Experimental and computational investigation of the mechanisms behind deep vein thrombosis

Deep vein thrombosis (DVT) is a life threatening condition which is on the rise in the western world [1] yet the mechanisms behind DVT remain unknown. Using microfluidics and simulations it is possible to determine the physical mechanisms that could be the cause of DVT. By mimicking the murine model (stenosis model) it was possible to see if the amount of stenosis and presence of side branches influenced flow. I was determined that the influence of a restriction did not alter the flow enough to encourage thrombus formation, however the stenosis would increase the number of cell-cell collisions which could be the reason for a thrombus occurring in vivo. Finite element modelling was also used to surpass the limitations of the experiment, resulting in a the same conclusions. A major limitation of the murine model is that it ignores the possibility of a bypass of the stenosed region, leading to the second model.The bypass model was used to determine which set of parameters are important to encouraging a bypass: position of side branch, width of side branch channel and the size of stenosis. Finally, a third model was also developed, the valve model to explore how flow is influenced by flexible valves. The valves are fabricated with varying stiffness to better understand how the stiffness of valves can influence flow through a vein inducing pro-thrombotic conditions. This model is more relevant for larger mammals. Three models of biology have been implemented to demonstrate DVT can be instigated by physical parameters and these fundamental conditions are not to be dismissed

Exploring the role of the microbiota member Bifidobacterium in modulating immune-linked diseases

The gut-associated microbiota is essential for multiple physiological processes, including immune development. Acquisition of our initial pioneer microbial communities, including the dominant early life genus Bifidobacterium, occurs at a critical period of immune maturation and programming. Bifidobacteria are resident microbiota members throughout our lifetime and have been shown to modulate specific immune cells and pathways. Notably, reductions in this genus have been associated with several diseases, including inflammatory bowel disease. In this review, we provide an overview of bifidobacteria profiles throughout life and how different strains of bifidobacteria have been implicated in immune modulation in disease states. The focus will be examining preclinical models and outcomes from clinical trials on immune-linked chronic conditions. Finally, we highlight some of the important unresolved questions in relation to Bifidobacterium-mediated immune modulation and implications for future directions, trials, and development of new therapies

Thioflavin T indicates mitochondrial membrane potential in mammalian cells

The fluorescent benzothiazole dye thioflavin T (ThT) is widely used as a marker for protein aggregates, most commonly in the context of neurodegenerative disease research and diagnosis. Recently, this same dye was shown to indicate membrane potential in bacteria due to its cationic nature. This finding prompted a question whether ThT fluorescence is linked to the membrane potential in mammalian cells, which would be important for appropriate utilization of ThT in research and diagnosis. Here, we show that ThT localizes into the mitochondria of HeLa cells in a membrane-potential-dependent manner. Specifically, ThT colocalized in cells with the mitochondrial membrane potential indicator tetramethylrhodamine methyl ester (TMRM) and gave similar temporal responses as TMRM to treatment with a protonophore, carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP). Additionally, we found that presence of ThT together with exposure to blue light (λ = 405 nm), but neither factor alone, caused depolarization of mitochondrial membrane potential. This additive effect of the concentration and blue light was recapitulated by a mathematical model implementing the potential-dependent distribution of ThT and its effect on mitochondrial membrane potential through photosensitization. These results show that ThT can act as a mitochondrial membrane potential indicator in mammalian cells, when used at low concentrations and with low blue light exposure. However, it causes dissipation of the mitochondrial membrane potential depending additively on its concentrations and blue light exposure. This conclusion motivates a re-evaluation of ThT’s use at micromolar range in live-cell analyses and indicates that this dye can enable future studies on the potential connections between mitochondrial membrane potential dynamics and protein aggregation

The early life microbiota protects neonatal mice from pathological small intestinal epithelial cell shedding

The early life gut microbiota plays a crucial role in regulating and maintaining the intestinal barrier, with disturbances in these communities linked to dysregulated renewal and replenishment of intestinal epithelial cells. Here we sought to determine pathological cell shedding outcomes throughout the postnatal developmental period, and which host and microbial factors mediate these responses. Surprisingly, neonatal mice (Day 14 and 21) were highly refractory to induction of cell shedding after intraperitoneal administration of liposaccharide (LPS), with Day 29 mice showing strong pathological responses, more similar to those observed in adult mice. These differential responses were not linked to defects in the cellular mechanisms and pathways known to regulate cell shedding responses. When we profiled microbiota and metabolites, we observed significant alterations. Neonatal mice had high relative abundances of Streptococcus, Escherichia, and Enterococcus and increased primary bile acids. In contrast, older mice were dominated by Candidatus Arthromitus, Alistipes, and Lachnoclostridium, and had increased concentrations of SCFAs and methyamines. Antibiotic treatment of neonates restored LPS-induced small intestinal cell shedding, whereas adult fecal microbiota transplant alone had no effect. Our findings further support the importance of the early life window for microbiota-epithelial interactions in the presence of inflammatory stimuli and highlights areas for further investigation

Aeromedical retrieval services characteristics globally: a scoping review

Background Aeromedical emergency retrieval services play an important role in supporting patients with critical and often life-threatening clinical conditions. Aeromedical retrieval services help to provide fast access to definitive care for critically ill patients in under-served regions. Typically, fixed-wing aeromedical retrieval becomes the most viable transport option compared with rotary-wing aircraft when distances away from centres of definitive care extend beyond 200 kms. To our knowledge, there are no studies that have investigated fixed-wing aeromedical services in the member countries of the organisation for economic cooperation and development (OECD). A description of the global characteristics of aeromedical services will inform international collaboration to optimise clinical outcomes for patients. Aim In this scoping review, we aimed to describe the features of government- and not-for-profit organisation-owned fixed-wing aeromedical retrieval services in some of the member countries of the OECD. Methods We followed scoping review methodology based on the grey literature search strategy identified in earlier studies. This mostly involved internet-based searches of the websites of fixed-wing aeromedical emergency retrieval services affiliated with the OECD member countries. Results We identified 460 potentially relevant records after searching Google Scholar (n = 24) and Google search engines (n = 436). After removing ineligible and duplicate information, this scoping review identified 86 government-and not-for-profit-operated fixed-wing aeromedical retrieval services as existing in 17 OECD countries. Concentrations of the services were greatest in the USA followed by Australia, Canada, and the UK. The most prevalent business models used across the identified OECD member countries comprised the government, not-for-profit, and hybrid models. Three-quarters of the not-for-profit and two-fifths of the hybrid business models were in the USA compared to other countries studied. The government or state-funded business model was most common in Australia (11/24, 46%), Canada (4/24, 17%), and the UK (4/24, 17%). The frequently used service delivery models adopted for patients of all ages included primary/secondary retrievals, secondary retrievals only, and service specialisation models. Of these service models, primary/secondary retrieval involving the transportation of adults and children from community clinics and primary health care facilities to centres of definitive care comprised the core tasks performed by most of the aeromedical retrieval services studied. The service specialisation model provided an extra layer of specialist health care dedicated to the transportation of neonates and paediatrics. At least eight aeromedical retrieval services catered solely for children from birth to 16 years of age. One aeromedical service, the royal flying doctor service in Australia also provided primary health care and telehealth services in addition to primary retrieval and interhospital transfer of patients. The doctor and registered nurse/paramedic (Franco-German model) and the nurse and/or paramedic (Anglo-American model) configurations were the most common staffing models used across the aeromedical services studied. Conclusions The development and composition of fixed-wing aeromedical emergency retrieval services operated by not-for-profit organisations and governments in the OECD countries showed diversity in terms of governance arrangements, services provided, and staffing models used. We do not fully understand the impact of these differences on the quality of service provision, including equitable service access, highlighting a need for further research.publishedVersio

Evaluating the relationship between interannual variations in the Antarctic ozone hole and Southern Hemisphere surface climate in chemistry-climate models

Studies have recently reported statistically significant relationships between observed year-to-year spring Antarctic ozone variability and the Southern Hemisphere Annular Mode and surface temperatures in spring-summer. This study investigates whether current chemistry-climate models (CCMs) can capture these relationships, in particular, the connection between November total column ozone (TCO) and Australian summer surface temperatures, where years with anomalously high TCO over the Antarctic polar cap tend to be followed by warmer summers. The interannual ozone-temperature teleconnection is examined over the historical period in the observations and simulations from the Whole Atmosphere Community Climate Model (WACCM) and nine other models participating in the Chemistry-Climate Model Initiative (CCMI). There is a systematic difference between the WACCM experiments forced with prescribed observed sea surface temperatures (SSTs) and those with an interactive ocean. Strong correlations between TCO and Australian temperatures are only obtained for the uncoupled experiment, suggesting that the SSTs could be important for driving both variations in Australian temperatures and the ozone hole, with no causal link between the two. Other CCMI models also tend to capture this relationship with more fidelity when driven by observed SSTs, though additional research and targeted modelling experiments are required to determine causality and further explore the role of model biases and observational uncertainty. The results indicate that CCMs can reproduce the relationship between spring ozone and summer Australian climate reported in observational studies, suggesting that incorporating ozone variability could improve seasonal predictions, however more work is required to understand the difference between the coupled and uncoupled simulations

Evaluating the relationship between interannual variations in the Antarctic ozone hole and Southern Hemisphere surface climate in chemistry-climate models

Studies have recently reported statistically significant relationships between observed year-to-year spring Antarctic ozone variability and the Southern Hemisphere Annular Mode and surface temperatures in spring-summer. This study investigates whether current chemistry-climate models (CCMs) can capture these relationships, in particular, the connection between November total column ozone (TCO) and Australian summer surface temperatures, where years with anomalously high TCO over the Antarctic polar cap tend to be followed by warmer summers. The interannual ozone-temperature teleconnection is examined over the historical period in the observations and simulations from the Whole Atmosphere Community Climate Model (WACCM) and nine other models participating in the Chemistry-Climate Model Initiative (CCMI). There is a systematic difference between the WACCM experiments forced with prescribed observed sea surface temperatures (SSTs) and those with an interactive ocean. Strong correlations between TCO and Australian temperatures are only obtained for the uncoupled experiment, suggesting that the SSTs could be important for driving both variations in Australian temperatures and the ozone hole, with no causal link between the two. Other CCMI models also tend to capture this relationship with more fidelity when driven by observed SSTs, though additional research and targeted modelling experiments are required to determine causality and further explore the role of model biases and observational uncertainty. The results indicate that CCMs can reproduce the relationship between spring ozone and summer Australian climate reported in observational studies, suggesting that incorporating ozone variability could improve seasonal predictions, however more work is required to understand the difference between the coupled and uncoupled simulations