Stereotactic radiotherapy as a valuable therapeutic procedure for controlling aldosterone-secreting adrenocortical carcinoma.

Aldosterone-secreting adrenocortical carcinomas (ACCs) are rare and usually present as large tumors. The only potentially curative treatment for ACC is surgical resection. However, surgery may be unfeasible in some patients who have multiple comorbidities or decline the procedure. We describe herein the case of a 44-year-old man with aldosterone-secreting ACC who declined surgery because of religious convictions. As a Jehovah's Witness, the patient was concerned about requiring blood transfusion during surgery. Treatment with mitotane was started but interrupted due to hepatotoxicity. Subsequently, the patient was successfully treated with stereotactic ablative radiotherapy (SABR). After SABR, the patient had progressive improvement of pain, reduction in antihypertensive drugs, control of blood pressure and hypokalemia, normalization of serum aldosterone and renin levels, and reduction in tumor size and weight. To our knowledge, this is the first report of a patient with a pure aldosterone-secreting ACC who received SABR. The patient's response was substantial, showing that SABR could be considered as an alternative local treatment for aldosterone-secreting ACCs when surgery is unfeasible.

Identifying prognostic hub genes and key pathways in pediatric adrenocortical tumors through RNA sequencing and Co-expression analysis.

Pediatric adrenocortical tumors (ACTs), rare conditions with uncertain prognoses, have high incidence in southern and southeastern Brazil. Pediatric ACTs are highly heterogeneous, so establishing prognostic markers for these tumors is challenging. We have conducted transcriptomic analysis on 14 pediatric ACT samples and compared cases with favorable and unfavorable clinical outcomes to identify prognostically significant genes. This comparison showed 1257 differentially expressed genes in favorable and unfavorable cases. Among these genes, 15 out of 60 hub genes were significantly associated with five-year event-free survival (EFS), and 10 had significant diagnostic value for predicting ACT outcomes in an independent microarray dataset of pediatric adrenocortical carcinomas (GSE76019). Overexpression of N4BP2, HSPB6, JUN, APBB1IP, STK17B, CSNK1D, and KDM3A was associated with poorer EFS, whereas lower expression of ISCU, PTPR, PRKAB2, CD48, PRF1, ITGAL, KLK15, and HIST1H3J was associated with worse outcomes. Collectively, these findings underscore the prognostic significance of these hub genes and suggest that they play a potential role in pediatric ACT progression and are useful predictors of clinical outcomes.

Sex-Stratified Genome-Wide Association Study in the Spanish Population Identifies a Novel Locus for Lacunar Stroke.

BACKGROUND: Ischemic stroke (IS) represents a significant health burden globally, necessitating a better understanding of its genetic underpinnings to improve prevention and treatment strategies. Despite advances in IS genetics, studies focusing on the Spanish population and sex-stratified analyses are lacking. METHODS: A case-control genome-wide association study was conducted with 9081 individuals (3493 IS cases and 5588 healthy controls). IS subtypes using Trial of ORG 10172 in Acute Stroke Treatment criteria were explored in a sex-stratified approach. Replication efforts involved the MEGASTROKE, GIGASTROKE, and the UK Biobank international cohorts. Post-genome-wide association study analysis included: in silico proteomic analysis, gene-based analysis, quantitative trait loci annotation, transcriptome-wide association analysis, and bioinformatic analysis using chromatin accessibility data. RESULTS: Identified as associated with IS and its subtypes were 4 significant and independent loci. Replication confirmed 5p15.2 as a new locus associated with small-vessel occlusion stroke, with rs59970332-T as the lead variant (beta [SE], 0.13 [0.02]; P=4.34×10-8). Functional analyses revealed CTNND2 given proximity and its implication in pathways involved in vascular integrity and angiogenesis. Integration of Hi-C data identified additional potentially modulated genes, and in silico proteomic analysis suggested a distinctive blood proteome profile associated with the lead variant. Gene-set enrichment analyses highlighted pathways consistent with small-vessel disease pathogenesis. Gene-based associations with known stroke-related genes such as F2 and FGG were also observed, reinforcing the relevance of our findings. CONCLUSIONS: We found CTNND2 as a potential key molecule in small-vessel occlusion stroke risk, and predominantly in males. This study sheds light on the genetic architecture of IS in the Spanish population, providing novel insights into sex-specific associations and potential molecular mechanisms. Further research, including replication in larger cohorts, is essential for a comprehensive understanding of these findings and for their translation to clinical practice.

Analysis of miR-483-3p and miR-630 expression profile in pediatric adrenocortical tumors and the effect of their modulation on adrenal tumorigenesis in vitro.

Pediatric adrenocortical tumors (ACT) are rare aggressive neoplasms with heterogeneous prognosis. MicroRNA (miRNA) signatures have been associated with cancer diagnosis, treatment response, and outcomes of several types of cancer. However, the role played by miRNAs in pediatric ACT has been poorly explored. In this study, we have evaluated the expression of miR-483-3p and miR-630 in 67 pediatric ACT and 19 non-neoplastic adrenal samples, the effects of the modulations of these miRNAs, and their relationship with the TGF-ß pathway in the H295R and H295A cell lines. Deregulation of both miRNAs was related to survival and disease advanced stages and hence to patients' prognosis. Moreover, modified miR-483-3p and miR-630 in vitro expression decreased cell viability and colony formation capacity, changed how some genes of the TGF-ß pathway, such as TGFBR1, TGFBR2, and SMAD7, are expressed, and altered Smad3, pSmad3, Smad 2/3, N-cadherin, and Vimentin protein expression. Besides that, when inhibition of the TGF-ß pathway was combined with miR-630 overexpression or miR-483-3p silencing, cell viability and colony formation capacity decreased, and protein expression in the TGF-ß pathway changed. Together, the data indicate that both miRNAs participate in the TGF-ß pathway and are therefore potential markers for predicting the prognosis of patients with pediatric ACT.

From guidelines to clinical practice in care for ischaemic stroke patients: A systematic review and expert opinion.

BACKGROUND AND PURPOSE: Guidelines help physicians to provide optimal care for stroke patients, but implementation is challenging due to the quantity of recommendations. Therefore a practical overview related to applicability of recommendations can be of assistance. METHODS: A systematic review was performed on ischaemic stroke guidelines published in scientific journals, covering the whole acute care process for patients with ischaemic stroke. After data extraction, experts rated the recommendations on dimensions of applicability, that is, actionability, feasibility and validity, on a 9-point Likert scale. Agreement was defined as a score of ≥8 by ≥80% of the experts. RESULTS: Eighteen articles were identified and 48 recommendations were ultimately extracted. Papers were included only if they described the whole acute care process for patients with ischaemic stroke. Data extraction and analysis revealed variation in terms of both content and comprehensiveness of this description. Experts reached agreement on 34 of 48 (70.8%) recommendations in the dimension actionability, for 16 (33.3%) in feasibility and for 15 (31.3%) in validity. Agreement on all three dimensions was reached for seven (14.6%) recommendations: use of a stroke unit, exclusion of intracerebral haemorrhage as differential diagnosis, administration of intravenous thrombolysis, performance of electrocardiography/cardiac evaluation, non-invasive vascular examination, deep venous thrombosis prophylaxis and administration of statins if needed. DISCUSSION AND CONCLUSION: Substantial variation in agreement was revealed on the three dimensions of the applicability of recommendations. This overview can guide stroke physicians in improving the care process and removing barriers where implementation may be hampered by validity and feasibility.

Full range leadership style and its effect on effectiveness, employee satisfaction, and extra effort: an empirical study.

The purpose of this study is to determine if there is a positive relationship between full-range leadership and employees' effort, efficiency, and satisfaction. A questionnaire was administered to 577 executives from Colombian companies, and the data was analyzed using a partial least squares structural equation modeling (PLS-SEM) approach. The results show that both transformational and transactional leadership have a direct and significant impact on extra effort, effectiveness, and satisfaction, with transformational leadership having the greatest impact on these factors. Conversely, passive-avoidant leadership has negative effects on these three constructs. This study validates the effectiveness of the MLQ 5X in a South American country, a geographical region where such studies are in their early stages. Finally, the whole range of leadership styles-transformational, transactional, and passive-avoidant-is looked at. These styles are seen as second-order constructs that challenge latent multidimensional models as they emerge.

Towards better mortality prediction in cancer patients in the ICU: a comparative analysis of prognostic scales: systematic literature review.

OBJECTIVE: To evaluate the predictive ability of mortality prediction scales in cancer patients admitted to intensive care units (ICUs). DESIGN: A systematic review of the literature was conducted using a search algorithm in October 2022. The following databases were searched: PubMed, Scopus, Virtual Health Library (BVS), and Medrxiv. The risk of bias was assessed using the QUADAS-2 scale. SETTING: ICUs admitting cancer patients. PARTICIPANTS: Studies that included adult patients with an active cancer diagnosis who were admitted to the ICU. INTERVENTIONS: Integrative study without interventions. MAIN VARIABLES OF INTEREST: Mortality prediction, standardized mortality, discrimination, and calibration. RESULTS: Seven mortality risk prediction models were analyzed in cancer patients in the ICU. Most models (APACHE II, APACHE IV, SOFA, SAPS-II, SAPS-III, and MPM II) underestimated mortality, while the ICMM overestimated it. The APACHE II had the SMR (Standardized Mortality Ratio) value closest to 1, suggesting a better prognostic ability compared to the other models. CONCLUSIONS: Predicting mortality in ICU cancer patients remains an intricate challenge due to the lack of a definitive superior model and the inherent limitations of available prediction tools. For evidence-based informed clinical decision-making, it is crucial to consider the healthcare team's familiarity with each tool and its inherent limitations. Developing novel instruments or conducting large-scale validation studies is essential to enhance prediction accuracy and optimize patient care in this population.

Pilot monitoring study in patients with diabetic kidney disease using NORA application.

INTRODUCTION: Diabetic Kidney Disease (DKD) is the most common cause of end-stage chronic kidney disease (CKD), conditioning these patients to a worse renal prognosis and higher cardiovascular mortality and/or requirement for renal replacement therapy. The use of novel information and communication technologies (ICTs) focused on the field of health, may facilitates a better quality of life and disease control in these patients. Our objective is to evaluate the effect of monitoring DKD patients using NORA-app. MATERIAL AND METHODS: Prospective feasibility/validation study of NORA-app in patients with DKD stage G3bA3 or higher, followed in outpatient clinics of a tertiary care hospital. NORA-app is an application for smartphones designed to control risk factors, share educational medical information, communicate via chat with health professionals, increase treatment compliance (Morisky-Green), and collect patient reported outcomes such as anxiety and depression using HADs scale. Clinical-laboratory variables were collected at 3 months and compared to control patients who declined using NORA-app. RESULTS: From 01/01/2021 to 03/03/2022 the use of NORA-app was offered to 118 patients, 82 accepted and 36 declined (controls). After a mean follow-up period of 6,04 months and at the time of data extraction 71 (86.6%) NORA-app patients remain active users, 2 have completed the follow-up at one year and 9 are inactive (3 due to death and 6 due to non-locatable). There were no differences in baseline characteristics including Creatinine [2.1 (1.6-2.4) vs. 1.9 (1.5-2.5)] mg/dL and alb/creat [962 (475-1784) vs. 1036 (560-2183)] mg/gr between Nora and control patients respectively. The therapeutic compliance rate in the NORA-app group was 77%, improving at 90 days to 91%. Patients in the NORA-group showed significantly lower levels of alb/creat than controls (768(411-1971) mg/g Vs 2039 (974-3214) p = 0.047) at 90-day follow-up. CONCLUSIONS: In patients with DKD the use of NORA-app was maintained in the long-term, leading to high levels of treatment compliance, and achieving a better disease control. Our study suggests that the generalized use of ICTs may help in the personalized monitoring of these patients to delay the progression of kidney disease.

Assessment of smoking care by stroke specialists in patients with recent TIA and minor stroke: an international prospective registry-based cohort study.

OBJECTIVES: The objectives are to assess smoking abstinence and its effects on vascular risk and to report tobacco-cessation counselling and pharmacotherapy use in patients who had a recent minor stroke or transient ischaemic attack (TIA). DESIGN AND SETTING: The TIA registry.org project is a prospective, observational registry of patients with TIA and minor stroke that occurred in the previous 7 days with a 5-year follow-up, involving 61 sites with stroke specialists in 21 countries (Europe, Asia, Latin America and Middle East). Of those, 42 sites had 5-year follow-up data on more than 50% of their patients and were included in the present study. PARTICIPANTS: From June 2009 through December 2011, 3847 patients were eligible for the study (80% of the initial cohort). OUTCOMES: Tobacco counselling and smoking-cessation pharmacotherapy use in smoking patients were reported at discharge. Association between 3-month smoking status and risk of a major cardiovascular event (MACE) was analysed with multivariable Cox regression model. RESULTS: Among 3801 patients included, 835 (22%) were smokers. At discharge, only 35.2% have been advised to quit and 12.5% had smoking-cessation pharmacotherapy prescription. At 3 months, 383/835 (46.9%) baseline smokers were continuers. Living alone and alcohol abuse were associated with persistent smoking; high level of education, aphasia and dyslipidaemia with quitting. The adjusted HRs for MACE at 5 years were 1.13 (95% CI 0.90 to 1.43) in former smokers, 1.31 (95% CI 0.93 to 1.84) in quitters and 1.31 (95% CI 0.94 to 1.83) in continuers. Using time-varying analysis, current smoking at the time of MACE non-significantly increased the risk of MACE (HR 1.31 (95% CI 0.97 to 1.78); p=0.080). CONCLUSION: In the TIAregistry.org, smoking-cessation intervention was used in a minority of patients. Surprisingly, in this population in which, at 5 years, other vascular risk factors were well controlled and antithrombotic treatment maintained, smoking cessation non-significantly decreased the risk of MACE.

Tenecteplase versus alteplase for thrombolysis in patients selected by use of perfusion imaging within 4·5 h of onset of ischaemic stroke (TASTE): a multicentre, randomised, controlled, phase 3 non-inferiority trial.

BACKGROUND: Intravenous tenecteplase increases reperfusion in patients with salvageable brain tissue on perfusion imaging and might have advantages over alteplase as a thrombolytic for ischaemic stroke. We aimed to assess the non-inferiority of tenecteplase versus alteplase on clinical outcomes in patients selected by use of perfusion imaging. METHODS: This international, multicentre, open-label, parallel-group, randomised, clinical non-inferiority trial enrolled patients from 35 hospitals in eight countries. Participants were aged 18 years or older, within 4·5 h of ischaemic stroke onset or last known well, were not being considered for endovascular thrombectomy, and met target mismatch criteria on brain perfusion imaging. Patients were randomly assigned (1:1) by use of a centralised web server with randomly permuted blocks to intravenous tenecteplase (0·25 mg/kg) or alteplase (0·90 mg/kg). The primary outcome was the proportion of patients without disability (modified Rankin Scale 0-1) at 3 months, assessed via masked review in both the intention-to-treat and per-protocol populations. We aimed to recruit 832 participants to yield 90% power (one-sided alpha=0·025) to detect a risk difference of 0·08, with an absolute non-inferiority margin of -0·03. The trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000243718, and the European Union Clinical Trials Register, EudraCT Number 2015-002657-36, and it is completed. FINDINGS: Recruitment ceased early following the announcement of other trial results showing non-inferiority of tenecteplase versus alteplase. Between March 21, 2014, and Oct 20, 2023, 680 patients were enrolled and randomly assigned to tenecteplase (n=339) and alteplase (n=341), all of whom were included in the intention-to-treat analysis (multiple imputation was used to account for missing primary outcome data for five patients). Protocol violations occurred in 74 participants, thus the per-protocol population comprised 601 people (295 in the tenecteplase group and 306 in the alteplase group). Participants had a median age of 74 years (IQR 63-82), baseline National Institutes of Health Stroke Scale score of 7 (4-11), and 260 (38%) were female. In the intention-to-treat analysis, the primary outcome occurred in 191 (57%) of 335 participants allocated to tenecteplase and 188 (55%) of 340 participants allocated to alteplase (standardised risk difference [SRD]=0·03 [95% CI -0·033 to 0·10], one-tailed pnon-inferiority=0·031). In the per-protocol analysis, the primary outcome occurred in 173 (59%) of 295 participants allocated to tenecteplase and 171 (56%) of 306 participants allocated to alteplase (SRD 0·05 [-0·02 to 0·12], one-tailed pnon-inferiority=0·01). Nine (3%) of 337 patients in the tenecteplase group and six (2%) of 340 in the alteplase group had symptomatic intracranial haemorrhage (unadjusted risk difference=0·01 [95% CI -0·01 to 0·03]) and 23 (7%) of 335 and 15 (4%) of 340 died within 90 days of starting treatment (SRD 0·02 [95% CI -0·02 to 0·05]). INTERPRETATION: The findings in our study provide further evidence to strengthen the assertion of the non-inferiority of tenecteplase to alteplase, specifically when perfusion imaging has been used to identify reperfusion-eligible stroke patients. Although non-inferiority was achieved in the per-protocol population, it was not reached in the intention-to-treat analysis, possibly due to sample size limtations. Nonetheless, large-scale implementation of perfusion CT to assist in patient selection for intravenous thrombolysis in the early time window was shown to be feasible. FUNDING: Australian National Health Medical Research Council; Boehringer Ingelheim.

Stent Retriever AssIsted Lysis Technique with Tirofiban: A Potential Bailout Alternative to Angioplasty and Stenting.

BACKGROUND AND PURPOSE: Angioplasty and stent placement have been described as a bailout technique in individuals with failed thrombectomy. We aimed to investigate Stent retriever AssIsted Lysis (SAIL) with tirofiban before angioplasty and stent placement. MATERIALS AND METHODS: Patients from 2 comprehensive stroke centers were reviewed (2020-2023). We included patients with failed thrombectomy and/or underlying intracranial stenosis who received SAIL with tirofiban before the intended angioplasty and stent placement. SAIL consisted of deploying a stent retriever through the occluding lesion to create a bypass channel and infuse 10 mL of tirofiban for 10 minutes either intra-arterially or IV. The stent retriever was re-sheathed before retrieval. The primary end points were successful reperfusion (expanded TICI 2b-3) and symptomatic intracerebral hemorrhage. Additional end points included 90-day mRS 0-2 and mortality. RESULTS: After a median of 3 (interquartile range, 2-4) passes, 44 patients received the SAIL bridging protocol with tirofiban, and later they were considered potential candidates for angioplasty and stent placement bailout (43.2%, intra-arterial SAIL). Post-SAIL successful reperfusion was obtained in 79.5%. A notable residual stenosis (>50%) after successful SAIL was observed in 45.7%. No significant differences were detected according to post-SAIL: successful reperfusion (intra-arterial SAIL, 80.0% versus IV-SAIL, 78.9%; P = .932), significant stenosis (33.3% versus 55.0%; P = .203), early symptomatic re-occlusion (0% versus 8.0%; P = .207), or symptomatic intracerebral hemorrhage (5.3% versus 8.0%; P = .721). Rescue angioplasty and stent placement were finally performed in 15 (34.1%) patients (intra-arterial SAIL 21.0% versus IV-SAIL 44%; P = .112). At 90 days, mRS 0-2 (intra-arterial SAIL 50.0% versus IV-SAIL 43.5%; P = .086) and mortality (26.3% versus 12.0%; P = .223) were also similar. CONCLUSIONS: In patients with stroke in which angioplasty and stent placement are considered, SAIL with tirofiban, either intra-arterial or IV, seems to safely induce sustained recanalization, offering a potential alternative to definitive angioplasty and stent placement.

Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage.

BACKGROUND: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. METHODS: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. RESULTS: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. CONCLUSIONS: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).

Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial.

BACKGROUND: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality. METHODS: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual. FINDINGS: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059). INTERPRETATION: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis. FUNDING: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.

Intracranial thrombus composition is associated with occlusion location and endovascular treatment outcomes: results from ITACAT multicenter study.

BACKGROUND: The impact of thrombolytics directed towards different thrombus components regarding site of occlusion in combination with mechanical thrombectomy (MT) to achieve endovascular complete recanalization is unclear. METHODS: Retrospective analysis of a prospective database in two stroke centers. Intracranial thrombi retrieved by MT were analyzed using hematoxylin-eosin staining for fibrin and red blood cell proportions, and CD61 immunostaining for platelets proportion in thrombus (PLTPT) assessment. Thrombi composition, baseline variables, etiology, treatment features and occlusion location were analyzed. RESULTS: Overall, 221 patients completed the per protocol analysis and 110 cases achieved a final expanded Thrombolysis in Cerebral Infarction (eTICI) 3 (49%) of which 70 were MT (32%) by first pass effect (FPE). Thrombi from medium distal vessel occlusions had higher PLTPT compared with thrombi from proximal large vessel occlusions (68% vs 61%, P=0.026). In particular, middle cerebral artery M2-M3 segment thrombi had the highest PLTPT (70%), and basilar artery thrombi the lowest PLTPT (41%). After logistic regression analysis adjusted for occlusion location and intravenous fibrinolysis, lower baseline National Institutes of Health Stroke Scale score (adjusted OR (aOR) 0.95, 95% CI 0.913 to 0.998) and PLTPT (aOR 0.97, 95% CI 0.963 to 0.993) were independently associated with FPE. Fewer MT passes (aOR 0.67, 95% CI 0.538 to 0.842) and platelet poor thrombus (<62% PLTPT; aOR 2.39, 95% CI 1.288 to 4.440) were independently associated with final eTICI 3. CONCLUSIONS: Occlusion location might be a surrogate parameter for thrombus composition. Platelet poor clots and fewer MT passes were independently associated with complete endovascular recanalization. Clinical trials testing the benefits of combining selective intra-arterial platelet antagonists with MT to improve endovascular outcomes are warranted.

The nightjar and the ant: Intercontinental migration reveals a cryptic interaction.

Birds and ants co-occur in most terrestrial ecosystems and engage in a range of interactions. Competition, mutualism and predation are prominent examples of these interactions, but there are possibly many others that remain to be identified and characterized. This study provides quantitative estimates of the frequency of toe amputations resulting from ant bites in a population of migratory red-necked nightjars (Caprimulgus ruficollis) monitored for 15 years (2009-2023) in S Spain, and identifies the attacker(s) based on taxonomic analyses of ant-mandible remains found on injured toes. Less than 1% of examined adults (N = 369) missed one or more toes. The analysis of ant remains identified African army ants (Dorylus sp.) as the primary cause of toe amputations in nightjars and revealed that body parts of the attacker may remain attached to the birds even after intercontinental migration. No cases of severe damage were observed in juveniles (N = 269), apart from the mandible of a Messor barbarus - a local ant species - attached to one of the teeth of the characteristic comb of the medial toe of nightjars. The incidence of ant-bite damage may appear unimportant for nightjar populations, but this might not be true if only birds that manage to survive their injuries and potential complications (e.g. severe bleeding and sepsis from opportunistic infections) return from the tropics. More field studies, ideally in tropical areas, that incorporate routine examination of ant-induced injuries into their protocols are needed to understand the true incidence and eco-evolutionary implications of antagonistic ant-bird interactions.

A Randomized Controlled Trial of Tenecteplase Versus Standard of Care for Minor Ischemic Stroke with Proven Occlusion (TEMPO-2): Rational and design of a multicenter, randomized open-label clinical trial.

BACKGROUND: Almost half of acute ischemic stroke patients present with mild symptoms and there are large practice variations in their treatment globally. Individuals with an intracranial occlusion who present with minor stroke are at an increased risk of early neurological deterioration and poor outcomes. Individual patient data meta-analysis in the subgroup of patients with minor deficits showed benefit of alteplase in improving outcomes; however, this benefit has not been seen with intravenous alteplase in published randomized trials. DESIGN: TEMPO-2 (A Randomized Controlled Trial of Tenecteplase Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion) is a prospective, open label with blinded outcome assessment, randomized controlled trial, designed to test the superiority of intravenous tenecteplase (0.25 mg/kg) over nonthrombolytic standard of care, with an estimated sample size of 1274 patients. Adult patients presenting with acute ischemic stroke with the National Institutes of Health Stroke Scale (NIHSS) ⩽ 5 and visible arterial occlusion or perfusion deficit within 12 h of onset are randomized to receive either tenecteplase (0.25 mg/kg) or standard of care. The primary outcome is return to baseline neurological functioning, measured by the modified Rankin scale (mRS) at 90 days. Safety outcomes include death and symptomatic hemorrhage (intra or extra-cranial). Other secondary outcomes include mRS 0-1, mRS 0-2, ordinal shift analysis of the mRS, partial, and full recanalization on follow-up computed tomography angiogram. CONCLUSION: Results of this trial will aid in determining whether there is benefit of using tenecteplase (0.25 mg/kg) in treating patients presenting with minor stroke who are at high risk of developing poor outcomes due to presence of an intracranial occlusion. DATA ACCESS STATEMENT: Data will be available upon reasonable request.

Effects of Achieving Rapid, Intensive, and Sustained Blood Pressure Reduction in Intracerebral Hemorrhage Expansion and Functional Outcome.

BACKGROUND AND OBJECTIVES: The time taken to achieve blood pressure (BP) control could be pivotal in the benefits of reducing BP in acute intracerebral hemorrhage (ICH). We aimed to assess the relationship between the rapid achievement and sustained maintenance of an intensive systolic BP (SBP) target with radiologic, clinical, and functional outcomes. METHODS: Rapid, Intensive, and Sustained BP lowering in Acute ICH (RAINS) was a multicenter, prospective, observational cohort study of adult patients with ICH <6 hours and SBP ≥150 mm Hg at 4 Comprehensive Stroke Centers during a 4.5-year period. Patients underwent baseline and 24-hour CT scans and 24-hour noninvasive BP monitoring. BP was managed under a rapid (target achievement ≤60 minutes), intensive (target SBP <140 mm Hg), and sustained (target stability for 24 hours) BP protocol. SBP target achievement ≤60 minutes and 24-hour SBP variability were recorded. Outcomes included hematoma expansion (>6 mL or >33%) at 24 hours (primary outcome), early neurologic deterioration (END, 24-hour increase in NIH Stroke Scale score ≥4), and 90-day ordinal modified Rankin scale (mRS) score. Analyses were adjusted by age, sex, anticoagulation, onset-to-imaging time, ICH volume, and intraventricular extension. RESULTS: We included 312 patients (mean age 70.2 ± 13.3 years, 202 [64.7%] male). Hematoma expansion occurred in 70/274 (25.6%) patients, END in 58/291 (19.9%), and the median 90-day mRS score was 4 (interquartile range, 2-5). SBP target achievement ≤60 minutes (178/312 [57.1%]) associated with a lower risk of hematoma expansion (adjusted odds ratio [aOR] 0.43, 95% confidence interval [CI] 0.23-0.77), lower END rate (aOR 0.43, 95% CI 0.23-0.80), and lower 90-day mRS scores (aOR 0.48, 95% CI 0.32-0.74). The mean 24-hour SBP variability was 21.0 ± 7.6 mm Hg. Higher 24-hour SBP variability was not related to expansion (aOR 0.99, 95% CI 0.95-1.04) but associated with higher END rate (aOR 1.15, 95% CI 1.09-1.21) and 90-day mRS scores (aOR 1.06, 95% CI 1.04-1.10). DISCUSSION: Among patients with acute ICH, achieving an intensive SBP target within 60 minutes was associated with lower hematoma expansion risk. Rapid SBP reduction and stable sustention within 24 hours were related to improved clinical and functional outcomes. These findings warrant the design of randomized clinical trials examining the impact of effectively achieving rapid, intensive, and sustained BP control on hematoma expansion. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in adults with spontaneous ICH and initial SBP ≥150 mm Hg, lowering SBP to <140 mm Hg within the first hour and maintaining this for 24 hours is associated with decreased hematoma expansion.

PRERISK: A Personalized, Artificial Intelligence-Based and Statistically-Based Stroke Recurrence Predictor for Recurrent Stroke.

BACKGROUND: Predicting stroke recurrence for individual patients is difficult, but individualized prediction may improve stroke survivors' engagement in self-care. We developed PRERISK: a statistical and machine learning classifier to predict individual risk of stroke recurrence. METHODS: We analyzed clinical and socioeconomic data from a prospectively collected public health care-based data set of 41 975 patients admitted with stroke diagnosis in 88 public health centers over 6 years (2014-2020) in Catalonia-Spain. A new stroke diagnosis at least 24 hours after the index event was considered as a recurrent stroke, which was considered as our outcome of interest. We trained several supervised machine learning models to provide individualized risk over time and compared them with a Cox regression model. Models were trained to predict early, late, and long-term recurrence risk, within 90, 91 to 365, and >365 days, respectively. C statistics and area under the receiver operating characteristic curve were used to assess the accuracy of the models. RESULTS: Overall, 16.21% (5932 of 36 114) of patients had stroke recurrence during a median follow-up of 2.69 years. The most powerful predictors of stroke recurrence were time from previous stroke, Barthel Index, atrial fibrillation, dyslipidemia, age, diabetes, and sex, which were used to create a simplified model with similar performance, together with modifiable vascular risk factors (glycemia, body mass index, high blood pressure, cholesterol, tobacco dependence, and alcohol abuse). The areas under the receiver operating characteristic curve were 0.76 (95% CI, 0.74-0.77), 0.60 (95% CI, 0.58-0.61), and 0.71 (95% CI, 0.69-0.72) for early, late, and long-term recurrence risk, respectively. The areas under the receiver operating characteristic curve of the Cox risk class probability were 0.73 (95% CI, 0.72-0.75), 0.59 (95% CI, 0.57-0.61), and 0.67 (95% CI, 0.66-0.70); machine learning approaches (random forest and AdaBoost) showed statistically significant improvement (P<0.05) over the Cox model for the 3 recurrence time periods. Stroke recurrence curves can be simulated for each patient under different degrees of control of modifiable factors. CONCLUSIONS: PRERISK is a novel approach that provides a personalized and fairly accurate risk prediction of stroke recurrence over time. The model has the potential to incorporate dynamic control of risk factors.

International consensus on mitotane treatment in pediatric patients with adrenal cortical tumors: indications, therapy, and management of adverse effects.

OBJECTIVE: Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects. METHODS: A Delphi method with 3 rounds of questionnaires within the pACC expert consortium of the international network groups European Network for the Study of Adrenal Tumors pediatric working group (ENSAT-PACT) and International Consortium of pediatric adrenocortical tumors (ICPACT) was used to create 21 final consensus statements. RESULTS: We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stages III and IV and with incomplete resection/tumor spillage. For stage II patients, mitotane is not generally indicated. The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m²/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14 and 20 mg/L. Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2-4 weeks), along with evaluation and assessment of laboratory values, are required. CONCLUSIONS: The Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.

Radial Versus Femoral Access for Mechanical Thrombectomy in Patients With Stroke: A Noninferiority Randomized Clinical Trial.

BACKGROUND: Transfemoral access is predominantly used for mechanical thrombectomy in patients with stroke with a large vessel occlusion. Following the interventional cardiology guidelines, routine transradial access has been proposed as an alternative, although its safety and efficacy remain controversial. We aim to explore the noninferiority of radial access in terms of final recanalization. METHODS: The study was an investigator-initiated, single-center, evaluator-blinded, noninferiority randomized clinical trial. Patients with stroke undergoing mechanical thrombectomy, with a patent femoral artery and a radial artery diameter ≥2.5 mm, were randomly assigned (1:1) to either transradial (60 patients) or transfemoral access (60 patients). The primary binary outcome was the successful recanalization (expanded Treatment in Cerebral Ischemia score, 2b-3) assigned by blinded evaluators. We established a noninferiority margin of -13.2%, considering an acceptable reduction of 15% in the expected recanalization rates. RESULTS: From September 2021 to July 2023, 120 patients were randomly assigned and 116 (58 transradial access and 58 transfemoral access) with confirmed intracranial occlusion on the initial angiogram were included in the intention-to-treat analysis. Successful recanalization was achieved in 51 (87.9%) patients assigned to transfemoral access and in 56/58 (96.6%) patients assigned to transradial (adjusted 1 side risk difference [RD], -5.0% [95% CI, -6.61% to +13.1%]) showing noninferiority of transradial access. Median time from angiosuite arrival to first pass (femoral, 30 [interquartile range, 25-37] minutes versus radial: 41 [interquartile range, 33-62] minutes; P<0.001) and from angiosuite arrival to recanalization (femoral: 42 (IQR, 28-74) versus radial: 59.5 (IQR, 44-81) minutes; P<0.050) were longer in the transradial access group. Both groups presented 1 severe access complication and there was no difference in the rate of access conversion: transradial 7 (12.1%) versus transfemoral 5 (8.6%) (P=0.751). CONCLUSIONS: Among patients who underwent mechanical thrombectomy, transradial access was noninferior to transfemoral access in terms of final recanalization. Procedural delays may favor transfemoral access as the default first-line approach. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05225636.