ABSTRACT
Since COVID-19, social distancing has become common, and the demand for untact services has increased rapidly, resulting in an economic phenomenon centered on untact worldwide. Due to social distancing, the untact service area is expanding not only to shopping but also to online learning, home training, and telemedicine, and untact services are expected to expand to more diverse areas in the future. This study investigates four types of untact services: online lectures, online meetings related to work and study, online seminars, and online performances, and the effects of concerns about untact services on the intention of use have been examined using a path analysis model. As a result of the analysis, the perceived usefulness had a positive effect on the user's continuous intention to use untact services. However, depending on the type of untact service, it can be confirmed that the factors that affect the intention to continue using the service differ from each other. Practitioners can use the results of this study when designing untact services in the future. © 2023 by the authors.
ABSTRACT
Introduction: Vaccines revolutionised the management of COVID19. Nevertheless, they lack efficacy in high-risk or vulnerable groups (e.g., immunosuppressed patients), who may not mount an appropriate immune response. Monoclonal antibodies represent the gold-standard agents for such cases;but they are limited by availability, need for parenteral administration and the risk for viral escape because of spike protein mutations. Therefore, there is a pressing need for new prophylactic agents less prone to resistance.The viral receptor ACE2 represents an ideal target as it is essential for viral entry and transmission and because being a host protein it is not affected by viral mutations. However, the regulation of ACE2 remains elusive, due to the lack of appropriatein vitromodels. Cholangiocytes show one of the highest ACE2 expression levels in the body, representing an ideal platform for these studies. Here, we use cholangiocyte organoids as proof-of-principleto identify that the bile acid receptor FXR regulates ACE2 expression and SARS-CoV-2 infectionin vitro. We validate these findings in lung and gut organoids, animal models, human organs perfusedex situand patient cohorts. Aims & Methods: 1. Identify pathways controlling the transcriptional regulation of ACE2 2. Identify drugs modulating these pathways as novel prophylactic and therapeutic agents for COVID19. Organoids were propagated using established protocols. Marker expression was assessed using single-cell RNA sequencing, QPCR, and immunofluorescence. FXR binding on DNA was assessed with chromatin immunoprecipitation. SARS-CoV-2 was isolated from bronchoalveolar lavage of a COVID19 patient. Syrian golden hamsters were infected via direct inoculation and QPCR on oral swab, nasal turbinate and lung samples was used to measure SARS-CoV-2 infection. Human livers and lungs not used for transplantation were perfusedex-situusing normothermic perfusion. Nasopharyngeal swabs were used to measure ACE2 expression in nasal epithelial cells of healthy individuals taking UDCA at the standard therapeutic dose of 15 mg/kg/day. Patient registry data were compared using propensity score matching for sex, age, diabetes, NAFLD and Child- Turcotte-Pugh score. Result(s): We identified that FXR directly regulates ACE2 transcription in cholangiocyte organoids, while FXR inhibition with the approved drug ursodeoxycholic acid (UDCA), reduced ACE2 expression and SARS-CoV-2 infectionin vitro. We confirmed this mechanism in organoids from other COVID19-affected tissues, including the respiratory and intestinal systems. We validated our findingsin vivoin Syrian golden hamsters, showing that treatment with UDCA downregulates ACE2 and prevents SARS-CoV-2 infection. We confirmed that UDCA reduces ACE2 and SARS-CoV-2 infection in human lungs and livers perfusedex-situ. We performed a clinical study demonstrating that UDCA lowers ACE2 levels in the nasal epithelium of 6 healthy volunteers. Finally, we identified a correlation between UDCA and better clinical outcomes (hospitalisation, ICU admission and death) in COVID19 patients receiving UDCA for cholestatic diseases using the COVID-Hep and SECURELiver registry data. Conclusion(s): We identified FXR as a novel regulator of ACE2 expression. Using a bench-to-bedside approach combining in vitroand in vivomodels, exsituperfused human organs and clinical data we showed that FXR inhibition prevents or reduces SARS-CoV-2 infection and identified UDCA as an approved, cost-effective drug which could be repurposed for COVID19, paving the road for future clinical trials.
ABSTRACT
commonly worldwide but their effectiveness in participants with cirrhosis is unknown. We explored the effectiveness of vaccination with the Janssen Ad.26.COV2.S compared to the mRNA Pfizer BNT162b2 or Moderna 1273-mRNA vaccine in participants with cirrhosis. Method: This was a test-negative case control study among participants with cirrhosis. This study design is widely used in evaluations of vaccine effectiveness and has the advantage of minimizing biases associated with access to vaccination or health care. Cases were those who were SARS CoV2 PCR positive, controls were those who tested negative during the study period between March 15, 2021 and October 3, 2021. Participants who did not undergo SARS CoV2 PCR testing, who had COVID-19 before the study period, or received a liver transplant, were excluded. COVID-19 was classified based on individual chart review using the National Institute of Health (NIH) COVID-19 severity scale as asymptomatic, mild, moderate, severe or critical illness. Propensity score matching was used to match test positive cases and test negative controls. The propensity score of having COVID-19 were derived from a logistic regression that adjusted for the participant's sex, age, date of testing, race/ethnicity, location, alcohol as the etiology of liver disease, body mass index (BMI), diabetes mellitus, current tobacco use, current alcohol use, co-morbidities, and the Child Turcotte Pugh score. Multinomial logistic regression models were fit for COVID-19, to assess the adjusted effect from vaccination with either the Ad.26.COV2.S or the mRNA-1273 or BNT162b2 vaccines. Results: A total of 955 cases and 955 matched controls were included in the study population. The two groups were well matched to all baseline characteristics. The Ad.26.COV2.S vaccine had an effectiveness of 64% against COVID-19 (adjusted Odds Ratio [aOR] 0.36, 95% CI 0.20-0.62, p=0.005). Effectiveness was lowest with asymptomatic illness (aOR 0.42, 0.18-0.73, p=0.03), and higher against mild (aOR 0.36, 0.15-0.63, p= 0.006), moderate (aOR 0.33, 0.14-0.49, p=0.002) and severe/critical (aOR 0.24, 0.08-0.83, p=0.04) COVID-19. In the same period, mRNA vaccines had a 73% effectiveness against overall COVID-19 (aOR 0.27, 0.19-0.37, p<0.0001), progressively higher from asymptomatic (aOR 0.38, 0.23-0.59, p=0.0004) to mild (aOR 0.29, 0.18-0.42, p<0.0001), moderate (aOR 0.27, 0.18-0.36, p<0.0001), and severe or critical illness (aOR 0.17, 0.06-0.32, p<0.0001). There were no statistically significant differences between the viral vector and mRNA vaccines. Conclusion: In participants with cirrhosis, the Ad.26.COV2.S demonstrated a 64% effectiveness against COVID-19, and a 74% effectiveness against severe or critical COVID-19, similar to that associated with mRNA vaccines. (Figure Presented)
ABSTRACT
Introduction: Patients presenting to the Emergency Department (ED) with renal colic are typically managed symptomatically and discharged to a dedicated Stone Clinic to ensure passage of stone. Due to COVID-19 and reduction in Consultant clinic capacity, it became apparent there was an increasing and significant delay in stone patients being reviewed, imaged and referred for intervention. To reduce this delay and associated patient morbidity, a new virtual acute stone clinic (VASC) was developed. Patients and Methods: The VASC involves a Nurse Specialist and Consultant. A new referral pathway from ED was created to ensure baseline imaging, metabolic screen and performance status completed. ED referrals are triaged within 1 week and follow up imaging arranged prior to virtual review (telephone or video consultation) at 4-6 weeks with the SNS. Results: Over three months, 105 patients were reviewed in the VASC, with mean age 52.2 years and 74% men. Time to review was reduced significantly with the mean time being 5.22 weeks. Only 31.4% of patients required Consultant review, primarily for radiolucent, complex stones or medical co-morbidities. After full evaluation, 12 patients were discharged, with 14 listed for stone intervention (ESWL or Ureteroscopy). Conclusion: The VASC has reduced treatment delays, time to be seen and associated morbidity from obstructing ureteric stones. Clinic pressures have been eased and consultant clinic capacity increased by the development of the VASC. The VASC has allowed training and development of the Nurse Specialist skill set with scope to evolve the clinic in the future.
ABSTRACT
Background: Liver transplant is an important curative option for select patients with hepatocellular carcinoma (HCC). The acuity circles-based allocation in February 2021 and a change setting model for end stage liver disease (MELD) exception points for HCC to the regional median MELD minus three, have the potential to create a difference in transplant opportunity for HCC patients despite having the same disease. We analyzed the effect of allocation changes on deceased donor liver transplant (DDLTs) for HCC in various regions of the US. Methods: Characteristics of HCC and non-HCC DDLTs in the year before (2/4/2019-2/3/2020) and after (2/4/2020-2/4/2021) introduction of the acuity circle policy were assessed using the Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) database. Based on the median national MELD at transplant of 28, OPTN regions were stratified into low (≤28) and high (>28) MELD regions. We performed chi-squared proportional testing to compare differences in transplant volumes in both eras. Results: In the pre-acuity circle era there were 6699 DDLTs performed compared to 6660 DDLTs in the post-acuity circle area era (-0.6%). The 0.6% decrease in the number of DDLTs was driven entirely by a decrease in DDLTs for HCC (1529 to 1351;-11.6%) (Figure 1). There was a reduction in the absolute numbers of HCC transplants performed in most regions. There were statistically significant decreases in regions 2 (-37.8%, p<0.001) and 4 (-28.3%, p=0.001) and a numerical decrease in region 11 (-20.3% p=0.088), all low MELD regions. Conversely, there were absolute increases in DDLTs for HCC in region 9 (+17.6%, p=0.388), region 1 (+3.0%, p=0.875), and region 5 (+1.6%, p=0.811), all high MELD regions. To assess if the reduction in HCC transplants was attributable to the COVID-19 pandemic, we examined changes in the proportion of all DDLT being performed for HCC. Similar to the changes in the absolute number of DDLTs, the overall percentage of DDLTs performed for HCC decreased after the new allocation system nationally (22.8% to 20.3%) with statistically significant decreases in regions 2 (26.5% to 18.3%, p<0.001) and 4 (27.8% to 20.5%, p=0.001). Conclusion: After introduction of new organ allocation policies in early 2020, there were large shifts in regional sharing of organs and statistically significant decreases in DDLT for HCC both nationally and in low MELD regions. The COVID-19 pandemic-related changes are unlikely to account for disproportionate decreases in HCC transplants. Ongoing investigation of these trends are needed to ensure that HCC patients are not unfairly disadvantaged because of geographic differences in score allocation for the same disease.
ABSTRACT
Background: The COVID-19 pandemic has provided a unique opportunity to evaluate global intensive care unit (ICU) admission practices. Patients with chronic liver disease (CLD) and cirrhosis may have limited or variable access to ICU. We aimed to describe international ICU admission rates and outcomes in critically-ill patients with CLD and COVID-19. Methods: Data were combined from two international registries (SECURE-Liver and COVID-Hep) for patients with CLD and lab-confirmed COVID-19 deemed sick enough to require ICU admission by the reporting clinician. Rates of ICU admission or decline, and respective outcomes were compared by country. We performed a secondary analysis comparing ICU admissions/declines and outcomes from the United States (US) and United Kingdom (UK), the two greatest contributing countries. Results: Between 25 March 2020 and 3 February 2021, 319 patients with CLD and COVID-19 from 27 countries were deemed to require ICU care. There was considerable country-level variability in ICU decline rates (Figure 1A), although mortality following ICU admission was similar by country (Figure 1B). Rates of ICU admission differed significantly between the US (75/79, 95%) and UK (22/77, 29%) (p<0.001). However, there were no differences in the US and UK in mortality after ICU admission (42/75 [56%] vs. 10/22 [45%];p=0.468;Figure 1B) or mortality after invasive ventilation (29/59 [49%] vs. 9/17 [53%];p=1.000). Both in those requiring ICU admission and admitted to the ICU, there were no differences in age, sex, Charlson Comorbidity Index or Child Pugh Score. Only four US patients were declined ICU admission of whom 2 (50%) died compared to 55 UK patients declined ICU admission of whom 51 (93%) died. Baseline factors associated with being declined ICU admission in the UK were older age, alcohol-related liver disease, and Child B/C cirrhosis. In both US and UK cohorts, the reason for not admitting patients to ICU was due to this being deemed inappropriate (futile) by the responsible clinician, except for one case in both countries in which no ICU bed was available. Information relating to patient goals of care, longterm outcomes in survivors, and granular detail regarding organ support requirements were not available. Conclusion: Patients with CLD and critical COVID-19 were over 3-times more likely to be admitted to ICU in the US than the UK despite having similar baseline characteristics. However, the rates of mortality following ICU admission were comparable between the two countries. ICU bed availability was not a key factor in decline rates. The differing thresholds for escalation to ICU with similar post admission outcomes warrants further discussion.
ABSTRACT
Background: Despite recent advances, the management of COVID19 is complicated by vaccine availability, the modest efficacy of existing treatments, and the potential for viral resistance. Therefore, there is a pressing need for new prophylactic and therapeutic agents. Modifying the expression of the SARS-CoV-2 entry receptor ACE2 could prevent viral infection and limit disease progression. Here, we identify that ACE2 expression is controlled by the transcription factor farnesoid X receptor (FXR) and demonstrate that ACE2 downregulation through FXR antagonism, using approved drugs, such as ursodeoxycholic acid (UDCA), could represent a novel therapeutic strategy to complement current approaches. Methods: Primary cholangiocyte, pulmonary and intestinal organoids were propagated using established protocols. Marker expression was assessed using singlecell RNA sequencing, QPCR, immunofluorescence and flow cytometry. FXR binding on DNA was assessed with chromatin immunoprecipitation. SARS-CoV-2 was isolated from bronchoalveolar lavage of a COVID19 patient. Viral load was measured via QPCR. Human livers not used for transplantation were perfused ex-situ using the metra (OrganOx) normothermic perfusion device. Serum ACE2 activity was measured with commercial kits. Patient data from the COVID-Hep and SECURE-Liver registries were compared using propensity score matching. Results: FXR activation directly upregulated ACE2 transcription in organoids from COVID19 affected tissues, including the biliary, gastrointestinal and respiratory systems. Conversely, FXR antagonism with z-guggulsterone or UDCA, had the opposite effect. Importantly, both drugs reduced susceptibility to SARS-CoV-2 infection in lung, cholangiocyte and gut organoids. Furthermore, systemic administration of UDCA in human organs perfused ex-situ downregulated ACE2 and reduced SARS-CoV-2 infection ex-vivo. Oral UDCA rapidly reduced serum ACE2 in vivo. Registry data showed a correlation between UDCA administration and better clinical outcomes in COVID19 patients, including hospitalisation, ICU admission, mechanical ventilation and death. Conclusion: We discovered FXR as a novel therapeutic target against SARS-CoV-2 and we identified approved FXR inhibitors which could be repurposed to potentially treat COVID19, paving the road for future clinical trials to validate these results.
ABSTRACT
Background: A number of factors can inform ICU escalation decisions, including the likelihood of survival and patient co-morbidities. This study examined prior liver transplant (LT) recipients and patients with chronic liver disease (CLD) diagnosed with SARS-CoV-2, and compared the rate of ICU admission and decline amongst those who were sick enough to require ICU care. Methods: Patient data from 12 March 2020 to 6 May 2021 was extracted using two international reporting registries (SECURE-Liver and COVID-Hep). Patients had a history of LT or CLD, laboratory-confirmed SARS-CoV-2, and were deemed ill enough to require ICU care. Patients were either admitted to the ICU, or declined admission due to inadequate capacity or because ICU escalation was deemed inappropriate. We compared patient characteristics by ICU decline, and compared ICU decline rates by LT and CLD categories with unadjusted and multivariable logistic regression. Results: 173 LT recipients were admitted to the hospital with SARS-CoV-2 (transplant year 1986-2020, median age 63, 74% male), and 66 (38.2%) were deemed unwell enough to require ICU care. Among those sick enough to require ICU care, 55 (83.3%) were admitted to the ICU and 11 (16.7%) were declined admission. Compared to those admitted to the ICU, patients declined ICU admission were significantly older (median 69 yrs vs 62 yrs, p=0.01) but otherwise similar in other characteristics. ICU decline rates in prior LT recipients (16.7%) were similar to patients with non-cirrhotic CLD (16.1%, p=0.96), but substantially lower than patients with Child A cirrhosis (31.8%, p=0.03), Child B cirrhosis (37.1%, p=0.006) and Child C cirrhosis (38.7%, p=0.004). Differences in ICU decline between LT recipients and Child B or C cirrhosis remained statistically significant after adjustment for age, sex and major co-morbidities. Among patients admitted to the ICU, mortality was higher in LT recipients compared to non-cirrhotic CLD (OR 0.31, 95% CI 0.14-0.71) but lower in LT recipients compared to Child C cirrhosis (OR 3.85, 95% CI 1.47-10.11) after adjustment for age, sex and co-morbidities (see Figure 1). Conclusion: ICU decline was less likely in LT recipients compared to patients with decompensated cirrhosis. LT recipients may be seen as gaining more benefit from ICU care, given the higher mortality amongst patients with decompensated cirrhosis. This is in line with prior data showing decompensated cirrhosis is a predictor of higher mortality in patients with SARS-CoV-2. Moreover, large investment of resources in LT recipients may make them more likely to be admitted to the ICU.
ABSTRACT
Introduction The management of COVID19 is complicated by vaccine availability, the modest efficacy of existing treatments, and the potential for viral resistance. Therefore, there is a pressing need for new prophylactic and therapeutic agents. The viral receptor ACE2 is an ideal target as it is required for SARS-CoV-2 entry in host cells. Modifying ACE2 expression could prevent infection and/or limit disease progression. Nevertheless, the mechanisms controlling ACE2 expression remain elusive. Aims To identify pathways controlling the transcriptional regulation of ACE2, and exploit them to reduce SARS-CoV-2 infection. Methods Organoids from primary biliary, intestinal and pulmonary epithelia were derived and cultured as previously described. Single-cell RNA sequencing, QPCR, immunofluorescence and flow cytometry were used to assess marker expression. Chromatin immunoprecipitation was used to assess FXR binding on DNA. Bronchoalveolar lavage SARS-CoV-2 patient isolates were used for infection experiments. Human livers not used for transplantation were connected to the metra (OrganOx) normothermic perfusion device and perfused ex-situ using therapeutic doses of UDCA for 12 hours. ACE2 activity was measured following manufacturer's instructions. Patient data from the COVID-Hep and SECURE-Liver registries were compared using propensity score matching for sex, age and Child-Turcotte-Pugh score. Results We first demonstrated that cholangiocytes are susceptible to SARS-CoV-2 infection in vivo and in organoid culture. We then used cholangiocyte organoids to identify FXR as a transcriptional regulator of ACE2. We validated our results in pulmonary and intestinal organoids, showing that ACE2 regulation by FXR represents a broad mechanism present in multiple COVID19-affected tissues. We then demonstrated that approved FXR inhibitors, such as ursodeoxycholic acid (UDCA) and z-guggulsterone (ZGG), decrease ACE2 levels and reduce viral infection in vitro in primary biliary, intestinal and pulmonary organoids. We interrogated the impact of systemic UDCA administration in human livers perfused ex-situ, demonstrating reduced ACE2 levels and SARS-CoV-2 infection. Furthermore, we showed that commencing UDCA treatment lowers ACE2 levels in primary biliary cholangitis (PBC) patients. Finally, we identified a correlation between UDCA treatment and better clinical outcome in COVID-19 patients, including hospitalisation, ICU admission, mechanical ventilation and death, using registry data. Conclusion We identified FXR as a novel master regulator of ACE2 expression. Using a bench-to-bedside approach we combined in vitro, ex-vivo and patient data to demonstrate the efficacy of ACE2 downregulation against SARS-CoV-2 infection and identified approved and inexpensive drugs (UDCA, ZGG) which could be repurposed as prophylactic and therapeutic agents against SARS-CoV-2 infection, paving the road for future clinical trials.
ABSTRACT
Background: During the novel coronavirus-2019 (COVID-19) pandemic, physicians in residency and fellowship training programs are serving as essential healthcare workers while also attempting to continue their preparation for eventual independent practice in their field. We aimed to determine how level of exposure patients with COVID-19 affected the experience of graduate medical trainees in terms of their safety, professional development, and well-being during March and April 2020 Methods: We administered an anonymous, voluntary, web-based survey to physicians enrolled in residency or fellowship training programs in any specialty worldwide A convenience sampling of trainees was obtained through distribution of the survey by email and social media posts from April 20th to May 11th, 2020 To investigate the impact of burden of exposure to COVID-19 the trainee experience, we categorized respondents according to their self-reported estimate of the number of patients with COVID-19 that they provided care for in March and April 2020 (0, 1-30, 31-60, >60). Descriptive statistics were performed and the chi square test was used to evaluate for statistical significance. A multivariable logistic regression analysis was conducted to determine independent predictors of physician burnout Results: Surveys were completed by 1420 trainees, of whom 1031 (73%) were residents Most of the fellows who responded to the survey were training in gastroenterology/ hepatology (27%, 85/280) Trainees who cared for a greater number of COVID-19 patients were more likely to report limited access to PPE and COVID-19 testing and more likely to report testing positive for COVID-19 (Figure 1A) Compared to trainees who did not take care of COVID-19 patients, those who took care of 1-30 patients (adjusted odds ratio [AOR] 1 80, 95% CI 1 29-2 51), 31-60 patients (AOR 3.30, 95% CI 1.86-5.88) and >60 patients (AOR 4.03, 95% CI 2 12-7 63) were increasingly more likely to report burnout More than half (835, 58%) of trainees reported concern about their future preparedness for independent practice Trainees who cared for >60 COVID-19 patients compared to those who did not care for any COVID-19 patients reported similar levels of concern about their preparedness for independent practice (56%, 372/636 vs 58%, 71/125 respectively, p-value 0 57, Figure 1B) Conclusion: Physician trainees who were involved in the care of patients with COVID-19 were more likely to report unsafe working conditions and suffered from higher rates of physician burnout Trainees were concerned about the effects of lost training opportunities on their professional development irrespective of the number of COVID-19 patients they cared for.