Effective control of sars-cov-2 transmission between healthcare workers during a period of diminished community prevalence of covid-19

Previously, we showed that 3% (31/1032)of asymptomatic healthcare workers (HCWs) from a large teaching hospital in Cambridge, UK, tested positive for SARS-CoV-2 in April 2020. About 15% (26/169) HCWs with symptoms of coronavirus disease 2019 (COVID-19) also tested positive for SARS-CoV-2 (Rivett et al., 2020). Here, we show that the proportion of both asymptomatic and symptomatic HCWs testing positive for SARS-CoV-2 rapidly declined to nearzero between 25th April and 24th May 2020, corresponding to a decline in patient admissions with COVID-19 during the ongoing UK ‘lockdown’. These data demonstrate how infection prevention and control measures including staff testing may help prevent hospitals from becoming independent ‘hubs’ of SARS-CoV-2 transmission, and illustrate how, with appropriate precautions, organizations in other sectors may be able to resume on-site work safely

A model of access combining triage with initial management reduced waiting time for community outpatient services: a stepped wedge cluster randomised controlled trial

BACKGROUND: Long waiting times are associated with public community outpatient health services. This trial aimed to determine if a new model of care based on evidence-based strategies that improved patient flow in two small pilot trials could be used to reduce waiting time across a variety of services. The key principle of the Specific Timely Appointments for Triage (STAT) model is that patients are booked directly into protected assessment appointments and triage is combined with initial management as an alternative to a waiting list and triage system. METHODS: A stepped wedge cluster randomised controlled trial was conducted between October 2015 and March 2017, involving 3116 patients at eight sites across a major Australian metropolitan health network. RESULTS: The intervention reduced waiting time to first appointment by 33.8% (IRR = 0.663, 95% CI 0.516 to 0.852, P = 0.001). Median waiting time decreased from a median of 42 days (IQR 19 to 86) in the control period to a median of 24 days (IQR 13 to 48) in the intervention period. A substantial reduction in variability was also noted. The model did not impact on most secondary outcomes, including time to second appointment, likelihood of discharge by 12 weeks and number of appointments provided, but was associated with a small increase in the rate of missed appointments. CONCLUSIONS: Broad-scale implementation of a model of access and triage that combined triage with initial management and actively managed the relationship between supply and demand achieved substantial reductions in waiting time without adversely impacting on other aspects of care. The reductions in waiting time are likely to have been driven, primarily, by substantial reductions for those patients previously considered low priority. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12615001016527 registration date: 29/09/2015

Eight Syndrome - Horizontal Gaze Palsy Plus Ipsilateral Seventh Nerve Palsy

A 62-year-old woman developed a right horizontal gaze palsy and ipsilateral facial nerve palsy due to a right pontine tegmentum infarct. This constitutes a forme fruste of the eight-and-a-half syndrome that we have termed the eight syndrome

Endoplasmic Reticulum Aminopeptidase-1 Functions Regulate Key Aspects of the Innate Immune Response

<div><p>Endoplasmic reticulum aminopeptidase-1 (ERAP1) is a multifunctional, ubiquitously expressed enzyme whose peptide-trimming role during antigen processing for presentation by MHC I molecules is well established, however, a role for ERAP1 in modulating global innate immune responses has not been described to date. Here we demonstrate that, relative to wild type mice, mice lacking ERAP1 exhibit exaggerated innate immune responses early during pathogen recognition, as characterized by increased activation of splenic and hepatic NK and NKT cells and enhanced production of pro-inflammatory cytokines such as IL12 and MCP1. Our data also revealed that ERAP1 is playing a critical role in NK cell development and function. We observed higher frequencies of terminally matured NK cells, as well as higher frequencies of licensed NK cells (expressing the Ly49C and Ly49I receptors) in ERAP1-KO mice, results that positively correlated with an enhanced NK activation and IFNγ production by ERAP1-KO mice challenged with pro-inflammatory stimuli. Furthermore, during pathogen recognition, ERAP1 regulates IL12 production by CD11c⁺ DCs specifically, with increases in IL12 production positively correlated with an increased phagocytic activity of splenic DCs and macrophages. Collectively, our results demonstrate a previously unrecognized, more central role for the ERAP1 protein in modulating several aspects of both the development of the innate immune system, and its responses during the initial stages of pathogen recognition. Such a role may explain why ERAP1 has been implicated by GWAS in the pathogenesis of autoimmune diseases that may be precipitated by aberrant responses to pathogen encounters.</p></div

Mice lacking ERAP1 exhibit drastically increased activation of NK and NKT cells in the liver in response to rEA stimuli.

<p>C57BL/6 WT and ERAP1-KO mice were either mock (PBS) injected or intraperitoneally injected with 100 ng/mouse of rEA protein. Liver lymphocytes were prepared at 6 hpi, processed, stained for expression of surface markers (intracellular staining was performed for IFNγ), and analyzed by FACS as described in Materials and Methods. (<b>A, B</b>) CD69 activation and (<b>C, D</b>) IFNγ release by NK cells (<b>A, C</b>) and NKT cells (<b>B, D</b>) are shown. Bars represent mean ± SEM. Representative plots are shown. Statistical analysis was completed using a one-way ANOVA with a Student-Newman-Keuls post-hoc test. n = 4 for all groups of mice. *, ** - indicate values, statistically different from those in mock-injected mice, p<0.05, p<0.001, respectively.</p

Signaling pathways.

<p>Ad5-HIV-gag induced gene expression in livers of C57BL/6 mice (fold over WT_Mock, 6 hpi). The numbers represent Mean ± SD. Statistical analysis was completed using One Way ANOVA with a Student-Newman-Keuls post-hoc test, p<0.05 was deemed a statistically significant difference. n = 4 for all Mock injected groups, n = 6 for all Ad5-HIV-gag injected groups.</p>a<p>Significant differences as compared to WT_Mock;</p>b<p>significant differences in transcriptional activation in ERAP1-KO_Ad5-HIV-gag group as compared to WT_Ad5-HIV-gag group (also indicated by boldface font).</p

Mice lacking ERAP1 exhibit increased activation of NK cells in the spleen in response to rEA stimuli.

<p>C57BL/6 WT and ERAP1-KO mice were either mock (PBS) injected or intraperitoneally injected with 100 ng/mouse of rEA protein. Splenocytes were prepared at 12 hpi, processed, stained for expression of surface markers and analyzed by FACS as described in Materials and Methods. CD69 activation NK cells is shown, Bars represent mean ± SEM. Representative plots are shown. Statistical analysis was completed using a one-way ANOVA with a Student-Newman-Keuls post-hoc test. n = 4–7 for all groups of mice. *** - indicate values, statistically different from those in mock-injected mice, p<0.0001.</p

Innate Immune genes.

<p>Ad5-gag induced gene expression in livers of C57BL/6 mice (fold over WT_Mock, 6 hpi). The numbers represent Mean ± SD. Statistical analysis was completed using One Way ANOVA with a Student-Newman-Keuls post-hoc test, p<0.05 was deemed a statistically significant difference. n = 4 for all Mock injected groups, n = 6 for all Ad5-HIV-gag injected groups.</p>a<p>Significant differences as compared to WT_Mock;</p>b<p>significant differences in transcriptional activation in ERAP1-KO_Ad5-HIV-gag group as compared to WT_Ad5-HIV-gag group (also indicated by boldface font).</p>*<p>denotes significant differences between WT_Mock and ERAP1-KO_Mock (baseline levels).</p

Mice lacking ERAP1 exhibit dramatically enhanced activation of B cells, CD8⁺ and CD8⁻ T cells in response to rEA stimuli.

<p>C57BL/6 WT and ERAP1-KO mice were either mock (PBS) injected or intraperitoneally injected with 100 ng/mouse of rEA protein. Splenocytes were harvested at 6 hpi, processed, stained for expression of surface markers, and analyzed by FACS as described in Materials and Methods. CD69 activation of (<b>A</b>) CD8⁺ CD3⁺ T cells, (<b>B</b>) CD8<b>⁻</b> CD3⁺ T cells, and (<b>C</b>) B cells are shown. Bars represent mean ± SEM. Representative plots are shown. Statistical analysis was completed using a one-way ANOVA with a Student-Newman-Keuls post-hoc test. n = 4 for all groups of mice. *, ** - indicate values, statistically different from those in mock-injected mice, p<0.05, p<0.001, respectively.</p