Loss of the heterogeneous expression of flippase ATP11B leads to cerebral small vessel disease in a normotensive rat model.

Cerebral small vessel disease (SVD) is the leading cause of vascular dementia, causes a quarter of strokes, and worsens stroke outcomes. The disease is characterised by patchy cerebral small vessel and white matter pathology, but the underlying mechanisms are poorly understood. This microvascular and tissue damage has been classically considered secondary to extrinsic factors, such as hypertension, but this fails to explain the patchy nature of the disease, the link to endothelial cell (EC) dysfunction even when hypertension is absent, and the increasing evidence of high heritability to SVD-related brain damage. We have previously shown the link between deletion of the phospholipase flippase Atp11b and EC dysfunction in an inbred hypertensive rat model with SVD-like pathology and a single nucleotide polymorphism (SNP) in ATP11B associated with human sporadic SVD. Here, we generated a novel normotensive transgenic rat model, where Atp11b is deleted, and show pathological, imaging and behavioural changes typical of those in human SVD, but that occur without hypertension. Atp11bKO rat brain and retinal small vessels show ECs with molecular and morphological changes of dysfunction, with myelin disruption in a patchy pattern around some but not all brain small vessels, similar to the human brain. We show that ATP11B/ATP11B is heterogeneously expressed in ECs in normal rat and human brain even in the same transverse section of the same blood vessel, suggesting variable effects of the loss of ATP11B on each vessel and an explanation for the patchy nature of the disease. This work highlights a link between inherent EC dysfunction and vulnerability to SVD white matter damage with a marked heterogeneity of ECs in vivo which modulates this response, occurring even in the absence of hypertension. These findings refocus our strategies for therapeutics away from antihypertensive (and vascular risk factor) control alone and towards ECs in the effort to provide alternative targets to prevent a major cause of stroke and dementia.

Personalised 3D printed respirators for healthcare workers during the COVID-19 pandemic.

Widespread issues in respirator availability and fit have been rendered acutely apparent by the COVID-19 pandemic. This study sought to determine whether personalized 3D printed respirators provide adequate filtration and function for healthcare workers through a Randomized Controlled Trial (RCT). Fifty healthcare workers recruited within NHS Lothian, Scotland, underwent 3D facial scanning or 3D photographic reconstruction to produce 3D printed personalized respirators. The primary outcome measure was quantitative fit-testing to FFP3 standard. Secondary measures included respirator comfort, wearing experience, and function instrument (R-COMFI) for tolerability, Modified Rhyme Test (MRT) for intelligibility, and viral decontamination on respirator material. Of the 50 participants, 44 passed the fit test with the customized respirator, not significantly different from the 38 with the control (p = 0.21). The customized respirator had significantly improved comfort over the control respirator in both simulated clinical conditions (p < 0.0001) and during longer wear (p < 0.0001). For speech intelligibility, both respirators performed equally. Standard NHS decontamination agents were able to eradicate 99.9% of viral infectivity from the 3D printed plastics tested. Personalized 3D printed respirators performed to the same level as control disposable FFP3 respirators, with clear communication and with increased comfort, wearing experience, and function. The materials used were easily decontaminated of viral infectivity and would be applicable for sustainable and reusable respirators.