severity was lower in patients on DOACs (median National Institutes of Health Stroke Scale 4, [interquartile range 2-11]) compared with VKA (6, [2-14]) and controls (7, [3-15], p < 0.001; quantile regression: β -2.1, 95% confidence interval [CI] -2.6 to -1.7). The IVT rate in potentially eligible patients was significantly lower in patients on VKA (156 of 247 [63%]; adjusted odds ratio [aOR] 0.67; 95% CI 0.50-0.90) and particularly in patients on DOACs (69 of 464 [15%]; aOR 0.06; 95% CI 0.05-0.08) compared with controls (1,544 of 2,504 [74%]). sICH after IVT occurred in 3.6% (2.6-4.7%) of controls, 9 of 195 (4.6%; 1.9-9.2%; aOR 0.93; 95% CI 0.46-1.90) patients on VKA and 2 of 65 (3.1%; 0.4-10.8%, aOR 0.56; 95% CI 0.28-1.12) of those on DOACs. After adjustments for prognostic confounders, DOAC pretreatment was associated with a favorable 3-month outcome (aOR 1.24; 1.01-1.51)., Interpretation: Prior DOAC therapy in patients with AF was associated with decreased admission stroke severity at onset and a remarkably low rate of IVT. Overall, patients on DOAC might have better functional outcome at 3 months. Further research is needed to overcome potential restrictions for IVT in patients taking DOACs. ANN NEUROL 2021;89:42-53., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Worldwide, 2 million patients aged 18-50 years suffer a stroke each year, and this number is increasing. Knowledge about global distribution of risk factors and aetiologies, and information about prognosis and optimal secondary prevention in young stroke patients are limited. This limits evidence-based treatment and hampers the provision of appropriate information regarding the causes of stroke, risk factors and prognosis of young stroke patients., Methods and Analysis: The Global Outcome Assessment Life-long after stroke in young adults (GOAL) initiative aims to perform a global individual patient data meta-analysis with existing data from young stroke cohorts worldwide. All patients aged 18-50 years with ischaemic stroke or intracerebral haemorrhage will be included. Outcomes will be the distribution of stroke aetiology and (vascular) risk factors, functional outcome after stroke, risk of recurrent vascular events and death and finally the use of secondary prevention. Subgroup analyses will be made based on age, gender, aetiology, ethnicity and climate of residence., Ethics and Dissemination: Ethical approval for the GOAL study has already been obtained from the Medical Review Ethics Committee region Arnhem-Nijmegen. Additionally and when necessary, approval will also be obtained from national or local institutional review boards in the participating centres. When needed, a standardised data transfer agreement will be provided for participating centres. We plan dissemination of our results in peer-reviewed international scientific journals and through conference presentations. We expect that the results of this unique study will lead to better understanding of worldwide differences in risk factors, causes and outcome of young stroke patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Mobile technologies offer the potential to reduce the costs of conducting clinical trials by collecting high-quality information on health outcomes in real-world settings that are relevant to patients and clinicians. However, widespread use of mobile technologies in clinical trials has been impeded by their perceived challenges. To advance solutions to these challenges, the Clinical Trials Transformation Initiative (CTTI) has issued best practices and realistic approaches that clinical trial sponsors can now use. These include CTTI recommendations on technology selection; data collection, analysis, and interpretation; data management; protocol design and execution; and US Food and Drug Administration submission and inspection. The scientific principles underpinning the clinical trials enterprise continue to apply to studies using mobile technologies. These recommendations provide a framework for including mobile technologies in clinical trials that can lead to more efficient assessment of new therapies for patients., Competing Interests: J.C.G., C.A.G., J.P.B., M.B., K.V., A.A., C.D., J.H., M.K., A.N., D.P., T.S., L.W., and A.D. have no conflicts of interest to declare. P.C. is an employee of Medidata Solutions with ownership interests. E.R.D. has received honoraria for speaking at American Academy of Neurology courses, American Neurological Association, and University of Michigan; received compensation for consulting services from 23andMe, Abbott, Abbvie, American Well, Biogen, Clintrex, DeciBio, Denali Therapeutics, GlaxoSmithKline, Grand Rounds, Karger, Lundbeck, MC10, MedAvante, Medical-legal services, Mednick Associates, National Institute of Neurological Disorders and Stroke, Olson Research Group, Optio, Prilenia, Putnam Associates, Roche, Sanofi, Shire, Sunovion Pharma, Teva, UCB, and Voyager Therapeutics; research support from Abbvie, Acadia Pharmaceuticals, AMC Health, Biosensics, Burroughs Wellcome Fund, Davis Phinney Foundation, Duke University, Food and Drug Administration, GlaxoSmithKline, Greater Rochester Health Foundation, Huntington Study Group, Michael J. Fox Foundation, National Institutes of Health/National Institute of Neurological Disorders and Stroke, National Science Foundation, Nuredis Pharmaceuticals, Patient-Centered Outcomes Research Institute, Pfizer, Prana Biotechnology, Raptor Pharmaceuticals, Roche, Safra Foundation, Teva Pharmaceuticals, University of California Irvine; editorial services for Karger Publications; and ownership interests with Blackfynn (data integration company) and Grand Rounds (second opinion service). C.J.M. is an employee of AstraZeneca and a shareholder of AstraZeneca, Abbott, Abbvie, and J&J. B.P. was at Philips Respironics from 2011 to 2017. D.S. has ownership interests in Validic. E.R. is an employee of Evidation Health. J.P.B. has been a full-time employee at Philips since 2017., (Copyright © 2019 by S. Karger AG, Basel.)

Neurological complications of infective endocarditis are frequent, especially ischaemic strokes. As intravenous thrombolysis in infective endocarditis-related ischaemic stroke has a controversial benefit/risk ratio, alternative treatment regimens have to be considered. We present the case of a young patient with septic embolism of the middle cerebral artery who was successfully treated with mechanical thrombectomy, and give a short review of the existing literature.

The relationship between handedness and mathematical ability is still highly controversial. While some researchers have claimed that left-handers are gifted in mathematics and strong right-handers perform the worst in mathematical tasks, others have more recently proposed that mixed-handers are the most disadvantaged group. However, the studies in the field differ with regard to the ages and the gender of the participants, and the type of mathematical ability assessed. To disentangle these discrepancies, we conducted five studies in several Italian schools (total participants: N = 2,314), involving students of different ages (six to seventeen) and a range of mathematical tasks (e.g., arithmetic and reasoning). The results show that (a) linear and quadratic functions are insufficient for capturing the link between handedness and mathematical ability; (b) the percentage of variance in mathematics scores explained by handedness was larger than in previous studies (between 3 and 10% vs. 1%), and (c) the effect of handedness on mathematical ability depended on age, type of mathematical tasks, and gender. In accordance with previous research, handedness does represent a correlate of achievement in mathematics, but the shape of this relationship is more complicated than has been argued so far.

Objectives: The aim of this study was to compare biweekly and monthly evolocumab with placebo and oral ezetimibe in patients with hypercholesterolemia in a phase III trial., Background: Evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced LDL-C in phase II trials., Methods: Patients 18 to 80 years of age with fasting low-density lipoprotein cholesterol (LDL-C) ≥100 and <190 mg/dl and Framingham risk scores ≤10% were randomized (1:1:1:1:2:2) to oral placebo and subcutaneous (SC) placebo biweekly; oral placebo and SC placebo monthly; ezetimibe and SC placebo biweekly; ezetimibe and SC placebo monthly; oral placebo and evolocumab 140 mg biweekly; or oral placebo and evolocumab 420 mg monthly., Results: A total of 614 patients were randomized and administered doses. Evolocumab treatment reduced LDL-C from baseline, on average, by 55% to 57% more than placebo and 38% to 40% more than ezetimibe (p < 0.001 for all comparisons). Evolocumab treatment also favorably altered other lipoprotein levels. Treatment-emergent adverse events (AEs), muscle-related AEs, and laboratory abnormalities were comparable across treatment groups., Conclusions: In the largest monotherapy trial using a PCSK9 inhibitor to date, evolocumab yielded significant LDL-C reductions compared with placebo or ezetimibe and was well tolerated in patients with hypercholesterolemia. (Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Subjects Currently Not Receiving Drug Therapy for Easing Lipid Levels-2 [MENDEL-2]; NCT01763827)., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in phase 2 studies. We conducted a phase 3 trial to evaluate the safety and efficacy of 52 weeks of treatment with evolocumab., Methods: We stratified patients with hyperlipidemia according to the risk categories outlined by the Adult Treatment Panel III of the National Cholesterol Education Program. On the basis of this classification, patients were started on background lipid-lowering therapy with diet alone or diet plus atorvastatin at a dose of 10 mg daily, atorvastatin at a dose of 80 mg daily, or atorvastatin at a dose of 80 mg daily plus ezetimibe at a dose of 10 mg daily, for a run-in period of 4 to 12 weeks. Patients with an LDL cholesterol level of 75 mg per deciliter (1.9 mmol per liter) or higher were then randomly assigned in a 2:1 ratio to receive either evolocumab (420 mg) or placebo every 4 weeks. The primary end point was the percent change from baseline in LDL cholesterol, as measured by means of ultracentrifugation, at week 52., Results: Among the 901 patients included in the primary analysis, the overall least-squares mean (±SE) reduction in LDL cholesterol from baseline in the evolocumab group, taking into account the change in the placebo group, was 57.0±2.1% (P<0.001). The mean reduction was 55.7±4.2% among patients who underwent background therapy with diet alone, 61.6±2.6% among those who received 10 mg of atorvastatin, 56.8±5.3% among those who received 80 mg of atorvastatin, and 48.5±5.2% among those who received a combination of 80 mg of atorvastatin and 10 mg of ezetimibe (P<0.001 for all comparisons). Evolocumab treatment also significantly reduced levels of apolipoprotein B, non-high-density lipoprotein cholesterol, lipoprotein(a), and triglycerides. The most common adverse events were nasopharyngitis, upper respiratory tract infection, influenza, and back pain., Conclusions: At 52 weeks, evolocumab added to diet alone, to low-dose atorvastatin, or to high-dose atorvastatin with or without ezetimibe significantly reduced LDL cholesterol levels in patients with a range of cardiovascular risks. (Funded by Amgen; DESCARTES ClinicalTrials.gov number, NCT01516879.).

Background: Evolocumab (AMG 145), a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein cholesterol (LDL-C) in phase 2 studies of 12 weeks' duration. The longer-term efficacy and safety of PCSK9 inhibition remain undefined., Methods and Results: Of 1359 randomized and dosed patients in the 4 evolocumab phase 2 parent studies, 1104 (81%) elected to enroll into the Open-Label Study of Long-term Evaluation Against LDL-C (OSLER) study. Regardless of their treatment assignment in the parent study, patients were randomized 2:1 to receive either open-label subcutaneous evolocumab 420 mg every 4 weeks with standard of care (SOC) (evolocumab+SOC, n=736) or SOC alone (n=368). Ninety-two percent of patients in the evolocumab+SOC group and 89% of patients in the SOC group completed 52 weeks of follow-up. Patients who first received evolocumab in OSLER experienced a mean 52.3% [SE, 1.8%] reduction in LDL-C at week 52 (P<0.0001). Patients who received 1 of 6 dosing regimens of evolocumab in the parent studies and received evolocumab+SOC in OSLER had persistent LDL-C reductions (mean reduction, 50.4% [SE, 0.8%] at the end of the parent study versus 52.1% [SE, 1.0%] at 52 weeks; P=0.31). In patients who discontinued evolocumab on entry into OSLER, LDL-C levels returned to near baseline levels. Adverse events and serious adverse events occurred in 81.4% and 7.1% of the evolocumab+SOC group patients and 73.1% and 6.3% of the SOC group patients, respectively., Conclusion: Evolocumab dosed every 4 weeks demonstrated continued efficacy and encouraging safety and tolerability over 1 year of treatment in the largest and longest evaluation of a PCSK9 inhibitor in hypercholesterolemic patients to date., Clinical Trial Registration Url: http://clinicaltrials.gov. Unique identifier: NCT01439880.

We investigated whether real-time ultrasound perfusion imaging (rt-UPI) is able to detect perfusion changes related to arterial recanalization in the acute phase of middle cerebral artery (MCA) stroke. Twenty-four patients with acute territorial MCA stroke were examined with rt-UPI and transcranial color-coded duplex ultrasound (TCCD). Ultrasound studies were consecutively performed within 24 h and 72-96 h after stroke onset. Real-time UPI parameters of bolus kinetics (time to peak, rt-TTP) and of refill kinetics (plateau A and slope β of the exponential replenishment curve) were calculated from regions of interest of ischemic versus normal brain tissue; these parameters were compared between early and follow-up examinations in patients who recanalized. At the early examination, there was a delay of rt-TTP in patients with MCA occlusion (rt-TTP [s]: 13.09 ± 3.21 vs. 10.16 ± 2.6; p = 0.01) and a lower value of the refill parameter β (β [1/s]: 0.62 ± 0.34 vs. 1.09 ± 0.58; p = 0.01) in ischemic compared with normal brain tissue, whereas there were no differences of the parameters A and Axβ. At follow-up, the delay of rt-TTP was reversible once recanalization of an underlying MCA obstruction was demonstrated: rt-TTP [s], 13.09 ± 3.21 at 24 h versus 10.95 ± 1.5 at 72-96 h (p = 0.03). Correspondingly, β showed a higher slope than at the first examination: β [1/s]: 0.55 ± 0.29 at 24 h versus 0.71 ± 0.27 at 72-96 h (p = 0.04). We conclude that real-time UPI can detect hemodynamic impairment in acute MCA occlusion and subsequent improvement following arterial recanalization. This offers the chance for bedside monitoring of the hemodynamic compromise (e.g. during therapeutic interventions such as systemic thrombolysis)., (Copyright © 2013 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases serum LDL-cholesterol (LDL-C) concentrations. We assessed the effects of AMG 145, a human monoclonal antibody against PCSK9, in patients with hypercholesterolaemia in the absence of concurrent lipid-lowering treatment., Methods: In a phase 2 trial done at 52 centres in Europe, the USA, Canada, and Australia, patients (aged 18-75 years) with serum LDL-C concentrations of 2·6 mmol/L or greater but less than 4·9 mmol/L were randomly assigned equally through an interactive voice response system to subcutaneous injections of AMG 145 70 mg, 105 mg, or 140 mg, or placebo every 2 weeks; subcutaneous AMG 145 280 mg, 350 mg, or 420 mg or placebo every 4 weeks; or oral ezetimibe 10 mg/day. The primary endpoint was percentage change from baseline in LDL-C concentration at week 12. Analysis was by modified intention to treat. Study personnel and patients were masked to treatment assignment of AMG 145 or placebo. Ezetimibe assignment was open label. This trial is registered with ClinicalTrials.gov, number NCT01375777., Findings: 406 patients were assigned to AMG 145 70 mg (n=45), 105 mg (n=46), or 140 mg (n=45) every 2 weeks; AMG 145 280 mg (n=45), 350 mg (n=45), or 420 mg (n=45) every 4 weeks; placebo every 2 weeks (n=45) or every 4 weeks (n=45); or ezetimibe (n=45). AMG 145 significantly reduced LDL-C concentrations in all dose groups (mean baseline LDL-C concentration 3·7 mmol/L [SD 0·6]; changes from baseline with every 2 weeks AMG 145 70 mg -41·0% [95% CI -46·2 to -35·8]; 105 mg -43·9% [-49·0 to -38·7]; 140 mg -50·9% [-56·2 to -45·7]; every 4 weeks AMG 145 280 mg -39·0% [-44·1 to -34·0]; 350 mg -43·2% [-48·3 to -38·1]; 420 mg -48·0% [-53·1 to -42·9]; placebo every 2 weeks -3·7% [-9·0 to 1·6]; placebo every 4 weeks 4·5% [-0·7 to 9·8]; and ezetimibe -14·7% [-18·6 to -10·8]; p<0·0001 for all doses vs placebo or ezetimibe). Treatment-emergent adverse events occurred in 136 (50%) of 271 patients in the AMG 145 groups, 41 (46%) of 90 patients in the placebo groups, and 26 (58%) of 45 patients in the ezetimibe group; no deaths or serious treatment-related adverse events were reported., Interpretation: The results of our study support the further assessment of AMG 145 in long-term studies with larger and more diverse populations including patients with documented statin intolerance., Funding: Amgen., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background and Purpose: The importance of cancer-associated hypercoagulability as a possible stroke etiology in patients with cancer has received relatively little attention to date. A recent study has suggested that cancer-associated hypercoagulation may be of special importance in the absence of conventional stroke mechanisms., Methods: We identified patients with ischemic stroke sequentially admitted to our stroke center with the additional diagnosis of active and malignant cancer from 2002 to 2011. By using our prospectively collected stroke, MRI, and laboratory data banks, the etiology and risk factors of stroke, types of cancer, deep vein thrombosis/pulmonary embolism, d-dimer levels, and diffusion-weighted imaging lesion patterns were compared to an age- and sex-matched control group. Patients with cancer with a conventional stroke etiology and patients with an unidentified and/or cancer-associated stroke etiology were analyzed separately., Results: One hundred forty patients with cancer and 140 control subjects were included. Unidentified stroke (P<0.001) and infarction in multiple vascular territories (P<0.001) were significantly more frequent and d-dimer levels significantly higher (P<0.05) in patients with cancer. Vice versa, risk factors such as hypertension (P<0.05) and hyperlipidemia (P<0.01) were more prevalent in control subjects. Deep vein thrombosis and pulmonary embolism were more frequent (P<0.01) and d-dimer levels higher (P<0.01) in the patients with unidentified and/or cancer-associated stroke etiology compared to the patients with cancer with a conventional stroke etiology. Lung and pancreatic cancer were significantly overrepresented and d-dimer levels higher in these patients compared with other patients with cancer (P<0.01)., Conclusions: Our data confirm the concept of cancer-associated hypercoagulation as a widely underestimated important stroke risk factor in patients with cancer, especially in those with severely elevated d-dimer levels and in the absence of conventional risk factors.

The Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) study was a randomized, double-blind, double-dummy, active- and placebo-controlled, multiple-dose, phase 3 study to assess the efficacy and safety of oral recombinant calcitonin for treatment of postmenopausal osteoporosis. A total of 565 women age 46 to 86 (mean 66.5) years were randomized (4:3:2) to receive oral recombinant salmon calcitonin (rsCT) tablets (0.2  mg/d) plus placebo nasal spray, synthetic salmon calcitonin (ssCT) nasal spray (200 IU/d) plus placebo tablets, or placebo (placebo tablets plus placebo nasal spray), respectively for 48 weeks. All women received calcium (≥1000  mg/d) and vitamin D (800 IU/d). Women randomized to oral rsCT had a mean ± SD percent increase from baseline in lumbar spine bone mineral density (BMD) (1.5% ± 3.2%) that was greater than those randomized to ssCT nasal spray (0.78% ± 2.9%) or placebo (0.5% ± 3.2%). Lumbar spine BMD change in those receiving nasal calcitonin did not differ from placebo. Oral rsCT treatment also resulted in greater improvements in trochanteric and total proximal femur BMD than ssCT nasal spray. Reductions in bone resorption markers with oral rsCT were greater than those observed in ssCT nasal spray or placebo recipients. Approximately 80% of subjects in each treatment group experienced an adverse event, the majority of which were mild or moderate in intensity. Gastrointestinal system adverse events were reported by nearly one-half of women in all treatment groups and were the principal reason for premature withdrawals. Less than 10% of women experienced a serious adverse event and no deaths occurred. Overall, oral rsCT was superior to nasal ssCT and placebo for increasing BMD and reducing bone turnover. Oral rsCT was safe and as well tolerated as ssCT nasal spray or placebo. Oral calcitonin may provide an additional treatment alternative for women with postmenopausal osteoporosis., (Copyright © 2012 American Society for Bone and Mineral Research.)

Fibromuscular dysplasia, predominantly found in adult women, is a rare disease of small and middle-sized arteries of the kidney and brain. We present a case of a 12-year-old girl with acute ischemic stroke, due to fibromuscular dysplasia of the distal internal carotid artery and the proximal middle cerebral artery, which was successfully treated with t-PA.

Most osteoporosis drugs act by inhibiting bone resorption. A need exists for osteoporosis therapies that stimulate new bone formation. 2-Methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D(3) (2MD) is a vitamin D analogue that potently stimulates bone formation activity in vitro and in the ovariectomized rat model. In this randomized, double-blind, placebo-controlled study of osteopenic women, the effect of daily oral treatment with 2MD on bone mineral density (BMD), serum markers of bone turnover, and safety were assessed over 1 year. Volunteers were randomly assigned to three treatment groups: placebo (n = 50), 220 ng of 2MD (n = 54), and 440 ng of 2MD (n = 53). In general, 2MD was well tolerated. Although 2MD caused a marked increase in markers of bone formation, it did not significantly increase BMD. Since 2MD also shows marked activity on bone resorption (as revealed by dose-dependent increases in serum C-telopeptide cross-links of type I collagen in this study), 2MD likely stimulated both bone formation and bone resorption, thereby increasing bone remodeling., (Copyright © 2011 American Society for Bone and Mineral Research.)

Background: The MOTION (Monthly Oral Therapy with Ibandronate for Osteoporosis Intervention) study reported that once-monthly ibandronate was noninferior to once-weekly alendronate in terms of increasing bone mineral density (BMD) at the lumbar spine and total hip over 12 months. On analysis of secondary and exploratory end points in MOTION, which included trochanter and femoral neck BMD, monthly ibandronate was found to be noninferior to weekly alendronate. The coprimary, secondary, and exploratory BMD end points from MOTION have been previously reported., Objective: This report presents additional results from the MOTION study, including response rates in terms of lumbar spine and total hip BMD gains above baseline; findings from a comparison of serum concentrations of bone turnover markers; and tolerability analysis, including adverse events that led to withdrawal and gastrointestinal (GI) adverse events., Methods: MOTION was a 12-month (with 15-day follow-up), randomized, multinational, multicenter, double-blind, double-dummy, parallel-group, noninferiority study in postmenopausal women aged 55 to <85 years with osteoporosis. Patients were randomly assigned to receive 150-mg-monthly oral ibandronate and weekly alendronate-matched placebo, or 70-mg-weekly oral alendronate and monthly ibandronate-matched placebo, for 12 months. At baseline, day 7 of treatment, 3 and 6 months, 6 months + 7 days, and 12 months, serum concentrations of markers of bone resorption (C-telopeptide of the a chain of type 1 collagen [sCTX]) and bone formation (serum N-terminal propeptides of type 1 collagen) were measured in a subset of the total trial population. At baseline and month 12, BMD was measured using dual-energy x-ray absorptiometry. Exploratory analyses of patients whose spine, total hip, and trochanter BMD at 12 months were above baseline (responders) were also performed., Results: A total of 1760 women were enrolled (ibandronate, 887 patients; alendronate, 873). The median changes in the trough concentrations of sCTX were -75.5% with monthly ibandronate and -81.2% with weekly alendronate. The percentage of patients with mean lumbar spine and total hip BMD gains above baseline (responders) were 90% and 87%, respectively, for ibandronate and 92% and 90%, respectively, for alendronate. GI adverse events were reported in