Intracerebral haemorrhage (ICH) is a devastating condition with limited treatment options, and current understanding of pathophysiology is incomplete. Spontaneous cerebral bleeding is a characteristic of the human condition that has proven difficult to recapitulate in existing pre-clinical rodent models. Zebrafish larvae are frequently used as vertebrate disease models and are associated with several advantages, including high fecundity, optical translucency and non-protected status prior to 5 days post-fertilisation. Furthermore, other groups have shown that zebrafish larvae can exhibit spontaneous ICH. The aim of this study was to investigate whether such models can be utilised to study the pathological consequences of bleeding in the brain, in the context of pre-clinical ICH research. Here, we compared existing genetic (bubblehead) and chemically inducible (atorvastatin) zebrafish larval models of spontaneous ICH and studied the subsequent disease processes. Through live, non-invasive imaging of transgenic fluorescent reporter lines and behavioural assessment we quantified brain injury, locomotor function and neuroinflammation following ICH. We show that ICH in both zebrafish larval models is comparable in timing, frequency and location. ICH results in increased brain cell death and a persistent locomotor deficit. Additionally, in haemorrhaged larvae we observed a significant increase in macrophage recruitment to the site of injury. Live in vivo imaging allowed us to track active macrophage-based phagocytosis of dying brain cells 24 hours after haemorrhage. Morphological analyses and quantification indicated that an increase in overall macrophage activation occurs in the haemorrhaged brain. Our study shows that in zebrafish larvae, bleeding in the brain induces quantifiable phenotypic outcomes that mimic key features of human ICH. We hope that this methodology will enable the pre-clinical ICH community to adopt the zebrafish larval model as an alternative to rodents, supporting future high throughput drug screening and as a complementary approach to elucidating crucial mechanisms associated with ICH pathophysiology.

Intracerebral haemorrhage (ICH) is a devastating condition with limited treatment options, and current understanding of pathophysiology is incomplete. Spontaneous cerebral bleeding is a characteristic of the human condition that has proven difficult to recapitulate in existing pre-clinical rodent models. Zebrafish larvae are frequently used as vertebrate disease models and are associated with several advantages, including high fecundity, optical translucency and non-protected status prior to 5 days post-fertilisation. Furthermore, other groups have shown that zebrafish larvae can exhibit spontaneous ICH. The aim of this study was to investigate whether such models can be utilised to study the pathological consequences of bleeding in the brain, in the context of pre-clinical ICH research. Here, we compared existing genetic (bubblehead) and chemically inducible (atorvastatin) zebrafish larval models of spontaneous ICH and studied the subsequent disease processes. Through live, non-invasive imaging of transgenic fluorescent reporter lines and behavioural assessment we quantified brain injury, locomotor function and neuroinflammation following ICH. We show that ICH in both zebrafish larval models is comparable in timing, frequency and location. ICH results in increased brain cell death and a persistent locomotor deficit. Additionally, in haemorrhaged larvae we observed a significant increase in macrophage recruitment to the site of injury. Live in vivo imaging allowed us to track active macrophage-based phagocytosis of dying brain cells 24 hours after haemorrhage. Morphological analyses and quantification indicated that an increase in overall macrophage activation occurs in the haemorrhaged brain. Our study shows that in zebrafish larvae, bleeding in the brain induces quantifiable phenotypic outcomes that mimic key features of human ICH. We hope that this methodology will enable the pre-clinical ICH community to adopt the zebrafish larval model as an alternative to rodents, supporting future high throughput drug screening and as a complementary approach to elucidating crucial mechanisms associated with ICH pathophysiology.

While strike action has been common since the industrial revolution, it often invokes a passionate and polarising response, from the strikers themselves, from employers, governments and the general public. Support or lack thereof from health workers and the general public is an important consideration in the justification of strike action. This systematic review sought to examine the impact of strike action on patient and clinician attitudes, specifically to explore (1) patient and health worker support for strike action and (2) the predictors for supporting strike action and the reasons given for engaging in strike action. A systematic scoping review was employed to identify all relevant literature, followed by a textual narrative synthesis.A total of 34 studies met inclusion criteria. Support for strike action was largely context-dependent. A range of factors impact support for strike action; broader cultural and structural factors, such as unionisation and general acceptance of strike action; systemic factors, such as the nature of the healthcare system, including infrastructure and work conditions; the strike itself and a range of individual factors, the most notable of which was being a student or in an early career stage. There were also some surprising results, for example, during doctors strike, nurses were provided with the opportunity to expand their role, which led to greater professional autonomy and job satisfaction.

The placenta mediates the transfer of maternal nutrients into the fetal circulation while removing fetal waste products, drugs and environmental toxins that may otherwise be detrimental to fetal development. This study investigated the role of drug transporters and protein binding in the transfer of the antidiabetic drug glibenclamide across the human placental syncytiotrophoblast using placental perfusion experiments and computational modelling. In the absence of albumin, placental glibenclamide uptake from the fetal circulation was not affected by competitive inhibition with bromosulphothalein (BSP), indicating that OATP2B1 does not mediate placental glibenclamide uptake from the fetus. In the presence of maternal and fetal albumin, BSP increased placental glibenclamide uptake from the fetal circulation by displacing glibenclamide from BSA, increasing the free fraction of glibenclamide driving diffusive transport. The P-gp and BCRP inhibitor GF120918 did not affect placental glibenclamide uptake from the maternal circulation and as such this study did not find any evidence for the apical efflux transporters in placental glibenclamide transfer. Computational modelling confirmed that albumin binding and not transporter activity, is the dominant factor in the transfer of glibenclamide across the human placenta. The effect of BSP binding to albumin on promoting the diffusive transfer of glibenclamide highlights the importance of drug-protein binding interactions and their interpretation using computational modelling.