BackgroundNon-invasive ventilation is sometimes unable to provide the respiratory needs of very premature infants in the delivery room. While airway obstruction is thought to be the main problem, the site of obstruction is unknown. We investigated whether closure of the larynx and epiglottis is a major site of airway obstruction.MethodsWe used phase contrast X-ray imaging to visualise laryngeal function in spontaneously breathing premature rabbits immediately after birth and at approximately 1 hour after birth. Non-invasive respiratory support was applied via a facemask and images were analysed to determine the percentage of the time the glottis and the epiglottis were open.HypothesisImmediately after birth, the larynx is predominantly closed, only opening briefly during a breath, making non-invasive intermittent positive pressure ventilation (iPPV) ineffective, whereas after lung aeration, the larynx is predominantly open allowing non-invasive iPPV to ventilate the lung.ResultsThe larynx and epiglottis were predominantly closed (open 25.5%±1.1% and 17.1%±1.6% of the time, respectively) in pups with unaerated lungs and unstable breathing patterns immediately after birth. In contrast, the larynx and the epiglottis were mostly open (90.5%±1.9% and 72.3%±2.3% of the time, respectively) in pups with aerated lungs and stable breathing patterns irrespective of time after birth.ConclusionLaryngeal closure impedes non-invasive iPPV at birth and may reduce the effectiveness of non-invasive respiratory support in premature infants immediately after birth.

Simulations of tissue-specific effects of primary acute viral infections like COVID-19 are essential for understanding disease outcomes and optimizing therapies. Such simulations need to support continuous updating in response to rapid advances in understanding of infection mechanisms, and parallel development of components by multiple groups. We present an open-source platform for multiscale spatiotemporal simulation of an epithelial tissue, viral infection, cellular immune response and tissue damage, specifically designed to be modular and extensible to support continuous updating and parallel development. The base simulation of a simplified patch of epithelial tissue and immune response exhibits distinct patterns of infection dynamics from widespread infection, to recurrence, to clearance. Slower viral internalization and faster immune-cell recruitment slow infection and promote containment. Because antiviral drugs can have side effects and show reduced clinical effectiveness when given later during infection, we studied the effects on progression of treatment potency and time-of-first treatment after infection. In simulations, even a low potency therapy with a drug which reduces the replication rate of viral RNA greatly decreases the total tissue damage and virus burden when given near the beginning of infection. Many combinations of dosage and treatment time lead to stochastic outcomes, with some simulation replicas showing clearance or control (treatment success), while others show rapid infection of all epithelial cells (treatment failure). Thus, while a high potency therapy usually is less effective when given later, treatments at late times are occasionally effective. We illustrate how to extend the platform to model specific virus types (e.g., hepatitis C) and add additional cellular mechanisms (tissue recovery and variable cell susceptibility to infection), using our software modules and publicly-available software repository.

Angiogenesis occurs in distinct phases: initial spouting is followed by remodelling in which endothelial cells (ECs) composing blood vessels rearrange by migrating against the direction of flow. Abnormal remodelling can result in vascular malformation. Such is the case in mutation of the Alk1 receptor within the mouse retina which disrupts flow-migration coupling, creating mixed populations of ECs polarised with/against flow which aggregate into arteriovenous malformations (AVMs). The lack of live imaging options in vivo means that the collective EC dynamics that drive AVM and the consequences of mixed populations of polarity remain a mystery. Therefore, our goal is to present a novel agent-based model to provide theoretical insight into EC force transmission and collective dynamics during angiogenic remodelling. Force transmission between neighbouring agents consists of extrusive forces which maintain spacing and cohesive forces which maintain the collective. We performed migration simulations within uniformly polarised populations (against flow) and mixed polarity (with/against flow). Within uniformly polarised populations, extrusive forces stabilised the plexus by facilitating EC intercalation which ensures that cells remained evenly distributed. Excess cohesion disrupts intercalation, resulting in aggregations of cells and functional shunting. Excess cohesion between ECs prevents them from resolving diameter balances within the plexus, leading to prolonged flow reversals which exert a critical behaviour change within the system as they switch the direction of cell migration and traffic patterns at bifurcations. Introducing mixtures of cell polarity dramatically changed the role of extrusive forces within the system. At low extrusion, opposing ECs were able to move past each other; however, at high extrusion the pushing between cells resulted in migration speeds close to zero, forming traffic jams and disrupting migration. In our study, we produced vascular malformations and functional shunting with either excess cohesion between ECs or mixtures of cell polarity. At the centre of both these mechanisms are cell-cell adherens junctions, which are involved in flow sensing/polarity and must remodelling dynamically to allow rearrangements of cells during vascular patterning. Thus, our findings implicate junctional dysfunction as a new target in the treatment and prevention of vascular disease and AVMs.

Antenatal glucocorticoids, exogenous surfactant, and positive end-expiratory pressure (PEEP) ventilation are commonly provided to preterm infants to enhance respiratory function after birth. It is unclear how these treatments interact to improve the transition to air-breathing at birth. We investigated the relative contribution of antenatal betamethasone, prophylactic surfactant, and PEEP (3 cmHO) on functional residual capacity (FRC) and dynamic lung compliance (C) in preterm (28 day GA) rabbit kittens at birth. Kittens were delivered by cesarean section and mechanically ventilated. FRC was calculated from X-ray images, and C was measured using plethysmography. Without betamethasone, PEEP increased FRC recruitment and C Surfactant did not further increase FRC, but significantly increased C Betamethasone abolished the benefit of PEEP on FRC, but surfactant counteracted this effect of betamethasone. These findings indicate that low PEEP levels are insufficient to establish FRC at birth following betamethasone treatment. However, surfactant reversed the effect of betamethasone and when combined, these two treatments enhanced FRC recruitment irrespective of PEEP level.