Preparation for the next major incident: are we ready? Comparing major trauma centres and other hospitals

OBJECTIVES: A major incident is any emergency requiring special arrangements by the emergency services. All hospitals are required by law to keep a major incident plan (MIP) detailing the response to such events. In 2006 and 2019, we assessed the preparedness and knowledge of key individuals in hospitals across England and found a substantial gap in responding to the MIP. In this report, we compare responses from doctors at major trauma centres (MTCs) and other hospitals (non-MTCs). METHODS: We identified trusts in England that received over 30 000 patients through the ED in the fourth quarter of 2016/2017. We contacted the on-call anaesthetic, emergency, general surgery and trauma and orthopaedic registrar at each location and asked three questions assessing their confidence in using their hospital’s MIP: (1) Have you read your hospital’s MIP? (2) Do you know where you can access your hospital’s MIP guidelines? (3) Do you know what role you would play if an MIP came into effect while you are on call? We compared data from MTCs and non-MTCs using multinomial mixed proportional odds models. RESULTS: There was a modest difference between responses from individuals at MTCs and non-MTCs for question 2 (OR=2.43, CI=1.03 to 5.73, p=0.04) but no evidence of a difference between question 1 (OR=1.41, CI=0.55 to 3.63, p=0.47) and question 3 (OR=1.78, CI=0.86 to 3.69, p=0.12). Emergency medicine and anaesthetic registrars showed significantly higher preparedness and knowledge across all domains. No evidence of a systematic difference in specialty response by MTC or otherwise was identified. CONCLUSIONS: Confidence in using MIPs among specialty registrars in England remains low. Doctors at MTCs tended to be better prepared and more knowledgeable, but this effect was only marginally significant. We make several recommendations to improve education on major incidents

Epilysin (matrix metalloproteinase-28) contributes to airway epithelial cell survival

MMP28 is constitutively expressed by epithelial cells in many tissues, including the respiratory epithelium in the lung and keratinocytes in the skin. This constitutive expression suggests that MMP28 may serve a role in epithelial cell homeostasis. In an effort to determine its function in epithelial cell biology, we generated cell lines expressing wild-type or catalytically-inactive mutant MMP28 in two pulmonary epithelial cell lines, A549 and BEAS-2B. We observed that over-expression of MMP28 provided protection against apoptosis induced by either serum-deprivation or treatment with a protein kinase inhibitor, staurosporine. Furthermore, we observed increased caspase-3/7 activity in influenza-infected lungs from Mmp28-/- mice compared to wild-type mice, and this activity localized to the airway epithelium but was not associated with a change in viral load. Thus, we have identified a novel role of MMP28 in promoting epithelial cell survival in the lung

The integration of lipid-sensing and anti-inflammatory effects: how the PPARs play a role in metabolic balance

The peroxisomal proliferating-activated receptors (PPARs) are lipid-sensing transcription factors that have a role in embryonic development, but are primarily known for modulating energy metabolism, lipid storage, and transport, as well as inflammation and wound healing. Currently, there is no consensus as to the overall combined function of PPARs and why they evolved. We hypothesize that the PPARs had to evolve to integrate lipid storage and burning with the ability to reduce oxidative stress, as energy storage is essential for survival and resistance to injury/infection, but the latter increases oxidative stress and may reduce median survival (functional longevity). In a sense, PPARs may be an evolutionary solution to something we call the 'hypoxia-lipid' conundrum, where the ability to store and burn fat is essential for survival, but is a 'double-edged sword', as fats are potentially highly toxic. Ways in which PPARs may reduce oxidative stress involve modulation of mitochondrial uncoupling protein (UCP) expression (thus reducing reactive oxygen species, ROS), optimising forkhead box class O factor (FOXO) activity (by improving whole body insulin sensitivity) and suppressing NFkB (at the transcriptional level). In light of this, we therefore postulate that inflammation-induced PPAR downregulation engenders many of the signs and symptoms of the metabolic syndrome, which shares many features with the acute phase response (APR) and is the opposite of the phenotype associated with calorie restriction and high FOXO activity. In genetically susceptible individuals (displaying the naturally mildly insulin resistant 'thrifty genotype'), suboptimal PPAR activity may follow an exaggerated but natural adipose tissue-related inflammatory signal induced by excessive calories and reduced physical activity, which normally couples energy storage with the ability to mount an immune response. This is further worsened when pancreatic decompensation occurs, resulting in gluco-oxidative stress and lipotoxicity, increased inflammatory insulin resistance and oxidative stress. Reactivating PPARs may restore a metabolic balance and help to adapt the phenotype to a modern lifestyle

Functionally impaired plasmacytoid dendritic cells and non-haematopoietic sources of type I interferon characterize human autoimmunity

Autoimmune connective tissue diseases arise in a stepwise fashion from asymptomatic preclinical autoimmunity. Type I interferons have a crucial role in the progression to established autoimmune diseases. The cellular source and regulation in disease initiation of these cytokines is not clear, but plasmacytoid dendritic cells have been thought to contribute to excessive type I interferon production. Here, we show that in preclinical autoimmunity and established systemic lupus erythematosus, plasmacytoid dendritic cells are not effector cells, have lost capacity for Toll-like-receptor-mediated cytokine production and do not induce T cell activation, independent of disease activity and the blood interferon signature. In addition, plasmacytoid dendritic cells have a transcriptional signature indicative of cellular stress and senescence accompanied by increased telomere erosion. In preclinical autoimmunity, we show a marked enrichment of an interferon signature in the skin without infiltrating immune cells, but with interferon-κ production by keratinocytes. In conclusion, non-hematopoietic cellular sources, rather than plasmacytoid dendritic cells, are responsible for interferon production prior to clinical autoimmunity