ABSTRACT
Background: An interferon gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients. We previously demonstrated it negatively impacts on initial disease outcomes. Objectives: To 1) reproduce previous fndings demonstrating the harmful effects of the IGS on early RA clinical outcomes, 2) identify which IFN class is responsible for the IGS and 3) seek evidence that IFN-a exposure contributes to harmful epigenetic footprint at disease onset. Methods: In a large multicentre inception cohort (n=190) of eRA patients (RA-MAP TACERA) whole blood transcriptome, IGS (MxA, IFI44L, OAS1, ISG15, IFI6) and circulating interferons (IFN)-a,-β,-y and-), was examined at baseline and 6 months in conjunction with disease activity and clinical characteristics. A separate eRA cohort of paired methylome and transcriptome from CD4 T and CD19 B cells (n=41 for each) was used to explore any epigenetic influence of the IGS. Results: The baseline IGS reproducibly and signifcantly negatively impacts on 6-month clinical outcomes. In the high IGS cohort there was increased DAS-28 (p=0.025) and reduced probability of achieving a good EULAR response (p=0.034) at 6-months. In addition, the IGS in eRA is shown for the frst time to predominantly refect raised circulating IFN-a protein, not other classes of IFN and examination of whole blood upstream nucleic acid sensors expression suggest a RNA trigger. Both the IGS and IFN-a signifcantly fell in parallel at 6 months (p<0.0001), whereas other classes of IFN remained statistically static. There was a signifcant association with IFN-a and RF titre but not ACPA. Comparison of CD4 T and CD19 B cells between IGS high and low eRA patients demonstrated differentially methylated CPG sites and altered transcript expression of disease relevant genes e.g. PARP9, STAT1, EPTSI1 which was similarly, and persistently altered 6 months in the separate TACERA cohort. Differentially methylated CPGs implicated altered transcription factor binding in B cells (GATA3, ETSI, NFATC2, EZH2) and T cells (p300, HIF1a) which cumulatively suggested IFN-a induced epigenetic changes promoting increased, and sustained, lymphocyte activation, proliferation and loss of anergy in the IGS high cohort. Conclusion: We validate that the IGS is a robust prognostic biomarker in eRA predicting poor therapeutic response. Its persistent harmful effects may be driven via epigenetic modifcations. These data have relevance for other IFN-a states, such as COVID-19, but also provide a rationale for the initial therapeutic targeting of IFN-a signalling, such as with JAKi, at disease onset in stratifed eRA subsets.
ABSTRACT
Without timely assessments of the number of COVID-19 cases requiring hospitalisation, healthcare providers will struggle to ensure an appropriate number of beds are made available. Too few could cause excess deaths while too many could result in additional waits for elective treatment. As well as supporting capacity considerations, reliably projecting future "waves" is important to inform the nature, timing and magnitude of any localised restrictions to reduce transmission. In making the case for locally owned and locally configurable models, this paper details the approach taken by one major healthcare system in founding a multi-disciplinary "Scenario Review Working Group", comprising commissioners, public health officials and academic epidemiologists. The role of this group, which met weekly during the pandemic, was to define and maintain an evolving library of plausible scenarios to underpin projections obtained through an SEIR-based compartmental model. Outputs have informed decision-making at the system's major incident Bronze, Silver and Gold Commands. This paper presents illustrated examples of use and offers practical considerations for other healthcare systems that may benefit from such a framework.
ABSTRACT
Coronavirus disease 2019 (COVID-19) adult respiratory distress syndrome (C-ARDS) has led to ventilator related complications such as ventilator associated events (VAE), venous thromboembolic events (VTE), barotrauma, and ultimately profound diffuse pulmonary fibrosis. Barotrauma is one such complication, with reports of spontaneous pneumothorax (PTX) and pneumomediastinum. We present a case series of four patients with severe C-ARDS, complicated by subcutaneous emphysema and mediastinal emphysema with and without pneumothroracies, which required supportive care, except one patient with PTX. Of the four patients only one patient was discharged alive. C-ARDS can induce lung injury, resulting in subcutaneous and mediastinal emphysema, which may not represent a PTX as etiology. The exact mechanism of subcutaneous emphysema and mediastinal emphysema without pneumothoracies in the setting of severe C-ARDS has not been clearly elucidated. Two plausible mechanisms may be related to the “Macklin effect” vs. type I and II pneumocyte breakdown when infected by COVID-19. Strategies used to minimize worsening of subcutaneous and mediastinal emphysema with and without pneumothoracies, may be to minimize positive end-expiratory pressure (PEEP), continue to maintain a lung protective strategy (LPS), while utilizing a higher fraction of inspired oxygen (FiO2) concentration. In the majority of cases, supportive care is usually required, unless PTX presents or tension pneumomediastinum develops, at which time treatment with a thoracostomy tube placement may be necessary or cardiothoracic surgery consultation may be warranted, to perform “gills” procedure. © Journal of Emergency and Critical Care Medicine. All rights reserved.
ABSTRACT
Introduction Autoimmune Hepatitis (AIH) is a relapsing chronic inflammatory condition1 that waxes and wanes irrespective of outpatient clinic scheduling. York Teaching Hospital NHS Foundation Trust (YTHT) covers a wide geographical area.2 The COVID-19 pandemic has demonstrated that not all patients require regular clinical review in person. Aim To update the clinical registry of AIH patients within YTHT, ensuring appropriate monitoring during Covid-19, and prompt review for those requiring it. Methods An IT-based search identified individuals' with a diagnosis of AIH within YTHT. An electronic note review established demographic details, risk factors for co-existing liver disease, severity of AIH, disease treatment, and current blood results. Results 128 patients were identified, 81% of whom were female. The average age was 68 years (range 17-88). 51% were local to York Hospital and 34% closer to Scarborough Hospital, as demonstrated in figure 1. The remainder travel to their closest hub. 55% of the cohort had an elevated ALT suggesting ongoing disease activity (arguably ALT >31UI/L in males and ALT >21 UI/L in females). 62% were taking significant immunosuppression;Azathioprine 32%, Mycophenolate Mofetil 14.4%, Tacrolimus 9.6% and Prednisolone >20 mg/ day 6.4%. Discussion The COVID-19 pandemic has demonstrated the need to identify and offer timely follow-up for our most unwell patients, allowing those with a stable condition to safely shield. Virtual monitoring of patients is important to identify asymptomatic flares. We advocate incorporating nurseled monitoring of such patients, in combination with patient initiated follow-up for those with symptomatic disease.
ABSTRACT
Introduction: As of the March 20, 2020, the COVID-19 caseload in Canada was still fairly low. There were 917 reported cases compared to 13,882 by April 4, 2020. Recognizing the respiratory nature of the disease, and possible effect on anxiety levels particularly in lung cancer patients, a survey was fielded to measure and better understand how the pandemic was affecting the anxiety levels of lung cancer patients in Canada. Methods: OBJECTIVE: To measure the impact of the COVID-19 pandemic on Canadian lung cancer patient anxiety levels. STUDY DESIGN: An iterative approach was used in the survey design. A round table discussion made up of lung cancer patients was utilized to provide qualitative input. The resulting themes were converted into a quantitative survey, which was fielded digitally. A focus group was then gathered to analyze and discuss the results. Results: The study population was Canadian lung cancer patients. The responses (n = 113) were collected from 20 - 23 March 2020. All results were descriptive only. (Answer scale 1 to 10: 1 = not anxious at all;10 = extremely anxious, m = weighted average). The results were as follows: Respondent’s anxiety levels at time of survey, m = 6.01. Anxiety levels compared to prior to the pandemic, m = 6.26. Extent to which the outbreak affected feelings of isolation (m = 6.42), being in control (m = 6.01), hope (m= 5.57), vulnerability (m = 7.03). Anxiety experienced due to worry about impact on aspects of their lives: complete life goals (m =6.17), ability to spend quality time with family and loved ones (m = 7.27), participate in life events with those they love (m = 7.38). Importance of supports to help relieve feelings of anxiety, the most important was clear communication from healthcare team followed by increased communication from lung cancer organizations. Conclusion: The results of the survey suggest participants developed an increase in anxiety levels around certain aspects of such as enjoyment of life and quality of life. Results also indicated patients desired resources to increase awareness and education, which would help allay anxiety and improve well being during an outbreak. Variables that may have affected the data: Distribution shapes across the board were not even, with some clustering which potentially reflected the different levels of the outbreak of the across the country. Survey was carried out at the beginning of Canada’s COVID-19 response and a state of emergency had not been declared in all the provinces across the country. Due to the early nature of the outbreak at the time of the survey, and as the pandemic continued to evolve, patient anxiety levels were continuously measured. These are preliminary results based on the first survey. Patient mental health is an important aspect of care and influences outcomes. These results highlight areas that may be used to inform cancer care policy and stresses the importance of the inclusion of mental health considerations. Keywords: Lung Cancer Patients, COVID-19, Anxiety