ABSTRACT
BACKGROUND: Respiratory tract infections are readily transmitted in care homes. Airborne transmission of pathogens causing respiratory tract illness is largely unmitigated. Portable high-efficiency-particulate-air (HEPA) filtration units capture microbial particles from the air, but it is unclear whether this is sufficient to reduce infections in care home residents. The Air Filtration to prevent symptomatic winter Respiratory Infections (including COVID-19) in care homes (AFRI-c) randomized controlled trial will determine whether using HEPA filtration units reduces respiratory infection episodes in care home residents. METHODS: AFRI-c is a cluster randomized controlled trial that will be delivered in residential care homes for older people in England. Ninety-one care homes will be randomised to take part for one winter period. The intervention care homes will receive HEPA filtration units for use in communal areas and private bedrooms. Normal infection control measures will continue in all care homes. Anonymised daily data on symptoms will be collected for up to 30 residents. Ten to 12 of these residents will be invited to consent to a primary care medical notes review and (in intervention homes) to having an air filter switched on in their private room. The primary outcome will be number of symptomatic winter respiratory infection episodes. Secondary outcomes include specific clinical measures of infection, number of falls / near falls, number of laboratory confirmed infections, hospitalisations, staff sickness and cost-effectiveness. A mixed methods process evaluation will assess intervention acceptability and implementation. DISCUSSION: The results of AFRI-c will provide vital information about whether portable HEPA filtration units reduce symptomatic winter respiratory infections in older care home residents. Findings about effectiveness, fidelity, acceptability and cost-effectiveness will support stakeholders to determine the use of HEPA filtration units as part of infection control policies.
Subject(s)
Air Filters , COVID-19 , Respiratory Tract Infections , Seasons , Humans , COVID-19/prevention & control , COVID-19/epidemiology , COVID-19/transmission , England/epidemiology , Respiratory Tract Infections/prevention & control , Respiratory Tract Infections/epidemiology , Aged , SARS-CoV-2/isolation & purification , Nursing HomesABSTRACT
BACKGROUND: Angiogenesis is crucial to many physiological and pathological processes including development and cancer cell survival. Vascular endothelial growth factor-A (VEGFA) is the predominant mediator of angiogenesis in the VEGF family. During development, adverse environmental conditions like nutrient deprivation, hypoxia and increased protein secretion occur. IRE1alpha, PERK, and ATF6alpha, master regulators of the unfolded protein response (UPR), are activated under these conditions and are proposed to have a role in mediating angiogenesis. PRINCIPAL FINDINGS: Here we show that IRE1alpha, PERK, and ATF6alpha powerfully regulate VEGFA mRNA expression under various stress conditions. In Ire1alpha(-/-) and Perk(-/-) mouse embryonic fibroblasts and ATF6alpha-knockdown HepG2 cells, induction of VEGFA mRNA by endoplasmic reticulum stress is attenuated as compared to control cells. Embryonic lethality of Ire1alpha-/- mice is due to the lack of VEGFA induction in labyrinthine trophoblast cells of the developing placenta. Rescue of IRE1alpha and PERK in Ire1alpha(-/-) and Perk(-/-) cells respectively, prevents VEGFA mRNA attenuation. We further report that the induction of VEGFA by IRE1alpha, PERK and ATF6 involves activation of transcription factors, spliced-XBP-1, ATF4 and cleaved ATF6 respectively. CONCLUSIONS/SIGNIFICANCE: Our results reveal that the IRE1alpha-XBP-1, PERK-ATF4, and ATF6alpha pathways constitute novel upstream regulatory pathways of angiogenesis by modulating VEGF transcription. Activation of these pathways helps the rapidly growing cells to obtain sufficient nutrients and growth factors for their survival under the prevailing hostile environmental conditions. These results establish an important role of the UPR in angiogenesis.
Subject(s)
Gene Expression Regulation , Vascular Endothelial Growth Factor A/metabolism , Activating Transcription Factor 6/metabolism , Alternative Splicing , Animals , DNA-Binding Proteins/metabolism , Endoribonucleases/metabolism , Humans , Mice , Mice, Transgenic , Protein Serine-Threonine Kinases/metabolism , Regulatory Factor X Transcription Factors , Transcription Factors/metabolism , Unfolded Protein Response , X-Box Binding Protein 1 , eIF-2 Kinase/metabolismABSTRACT
Endoplasmic reticulum (ER) stress, which is caused by the accumulation of misfolded proteins in the ER, elicits an adaptive response, the unfolded protein response (UPR). One component of the UPR, the endoplasmic reticulum-associated protein degradation (ERAD) system, has an important function in the survival of ER stressed cells. Here, we show that HRD1, a component of the ERAD system, is upregulated in pancreatic islets of the Akita diabetes mouse model and enhances intracellular degradation of misfolded insulin. High ER stress in beta-cells stimulated mutant insulin degradation through HRD1 to protect beta-cells from ER stress and ensuing death. If HRD1 serves the same function in humans, it may serve as a target for therapeutic intervention in diabetes.
