Abstract
Plasmodium falciparum, the most virulent agent of human malaria, spread from Africa to all continents following the out-of-Africa human migrations. During the transatlantic slave trade ...between the 16th and 19th centuries, it was introduced twice independently to the Americas where it adapted to new environmental conditions (new human populations and mosquito species). Here, we analyzed the genome-wide polymorphisms of 2,635 isolates across the current P. falciparum distribution range in Africa, Asia, Oceania, and the Americas to investigate its genetic structure, invasion history, and selective pressures associated with its adaptation to the American environment. We confirmed that American populations originated from Africa with at least two independent introductions that led to two genetically distinct clusters, one in the North (Haiti and Colombia) and one in the South (French Guiana and Brazil), and an admixed Peruvian group. Genome scans revealed recent and more ancient signals of positive selection in the American populations. Particularly, we detected positive selection signals in genes involved in interactions with hosts (human and mosquito) cells and in genes involved in resistance to malaria drugs in both clusters. Analyses suggested that for five genes, adaptive introgression between clusters or selection on standing variation was at the origin of this repeated evolution. This study provides new genetic evidence on P. falciparum colonization history and on its local adaptation in the Americas.
In migratory animals, high mobility may reduce population structure through increased dispersal and enable adaptive responses to environmental change, whereas rigid migratory routines predict low ...dispersal, increased structure, and limited flexibility to respond to change. We explore the global population structure and phylogeographic history of the bar‐tailed godwit, Limosa lapponica, a migratory shorebird known for making the longest non‐stop flights of any landbird. Using nextRAD sequencing of 14,318 single‐nucleotide polymorphisms and scenario‐testing in an Approximate Bayesian Computation framework, we infer that bar‐tailed godwits existed in two main lineages at the last glacial maximum, when much of their present‐day breeding range persisted in a vast, unglaciated Siberian‐Beringian refugium, followed by admixture of these lineages in the eastern Palearctic. Subsequently, population structure developed at both longitudinal extremes: in the east, a genetic cline exists across latitude in the Alaska breeding range of subspecies L. l. baueri; in the west, one lineage diversified into three extant subspecies L. l. lapponica, taymyrensis, and yamalensis, the former two of which migrate through previously glaciated western Europe. In the global range of this long‐distance migrant, we found evidence of both (1) fidelity to rigid behavioural routines promoting fine‐scale geographic population structure (in the east) and (2) flexibility to colonise recently available migratory flyways and non‐breeding areas (in the west). Our results suggest that cultural traditions in highly mobile vertebrates can override the expected effects of high dispersal ability on population structure, and provide insights for the evolution and flexibility of some of the world's longest migrations.
Intracranial aneurysms (IAs) are exceptional in neonates accounting for less than 2% of all IAs occurring during the first decade of life. Little is known about this pathology in this specific ...population. Because of its scarcity and this specific age at onset, the treatment of IA in neonates is challenging. We describe a rare case of aneurysmal subarachnoid hemorrhage in a neonate and review the current literature.
A 21-day-old boy was admitted for hypotonia, vomiting, and seizures. Computed tomography scan revealed a subarachnoid hemorrhage in the sylvian fissure, a frontoparietal subdural hematoma, a left middle cerebral artery (MCA) aneurysm with a diameter of 11 mm, and an infarct of the MCA frontal region. He was successfully treated with endovascular coiling, neuroprotection, and antiepileptic drugs. Immediate postoperative magnetic resonance imaging showed a good aneurysm occlusion without any further ischemia. The outcome was favorable with extubation at day 10. At follow-up, the child experienced normal psychomotor development with no motor deficit.
Ruptured IAs in neonates are rare. Subarachnoid hemorrhage is the most common presentation. Intracranial aneurysms are frequently larger than 10 mm and located on the MCA. The treatment could be surgical or endovascular depending on the characteristics of the aneurysm. There is no recommendation concerning the prevention or treatment of vasospasm in neonates.
Whether thrombectomy alone is equally as effective as intravenous alteplase plus thrombectomy remains controversial. We aimed to determine whether thrombectomy alone would be non-inferior to ...intravenous alteplase plus thrombectomy in patients presenting with acute ischaemic stroke.
In this multicentre, randomised, open-label, blinded-outcome trial in Europe and Canada, we recruited patients with stroke due to large vessel occlusion confirmed with CT or magnetic resonance angiography admitted to endovascular centres. Patients were randomly assigned (1:1) via a centralised web server using a deterministic minimisation method to receive stent-retriever thrombectomy alone or intravenous alteplase plus stent-retriever thrombectomy. In both groups, thrombectomy was initiated as fast as possible with any commercially available Solitaire stent-retriever revascularisation device (Medtronic, Irvine, CA, USA). In the combined treatment group, intravenous alteplase (0·9 mg/kg bodyweight, maximum dose 90 mg per patient) was administered as early as possible after randomisation for 60 min with 10% of the calculated dose given as an initial bolus. Personnel assessing the primary outcome were masked to group allocation; patients and treating physicians were not. The primary binary outcome was a score of 2 or less on the modified Rankin scale at 90 days. We assessed the non-inferiority of thrombectomy alone versus intravenous alteplase plus thrombectomy in all randomly assigned and consenting patients using the one-sided lower 95% confidence limit of the Mantel-Haenszel risk difference, with a prespecified non-inferiority margin of 12%. The main safety endpoint was symptomatic intracranial haemorrhage assessed in all randomly assigned and consenting participants. This trial is registered with ClinicalTrials.gov, NCT03192332, and is closed to new participants.
Between Nov 29, 2017, and May 7, 2021, 5215 patients were screened and 423 were randomly assigned, of whom 408 (201 thrombectomy alone, 207 intravenous alteplase plus thrombectomy) were included in the primary efficacy analysis. A modified Rankin scale score of 0-2 at 90 days was reached by 114 (57%) of 201 patients assigned to thrombectomy alone and 135 (65%) of 207 patients assigned to intravenous alteplase plus thrombectomy (adjusted risk difference -7·3%, 95% CI -16·6 to 2·1, lower limit of one-sided 95% CI -15·1%, crossing the non-inferiority margin of -12%). Symptomatic intracranial haemorrhage occurred in five (2%) of 201 patients undergoing thrombectomy alone and seven (3%) of 202 patients receiving intravenous alteplase plus thrombectomy (risk difference -1·0%, 95% CI -4·8 to 2·7). Successful reperfusion was less common in patients assigned to thrombectomy alone (182 91% of 201 vs 199 96% of 207, risk difference -5·1%, 95% CI -10·2 to 0·0, p=0·047).
Thrombectomy alone was not shown to be non-inferior to intravenous alteplase plus thrombectomy and resulted in decreased reperfusion rates. These results do not support omitting intravenous alteplase before thrombectomy in eligible patients.
Medtronic and University Hospital Bern.
Intravenous thrombolysis is recommended before endovascular treatment, but its value has been questioned in patients who are admitted directly to centres capable of endovascular treatment. Existing ...randomised controlled trials have indicated non-inferiority of endovascular treatment alone or have been statistically inconclusive. We formed the Improving Reperfusion Strategies in Acute Ischaemic Stroke collaboration to assess non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment.
We conducted a systematic review and individual participant data meta-analysis to establish non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment. We searched PubMed and MEDLINE with the terms “stroke”, “endovascular treatment”, “intravenous thrombolysis”, and synonyms for articles published from database inception to March 9, 2023. We included randomised controlled trials on the topic of interest, without language restrictions. Authors of the identified trials agreed to take part, and individual participant data were provided by the principal investigators of the respective trials and collated centrally by the collaborators. Our primary outcome was the 90-day modified Rankin Scale (mRS) score. Non-inferiority of endovascular treatment alone was assessed using a lower boundary of 0·82 for the 95% CI around the adjusted common odds ratio (acOR) for shift towards improved outcome (analogous to 5% absolute difference in functional independence) with ordinal regression. We used mixed-effects models for all analyses. This study is registered with PROSPERO, CRD42023411986.
We identified 1081 studies, and six studies (n=2313; 1153 participants randomly assigned to receive endovascular treatment alone and 1160 randomly assigned to receive intravenous thrombolysis and endovascular treatment) were eligible for analysis. The risk of bias of the included studies was low to moderate. Variability between studies was small, and mainly related to the choice and dose of the thrombolytic drug and country of execution. The median mRS score at 90 days was 3 (IQR 1–5) for participants who received endovascular treatment alone and 2 (1–4) for participants who received intravenous thrombolysis plus endovascular treatment (acOR 0·89, 95% CI 0·76–1·04). Any intracranial haemorrhage (0·82, 0·68–0·99) occurred less frequently with endovascular treatment alone than with intravenous thrombolysis plus endovascular treatment. Symptomatic intracranial haemorrhage and mortality rates did not differ significantly.
We did not establish non-inferiority of endovascular treatment alone compared with intravenous thrombolysis plus endovascular treatment in patients presenting directly at endovascular treatment centres. Further research could focus on cost-effectiveness analysis and on individualised decisions when patient characteristics, medication shortages, or delays are expected to offset a potential benefit of administering intravenous thrombolysis before endovascular treatment.
Stryker and Amsterdam University Medical Centers, University of Amsterdam.
À l’ère de la thrombectomie mécanique (TM), l’utilité de la thrombolyse intraveineuse (TIV) fait débat. Peut-on se passer de la TIV en cas d’occlusion artérielle cérébrale proximale lorsque l’on a un ...accès rapide au plateau de neuroradiologie interventionnelle (NRI) ?
Comparer le pronostic fonctionnel à 3 mois des patients victimes d’un infarctus cérébral (IC) avec occlusion d’un gros vaisseau traités par thérapie combinée (TIV et TM) versus TM seule.
Étude descriptive, rétrospective au CHU de Rouen portant sur les IC survenus entre 11/2011 et 06/2019, directement admis au CHU. Inclusion des IC avec une occlusion proximale éligibles à une TM, associée ou non à une TIV. Comparaison du pronostic fonctionnel des patients traités par thérapie combinée versus TM seule. Inclusion des patients ayant recanalisé suite à la TIV seule. Critère de jugement principal : score de Rankin modifié (mRS) à 3 mois (bonne évolution clinique : mRS≤2).
Au total, 265 patients ont été inclus :115 ont reçu une thérapie combinée et 138 une TM seule. Douze patients ont recanalisé suite à la TIV seule. Bénéfice à la thérapie combinée sur le pronostic fonctionnel à 3 mois par rapport à la TM seule (p=0,006). Taux de décès supérieur dans le groupe traité par TM seule (p=0,048), et absence de différence significative concernant le taux de transformation hémorragique cérébrale, de nouvelles ischémies cérébrales ni du score de recanalisation TICI.
La TIV pourrait faciliter la lyse du thrombus et ainsi le geste de TM, raccourcir les délais de recanalisation sans majorer le risque hémorragique cérébral.
Nos résultats suggèrent de poursuivre la réalisation de la TIV lorsqu’elle est indiquée, en amont de la TM, comme recommandé actuellement. Des études randomisées complémentaires sont néanmoins nécessaires et en cours actuellement.
IMPORTANCE: The benefit of intravenous thrombolysis (IVT) for acute ischemic stroke declines with longer time from symptom onset, but it is not known whether a similar time dependency exists for IVT ...followed by thrombectomy. OBJECTIVE: To determine whether the benefit associated with IVT plus thrombectomy vs thrombectomy alone decreases with treatment time from symptom onset. DESIGN, SETTING, AND PARTICIPANTS: Individual participant data meta-analysis from 6 randomized clinical trials comparing IVT plus thrombectomy vs thrombectomy alone. Enrollment was between January 2017 and July 2021 at 190 sites in 15 countries. All participants were eligible for IVT and thrombectomy and presented directly at thrombectomy-capable stroke centers (n = 2334). For this meta-analysis, only patients with an anterior circulation large-vessel occlusion were included (n = 2313). EXPOSURE: Interval from stroke symptom onset to expected administration of IVT and treatment with IVT plus thrombectomy vs thrombectomy alone. MAIN OUTCOMES AND MEASURES: The primary outcome analysis tested whether the association between the allocated treatment (IVT plus thrombectomy vs thrombectomy alone) and disability at 90 days (7-level modified Rankin Scale mRS score range, 0 no symptoms to 6 death; minimal clinically important difference for the rates of mRS scores of 0-2: 1.3%) varied with times from symptom onset to expected administration of IVT. RESULTS: In 2313 participants (1160 in IVT plus thrombectomy group vs 1153 in thrombectomy alone group; median age, 71 IQR, 62 to 78 years; 44.3% were female), the median time from symptom onset to expected administration of IVT was 2 hours 28 minutes (IQR, 1 hour 46 minutes to 3 hours 17 minutes). There was a statistically significant interaction between the time from symptom onset to expected administration of IVT and the association of allocated treatment with functional outcomes (ratio of adjusted common odds ratio OR per 1-hour delay, 0.84 95% CI, 0.72 to 0.97, P = .02 for interaction). The benefit of IVT plus thrombectomy decreased with longer times from symptom onset to expected administration of IVT (adjusted common OR for a 1-step mRS score shift toward improvement, 1.49 95% CI, 1.13 to 1.96 at 1 hour, 1.25 95% CI, 1.04 to 1.49 at 2 hours, and 1.04 95% CI, 0.88 to 1.23 at 3 hours). For a mRS score of 0, 1, or 2, the predicted absolute risk difference was 9% (95% CI, 3% to 16%) at 1 hour, 5% (95% CI, 1% to 9%) at 2 hours, and 1% (95% CI, −3% to 5%) at 3 hours. After 2 hours 20 minutes, the benefit associated with IVT plus thrombectomy was not statistically significant and the point estimate crossed the null association at 3 hours 14 minutes. CONCLUSIONS AND RELEVANCE: In patients presenting at thrombectomy-capable stroke centers, the benefit associated with IVT plus thrombectomy vs thrombectomy alone was time dependent and statistically significant only if the time from symptom onset to expected administration of IVT was short.
Objective
Recent data have suggested that ineffective tissue reperfusion despite successful angiographic reperfusion was partly responsible for unfavorable outcomes after endovascular therapy (EVT) ...and might be modulated by intravenous thrombolysis (IVT) use before EVT. To specifically decipher the effect played by IVT before EVT, we compared the clinical and safety outcomes of patients who experienced a complete reperfusion at the end of EVT according to IVT use before EVT.
Methods
The Endovascular Treatment in Ischemic Stroke (ETIS) registry is an ongoing, prospective, observational study at 21 centers that perform EVT in France. Patients were included if they had an anterior large vessel occlusion of the intracranial internal carotid artery or middle cerebral artery (M1/M2 segments) and complete reperfusion (expanded Thrombolysis in Cerebral Infarction score = 3) with EVT within 6 hours, between January 2015 and December 2021. The cohort was divided into two groups according to IVT use before EVT, and propensity score matching (PSM) was used to balance the two groups. Primary outcome was the shift in the degree of disability as measured by the modified Rankin Scale (mRS) at 90 days. Secondary outcomes included favorable outcome (mRS 0–2) at 90 days. Safety outcomes included symptomatic intracranial hemorrhage and 90‐day mortality. Outcomes were estimated with multivariate logistic models adjusted for age, National Institutes of Health Stroke Scale, Alberta Stroke Program Early CT Score, and time from symptom onset to puncture.
Results
Among 5,429 patients included in the ETIS registry, 1,093 were included in the study, including 651 patients with complete recanalization treated with IVT before EVT. After PSM, 488 patients treated with IVT before EVT were compared to 337 patients without IVT. In the matched cohort analysis, the IVT+EVT group had a favorable shift in the overall mRS score distribution (adjusted odds ratio aOR = 1.41, 95% confidence interval CI = 1.04–1.91, p = 0.023) and higher rates of favorable outcome (61.1% vs 48.7%, aOR = 1.49, 95% CI = 1.02–2.20, p = 0.041) at 90 days compared with the EVT alone group. Rates of symptomatic intracerebral hemorrhage were comparable between both groups (6.0% vs 4.3%, aOR = 1.16, 95% CI = 0.53–2.54, p = 0.709).
Interpretation
In clinical practice, even after complete angiographic reperfusion by EVT, prior IVT use improves clinical outcomes of patients without increasing bleeding risk. ANN NEUROL 2024;95:762–773
Background and purpose
Patients with acute ischaemic stroke and a large vessel occlusion who present to a non‐endovascular‐capable centre often require inter‐hospital transfer for thrombectomy. ...Whether the inter‐hospital transfer time is associated with 3‐month functional outcome is poorly known.
Methods
Acute stroke patients enrolled between January 2015 and December 2022 in the prospective French multicentre Endovascular Treatment of Ischaemic Stroke registry were retrospectively analysed. Patients with an anterior circulation large vessel occlusion transferred from a non‐endovascular to a comprehensive stroke centre for thrombectomy were eligible. Inter‐hospital transfer time was defined as the time between imaging in the referring hospital and groin puncture for thrombectomy. The relationship between transfer time and favourable 3‐month functional outcome (modified Rankin Scale 0–2) was assessed through a mixed logistic regression model adjusting for centre and symptom‐onset‐to‐referring‐hospital imaging time, age, sex, diabetes, referring hospital National Institutes of Health Stroke Scale score, Alberta Stroke Programme Early Computed Tomography Score, occlusion site and intravenous thrombolysis use.
Results
Overall, 3769 patients were included (median inter‐hospital transfer time 161 min, interquartile range 128–195; 46% with favourable outcome). A longer transfer time was independently associated with lower rates of favourable outcome (p < 0.001). Compared to patients with transfer time below 120 min, there was a 15% reduction in the odds of achieving favourable outcome for transfer times between 120 and 180 min (adjusted odds ratio 0.85; 95% confidence interval 0.67–1.07), and a 36% reduction for transfer times beyond 180 min (adjusted odds ratio 0.64; 95% confidence interval 0.50–0.81).
Conclusions
A shorter inter‐hospital transfer time is strongly associated with favourable 3‐month functional outcome. A speedier inter‐hospital transfer is of critical importance to improve outcome.
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