Tranexamic acid versus placebo in individuals with intracerebral haemorrhage treated within 2 h of symptom onset (STOP-MSU): an international, double-blind, randomised, phase 2 trial.

BACKGROUND: Tranexamic acid, an antifibrinolytic agent, might attenuate haematoma growth after an intracerebral haemorrhage. We aimed to determine whether treatment with intravenous tranexamic acid within 2 h of an intracerebral haemorrhage would reduce haematoma growth compared with placebo. METHODS: STOP-MSU was an investigator-led, double-blind, randomised, phase 2 trial conducted at 24 hospitals and one mobile stroke unit in Australia, Finland, New Zealand, Taiwan, and Viet Nam. Eligible participants had acute spontaneous intracerebral haemorrhage confirmed on non-contrast CT, were aged 18 years or older, and could be treated with the investigational product within 2 h of stroke onset. Using randomly permuted blocks (block size of 4) and a concealed pre-randomised assignment procedure, participants were randomly assigned (1:1) to receive intravenous tranexamic acid (1 g over 10 min followed by 1 g over 8 h) or placebo (saline; matched dosing regimen) commencing within 2 h of symptom onset. Participants, investigators, and treating teams were masked to group assignment. The primary outcome was haematoma growth, defined as either at least 33% relative growth or at least 6 mL absolute growth on CT at 24 h (target range 18-30 h) from the baseline CT. The analysis was conducted within the estimand framework with primary analyses adhering to the intention-to-treat principle. The primary endpoint and secondary safety endpoints (mortality at days 7 and 90 and major thromboembolic events at day 90) were assessed in all participants randomly assigned to treatment groups who did not withdraw consent to use any data. This study was registered with ClinicalTrials.gov, NCT03385928, and the trial is now complete. FINDINGS: Between March 19, 2018, and Feb 27, 2023, 202 participants were recruited, of whom one withdrew consent for any data use. The remaining 201 participants were randomly assigned to either placebo (n=98) or tranexamic acid (n=103; intention-to-treat population). Median age was 66 years (IQR 55-77), and 82 (41%) were female and 119 (59%) were male; no data on race or ethnicity were collected. CT scans at baseline or follow-up were missing or of inadequate quality in three participants (one in the placebo group and two in the tranexamic acid group), and were considered missing at random. Haematoma growth occurred in 37 (38%) of 97 assessable participants in the placebo group and 43 (43%) of 101 assessable participants in the tranexamic acid group (adjusted odds ratio [aOR] 1·31 [95% CI 0·72 to 2·40], p=0·37). Major thromboembolic events occurred in one (1%) of 98 participants in the placebo group and three (3%) of 103 in the tranexamic acid group (risk difference 0·02 [95% CI -0·02 to 0·06]). By 7 days, eight (8%) participants in the placebo group and eight (8%) in the tranexamic acid group had died (aOR 1·08 [95% CI 0·35 to 3·35]) and by 90 days, 15 (15%) participants in the placebo group and 19 (18%) in the tranexamic acid group had died (aOR 1·61 [95% CI 0·65 to 3·98]). INTERPRETATION: Intravenous tranexamic acid did not reduce haematoma growth when administered within 2 h of intracerebral haemorrhage symptom onset. There were no observed effects on other imaging endpoints, functional outcome, or safety. Based on our results, tranexamic acid should not be used routinely in primary intracerebral haemorrhage, although results of ongoing phase 3 trials will add further context to these findings. FUNDING: Australian Government Medical Research Future Fund.

Markers of susceptibility to cardiac arrhythmia in experimental spinal cord injury and the impact of sympathetic stimulation and exercise training.

Injury to descending autonomic (sympathetic) pathways is common after high-level spinal cord injury (SCI) and associated with abnormal blood pressure and heart rate regulation. In individuals with high-level SCI, abnormal sympathovagal balance (such as during autonomic dysreflexia; paroxysmal hypertension provoked by sensory stimuli below the injury) is proarrhythmogenic. Exercise training is a key component of SCI rehabilitation and management of cardiovascular disease risk, but it is unclear whether exercise training influences susceptibility to cardiac arrhythmia. We aimed to evaluate: (i) whether susceptibility to arrhythmia increases in a rodent-model of SCI; (ii) the impact of the sympathomimetic drug dobutamine (DOB) on arrhythmia risk; (iii) whether exercise training ameliorates arrhythmia risk. Twenty-one Wistar rats were divided into 3 subgroups: T2-contusive SCI (T2, n = 7), T2-contusive SCI completing passive hindlimb cycling training (PHLC, n = 7), and T10-contusive SCI (T10, n = 7). Known electrocardiographic arrhythmia markers and heart rate variability parameters were evaluated before (PRE), 1-week (POST) and 5-weeks post-SCI (TERM) at baseline and during DOB infusion (30 µg/kg/min). Baseline markers of arrhythmia risk were increased in both T2 and T10 animals. DOB decreased R-R interval (p < 0.001), and increased markers of risk for ventricular arrhythmia, particularly in high-level (T2) animals (p < 0.05). Exercise training blunted the exacerbation of markers of arrhythmia risk in the presence of DOB. Markers of risk for cardiac arrhythmia are increased in experimental SCI, and DOB further increases arrhythmia risk in high-level SCI. Exercise training did not improve markers of arrhythmia risk at rest, but did ameliorate markers of arrhythmia risk during sympathetic stimulation.

Epigenetic alterations following early postnatal stress: a review on novel aetiological mechanisms of common psychiatric disorders.

Stressor exposure during early life has the potential to increase an individual's susceptibility to a number of neuropsychiatric conditions such as mood and anxiety disorders and schizophrenia in adulthood. This occurs in part due to the dysfunctional stress axis that persists following early adversity impairing stress responsivity across life. The mechanisms underlying the prolonged nature of this vulnerability remain to be established. Alterations in the epigenetic signature of genes involved in stress responsivity may represent one of the neurobiological mechanisms. The overall aim of this review is to provide current evidence demonstrating changes in the epigenetic signature of candidate gene(s) in response to early environmental adversity. More specifically, this review analyses the epigenetic signatures of postnatal adversity such as childhood abuse or maltreatment and later-life psychopathology in human and animal models of early life stress. The results of this review shows that focus to date has been on genes involved in the regulation of hypothalamic-pituitary-adrenal (HPA) axis and its correlation to subsequent neurobiology, for example, the role of glucocorticoid receptor gene. However, epigenetic changes in other candidate genes such as brain-derived neurotrophic factor (BDNF) and serotonin transporter are also implicated in early life stress (ELS) and susceptibility to adult psychiatric disorders. DNA methylation is the predominantly studied epigenetic mark followed by histone modifications specifically acetylation and methylation. Further, these epigenetic changes are cell/tissue-specific in regulating expression of genes, providing potential biomarkers for understanding the trajectory of early stress-induced susceptibility to adult psychiatric disorders.

Maternal separation modifies behavioural and neuroendocrine responses to stress in CCR7 deficient mice.

Alterations in immune function of various humoral and cellular factors, including chemokines, secondary to early stress may play a role in the enhanced vulnerability to psychiatric conditions in those with a history of childhood adversity. C57BL/6 (WT) mice and mice deficient for the chemokine receptor type 7 (CCR7(-/-)) were used to determine the effects of maternal separation on a range of behaviours and the biological stress response. Unpredictable maternal separation (MS) was conducted for 3h daily from postnatal day 1 to 14, with subsequent behavioural testing at 10 weeks of age. Corticosterone was quantified in 11-week-old mice. Maternally separated (MS) CCR7(-/-), but not WT mice, displayed reduced interest in social novelty compared to CCR7(-/-) naïve mice. Separated CCR7(-/-) mice also exhibited significantly lower serum corticosterone concentrations compared to non-separated mice. CCR7(-/-) mice spent less time in the centre during an open field test and more time in the closed arm of the elevated zero maze compared to their wild-type (WT) controls suggesting they were more anxious, however, no difference was observed between MS and control mice in either strain or test. Together these findings suggest that CCR7 is involved in mediating social behaviour and stress response following maternal separation, whereas other behaviours such as anxiety appear to be modified by CCR7 independent of maternal separation. The observed altered cell-mediated immune function possibly underlying the behavioural and neuroendocrine differences in CCR7(-/-) mice following maternal separation requires further investigation.