Journal of Investigative Medicine最新文献

Background and objectives: Loberamisal, a novel agent that dissociates the post-synaptic density protein 95/neuronal nitric oxide synthase complex and potentiates the α2-containing γ-aminobutyric acid type A receptors, is a potential neuroprotectant that is effective in preclinical studies for acute ischaemic stroke. This trial aims to demonstrate the efficacy and safety of intravenous loberamisal in patients with acute ischaemic stroke (AIS) within 48 hours of onset.

Methods and design: The LAIS (Loberamisal for Acute Ischaemic Stroke) trial is a multicentre, prospective, randomised, double-blind, placebo-controlled phase 3 trial. A total of 998 eligible patients will be randomly assigned to receive either loberamisal or placebo in a 1:1 ratio.

Outcomes: The primary efficacy outcome is proportion of individuals achieving an excellent functional outcome, defined as modified Rankin Scale (mRS) 0-1 at 90 days. Secondary efficacy outcomes include favourable functional outcome (defined as an mRS score of 0 in patients with a baseline NIHSS score of 4 to 7; an mRS score of 0 to 1 in patients with a baseline NIHSS score of 8 to 14; and an mRS score of 0 to 2 in patients with a baseline NIHSS score of 15 to 25), distribution of mRS at 90 days, patients with ≥4 points reduction in National Institutes of Health Stroke Scale score from baseline at 10 days and 30 days, and Barthel Index ≥95 at 90 days. Safety outcomes were adverse events. Exploratory outcomes include the incidence of depressive and anxiety symptoms at 90 days.

Discussion: The LAIS trial will evaluate the potential of loberamisal as a novel neuroprotectant in acute ischaemic stroke.

Trial registration number: NCT06517173.

Aim: Moyamoya disease (MMD) is a chronic, occlusive cerebrovascular disorder with no unified management guidelines. This consensus aims to provide updated, evidence-based recommendations for the diagnosis and treatment of MMD.

Methods: We integrated recent findings from epidemiology, genetics and imaging studies-particularly those published since 2017-along with expert input from over 20 clinical centres. Advances in diagnostic criteria, treatment strategies and perioperative management were reviewed and incorporated to update the 2017 consensus.

Results: Refinements in diagnosis include high-resolution imaging and revised Suzuki staging supplemented by new collateral circulation grading. Treatment strategies emphasise individualised surgical planning, especially extracranial-intracranial bypass, and pharmacological management targeting ischaemic events, cognitive decline and collateral vessel formation. Perioperative care focuses on managing complications such as transient neurological dysfunction and stroke through haemodynamic monitoring and timely imaging.

Conclusions: This updated consensus underscores the value of early diagnosis using advanced imaging, personalised interventions and standardised perioperative care. This initiative aims to enhance clinical outcomes and health-related quality of life in MMD patients, offering a contemporary, evidence-based approach to managing MMD.

Background and purpose: Continuous enteral nutrition treatment is routinely provided in the intensive care unit (ICU) for patients with critically ill stroke and contributes to circadian rhythm disruption because a time-limited diet is part of the normal biological rhythm of diurnal species. Our study aims to evaluate the safety as well as the effectiveness of time-restricted enteral nutrition in ICU patients who have had a severe stroke.

Methods and design: The Time-restricted Enteral Nutrition vs continuous Enteral nutriTion (TENET) research is a multicentre, prospective, randomised, open-blinded, endpoint trial that compares continuous enteral nutrition to time-restricted enteral nutrition in persons who have had a severe stroke. People with severe stroke who score ≥11 points on the National Institutes of Health Stroke Scale (NIHSS) or ≤12 points on the Glasgow Coma Scale (GCS) will be included and randomly assigned to restrict the duration of daytime enteral nutrition to 8-12 hours (time-limited enteral nutrition group) or a 24-hour cycle of continuous enteral nutrition (control group). Until the patient stops receiving enteral nutritional support, passes away, is moved out of the ICU or enteral nutrition is used for 28 days, whichever occurs first, enteral nutritional support will continue. Every patient will have a 90-day follow-up.

Study outcomes: A poor 90-day functional prognosis (which is indicated by a ≥3 points modified Rankin scale (mRS) score) is the primary efficacy endpoint. The secondary efficacy endpoints include the GCS, NIHSS, mRS, the Barthel index (all recorded at discharge), the 90-day Barthel index and the duration of ICU stay. The safety outcomes include adverse events and serious adverse events during hospitalisation, along with the 28- and 90-day mortality.

Discussion: Clinical evidence for the safety as well as effectiveness of time-restricted enteral nutrition in persons with severe stroke will be provided by this TENET study.

Trial registration number: NCT06161948.

Rationale: The potential value of rescue intra-arterial thrombolysis in patients with large vessel occlusion (LVO) stroke treated with mechanical thrombectomy (MT) remains to be validated in randomised trials.

Aim: The Chemical Optimization of Cerebral Embolectomy 2 (CHOICE 2) trial is designed to confirm whether adjunctive intra-arterial alteplase, administered after successful MT, improves clinical outcomes in patients with LVO stroke.

Sample size estimates: A total of 440 patients (220 per group) randomised in a 1:1 ratio to receive intra-arterial thrombolysis or not intra-arterial thrombolysis provides 80% statistical power to detect a 14% absolute benefit in the primary endpoint (the proportion of patients achieving modified Rankin Scale (mRS) 0-1 at 90 days), assuming a rate of 40% in the control group, a 5% two-sided type I error. The sample size also provides >95% power for detecting an 18% absolute benefit in secondary imaging endpoints, assuming a 58% rate in the control group.

Methods and design: Multicentre, randomised, open, blinded end-point assessment phase III trial. Eligible patients are adults (≥18 years) with symptomatic LVO who undergo MT with successful or complete reperfusion at end of the procedure. Patients in the intervention group will receive a 15 min intra-arterial infusion of alteplase (1.0 mg/mL, maximum dose 20 mg).

Study outcomes: The primary outcome is the proportion of patients achieving excellent functional outcome (mRS 0-1) at 90 days. Key secondary outcomes are the presence of hypoperfusion on brain CT perfusion at 36±24 hours post randomisation, infarct expansion, Barthel Index and quality of life. Mortality and symptomatic intracerebral haemorrhage will also be evaluated.

Discussion: This trial will provide evidence whether rescue intra-arterial thrombolysis improves clinical outcome in patients with LVO stroke who achieve successful or complete angiographic reperfusion following MT.

Stroke is a global health concern, requiring early and accurate diagnosis for effective treatment. Differentiating between ischaemic stroke and haemorrhagic stroke is critical, as treatment strategies differ significantly. While neuroimaging is the gold standard for differential diagnosis of stroke code patients, blood biomarkers could be a promising and cost-effective diagnostic method for earlier diagnosis in the prehospital setting, where neuroimaging is unavailable. Studies demonstrate that the biomarker glial fibrillary acidic protein (GFAP) can distinguish ischaemic and haemorrhagic stroke with high specificity, though sensitivity varies based on sampling timing and assay methodology. This narrative review explores the potential of GFAP as a diagnostic biomarker in severe strokes and in identifying large vessel occlusions (LVOs). While studies suggest a correlation between higher GFAP levels and stroke severity in haemorrhagic stroke, evidence for this in ischaemic stroke is inconclusive. Combining GFAP with clinical stroke scales and additional biomarkers has shown promise in identifying LVO. Future research should focus on refining the diagnostic role of GFAP in severe strokes, optimising sample timing and including large cohorts representing the full spectrum of stroke severities.

Background: Intracerebral haemorrhage (ICH) is a critical condition that leads to significant mortality or profound disability. Surgery serves as an important intervention that can save lives; however, the surgical techniques employed globally exhibit considerable variability, and their efficacy remains ambiguous.

Methods: PubMed, Embase, Web of Science and CENTRAL were searched for randomised controlled trials (RCTs). Two independent reviewers extracted data, assessed bias (Cochrane Risk of Bias Tool, V.2) and evidence certainty (Confidence in Network Meta-Analysis). Frequentist network meta-analysis calculated relative risks (RRs) and 95% CIs.

Results: A total of 26 RCTs with 4892 patients with ICH were included. The very-low-certainty evidence network meta-analysis demonstrated that, compared with standard medical care, both endoscopic surgery (mortality: RR 0.66; 95% CI 0.50 to 0.87) and minimally invasive puncture surgery (mortality: RR 0.77; 95% CI 0.64 to 0.93) were associated with decreased mortality. Moreover, low-certainty evidence showed that endoscopic surgery (functional independence: RR 1.62; 95% CI 1.28 to 2.05) and minimally invasive puncture surgery (functional independence: RR 1.53; 95% CI 1.34 to 1.76) were associated with a higher likelihood of functional independence. In contrast, conventional craniotomy (mortality: RR 0.86; 95% CI 0.72 to 1.02; functional independence: RR 1.07; 95% CI 0.90 to 1.28) showed no statistically significant differences.

Conclusions: This systematic review and network meta-analysis found that endoscopic surgery and minimally invasive puncture surgery were associated with lower mortality and better functional outcomes compared with other interventions. However, the certainty of evidence was limited due to heterogeneity in patient populations and treatment protocols. More definitive conclusions will require future large-scale, rigorously designed RCTs that standardise protocols and minimise confounding factors.

Rationale: Adjunctive neuroprotection is a promising strategy for improving functional recovery in patients with acute ischaemic stroke (AIS) treated with mechanical thrombectomy (MT). Remote ischaemic conditioning (RIC) has been shown to be safe and effective in patients with AIS; however, its specific impact on neurological outcomes in patients undergoing MT remains to be established.

Aim: To evaluate the safety and efficacy of adjunctive RIC in improving 90-day functional outcomes in patients with AIS treated with MT, and to compare two treatment durations (14 days vs 30 days).

Methods and design: Safety and Efficacy of Remote Ischaemic Conditioning for Acute Ischaemic Stroke Treated with Mechanical Thrombectomy (RECAST-MT) is a multicentre, randomised, controlled, open-label trial with blinded end-point assessment conducted in China. Patients with AIS caused by large-vessel occlusion in the anterior circulation who are scheduled to undergo MT will be enrolled and randomly assigned in a 1:1:1 ratio to receive 14-day RIC, 30-day RIC or standard treatment alone. To allow for early termination due to futility, an interim analysis will be conducted. Total enrolment will range from a minimum of 1526 patients (if one arm is terminated early) to a maximum of 2105 patients (if all arms reach full recruitment). RIC is performed by intermittently inflating cuffs on the upper arm to a pressure of 200 mm Hg.

Study outcomes: The primary end point is the proportion of patients achieving functional independence (modified Rankin Scale (mRS) score 0-2) at 90 days. Secondary end points include a shift analysis of mRS scores, early neurological improvement and infarct volume on imaging. The primary safety outcome is the incidence of any intracranial haemorrhage within 14 days or at discharge.

Discussion: The RECAST-MT trial will provide phase III evidence on the efficacy of RIC in combination with MT for patients with AIS. If successful, this approach could offer a safe, easy-to-implement and cost-effective neuroprotective therapy in this population.

Trial registration number: NCT06559241.

Background and aims: Loberamisal is a small-molecule agent that inhibits the nNOS-postsynaptic density protein 95 coupling and enhances α2-containing γ-aminobutyric acid type A receptor, which has been shown effective in animal studies. This trial aimed to investigate its safety and therapeutic efficacy in patients with acute ischaemic stroke (AIS) within 48 hours of symptom onset.

Methods: Patients were randomly assigned in a 1:1:1:1 ratio to one of four groups: a low-dose loberamisal group (20 mg/dose), a medium-dose group (40 mg/dose), a high-dose group (60 mg/dose) or a placebo group. All patients received a continuous intravenous infusion treatment once a day for 10 days (60±10 min/dose). The primary efficacy outcome was the proportion of patients achieving an excellent functional outcome (a modified Rankin Scale score of 0-1 at 90 days). The primary safety outcome was the incidence of adverse events (AEs).

Results: A total of 240 patients were randomised, of whom 224 received study treatment from 4 June 2023 to 18 November 2023. The proportion of patients with excellent functional outcome was highest in the medium-dose group (76.7%, 46/60), followed by the high-dose group (70.0%, 42/60), the low-dose group (67.8%, 40/59) and the placebo group (60.7%, 37/61) (p=0.164). Regarding safety, 210 patients experienced at least one AE, with incidences of 80.0% (48/60), 88.3% (53/60) and 91.5% (54/59) in the high, medium and low-dose loberamisal groups, respectively, and 90.2% (55/61) in the placebo group (p=0.260).

Conclusions: Loberamisal injection was well tolerated in patients with AIS within 48 hours of symptom onset in China. The efficacy and optimal dosage of loberamisal for AIS need prospective validation.

Trial registration number: ChiCTR2400081662, NCT06429384.