Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None

A dynamic and mechanistic model of PCB bioaccumulation in the European hake (Merluccius merluccius)

Bioaccumulation is difficult to document because responses differ among chemical compounds, with environmental conditions. and physiological processes characteristic of each species. We use a mechanistic model, based on the Dynamic Energy Budget (DEB) theory, to take into account this complexity and study factors impacting accumulation of organic pollutants in fish through ontogeny. The bioaccumulation model proposed is a comprehensive approach that relates evolution of hake PCB contamination to physiological information about the fish, such as diet, metabolism, reserve and reproduction status. The species studied is the European hake (Merluccius merluccius, L 1758). The model is applied to study the total concentration and the lipid normalised concentration of 4 PCB congeners in male and female hakes from the Gulf of Lions (NW Mediterranean sea) and the Bay of Biscay (NE Atlantic ocean). Outputs of the model compare consistently to measurements over the life span of fish. Simulation results clearly demonstrate the relative effects of food contamination, growth and reproduction on the PCB bioaccumulation in hake. The same species living in different habitats and exposed to different PCB prey concentrations exhibit marked difference in the body accumulation of PCBs. At the adult stage, female hakes have a lower PCB concentration compared to males for a given length. We successfully simulated these sex-specific PCB concentrations by considering two mechanisms: a higher energy allocation to growth for females and a transfer of PCBs from the female to its eggs when allocating lipids from reserve to eggs. Finally, by its mechanistic description of physiological processes, the model is relevant for other species and sets the stage for a mechanistic understanding of toxicity and ecological effects of organic contaminants in marine organisms

Differential biomagnification of PCB, PBDE, Hg and Radiocesium in the food web of the European hake from the NW Mediterranean

International audienceConsumption of marine organisms represents one of the main exposure sources of contaminants for human populations. To obtain a global view of the contamination in commercial fish in the NW Mediterranean Sea, we analysed four types of priority contaminants (PCBs, PBDEs, Hg and 137Cs) in the European hake, Merluccius merluccius, from the Gulf of Lions in relation with organism's trophic level (δ 15N). All contaminants presented a significant increase in concentration in hake muscle with trophic level. However, obvious differences between contaminants were evidenced. Biomagnification factors (BMF and FWMF) along the hake food web were higher for Hg and CB-153 than for BDE-47 and 137Cs, and increase in contaminant concentration with trophic level occurred at different rates depending on contaminants. Such differences of biomagnification patterns can be related to physico-chemical properties of the different contaminants. © 2012 Elsevier Ltd