Hepatocellular carcinoma surveillance in the telehealth era: A single-centre review.

BACKGROUND: Real-world hepatocellular carcinoma (HCC) surveillance uptake remains suboptimal, despite evidence that surveillance is associated with lower cancer-related mortality in patients with cirrhosis and chronic hepatitis B. We aimed to examine the impact of telehealth consultations on HCC surveillance rates within a specialist liver clinic. METHODS: We conducted a retrospective observational study within an Australian outreach liver clinic within a culturally diverse community, comparing standard consultations before the COVID-19 pandemic to telehealth consultations during the pandemic. The primary outcome was surveillance uptake defined as the percentage of time up-to-date with surveillance (PTUDS) with the 6-month interval following each scan considered up-to-date. RESULTS: Over 18 months of follow-up for each cohort, the median PTUDS was 86.5% in the standard consultation cohort and 85.5% in the telehealth consultation cohort (p = 0.12). HCC diagnoses did not differ between groups and hospitalisation and mortality rates were low. Using multivariate regression, increasing age, the need for an interpreter and being born in South-East Asia independently predicted PTUDS in the standard consultation cohort, whereas being born in Australia or New Zealand was predictive of a lower PTUDS. Current alcohol use and distance from the clinic predicted a lower PTUDS in the telehealth consultation cohort. In both groups, missed clinic attendances were strongly predictive of a lower PTUDS. CONCLUSION: Telehealth hepatology consultations effectively coordinate HCC surveillance and are associated with similar outcomes to standard consultations. Its implementation should be widely considered given its advantages with regards to accessibility for patients.

The Pathogenesis of Gastrointestinal, Hepatic, and Pancreatic Injury in Acute and Long Coronavirus Disease 2019 Infection.

The gastrointestinal (GI) tract is targeted by severe acute respiratory syndrome coronavirus-2. The present review examines GI involvement in patients with long coronavirus disease and discusses the underlying pathophysiological mechanisms that include viral persistence, mucosal and systemic immune dysregulation, microbial dysbiosis, insulin resistance, and metabolic abnormalities. Due to the complex and potentially multifactorial nature of this syndrome, rigorous clinical definitions and pathophysiology-based therapeutic approaches are warranted.

MIF is a Common Genetic Determinant of COVID-19 Symptomatic Infection and Severity.

BACKGROUND: Genetic predisposition to COVID-19 may contribute to its morbidity and mortality. Because cytokines play an important role in multiple phases of infection, we examined whether commonly occurring, functional polymorphisms in macrophage migration inhibitory factor (MIF) are associated with COVID-19 infection or disease severity. AIM: To determine associations of common functional polymorphisms in MIF with symptomatic COVID-19 or its severity. METHODS: This retrospective case control study utilized 1171 patients with COVID-19 from three tertiary medical centers in the United States, Hungary, and Spain, together with a group of 637 pre-pandemic, healthy control subjects. Functional MIF promoter alleles (-794 CATT5-8, rs5844572), serum MIF and soluble MIF receptor levels, and available clinical characteristics were measured and correlated with COVID-19 diagnosis and hospitalization. Experimental mice genetically engineered to express human high- or low-expression MIF alleles were studied for response to coronavirus infection. RESULTS: In patients with COVID-19, there was a lower frequency of the high-expression MIF CATT7 allele when compared to healthy controls (11% vs. 19%, OR: 0.54 [0.41, 0.72], p < 0.0001). Among inpatients with COVID-19 (n = 805), there was a higher frequency of the MIF CATT7 allele compared to outpatients (n = 187) (12% vs. 5%, OR: 2.87 [1.42, 5.78], p = 0.002). Inpatients presented with higher serum MIF levels when compared to outpatients or uninfected healthy controls (87 ng/ml vs. 35 ng/ml vs. 29 ng/ml, p < 0.001, respectively). Among inpatients, circulating MIF concentrations correlated with admission ferritin (r = 0.19, p = 0.01) and maximum CRP (r = 0.16, p = 0.03) levels. Mice with a human high-expression MIF allele showed more severe disease than those with a low-expression MIF allele. CONCLUSIONS: In this multinational retrospective study of 1171 subjects with COVID-19, the commonly occurring -794 CATT7  MIF allele is associated with reduced susceptibility to symptomatic SARS-CoV-2 infection but increased disease progression as assessed by hospitalization. These findings affirm the importance of host genetics in different stages of COVID-19 infection.

Three Zone Scanning Protocol For Lung Ultrasound: An Anatomical Basis.

Lung ultrasound is rapidly gaining popularity based on point of care ease of use, diagnostic fidelity and lack of ionizing radiation. This was particularly notable at the beginning of the COVID-19 pandemic, where concerns of contamination of the x-ray department led to a reluctance to order frequent chest x-rays. Early COVID-19 lung involvement is of a bronchopneumonia, and patches of consolidation adjacent to the chest wall were easily detectable by ultrasound. A large number of proposed scanning protocols were advocated and are often complex and largely based on traditional stethoscope examination or access points on the chest wall rather than the underlying lung anatomy. A surgical understanding of lung anatomy and related surface anatomy has led us to develop a simplified three zone scanning protocol in 2013. The anterior zone corresponds to the upper lobe, and the posterior zone is divided between upper lobe and lower lobe. The relationship between lung lobes and the surface of the chest wall provides the anatomical basis for a simple three scanning zone lung ultrasound protocol.

The pathogenesis of gastrointestinal, hepatic and pancreatic injury in acute and long COVID-19 infection

Synopsis The gastrointestinal tract (GI) is targeted by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The present review examines GI involvement in patients with long COVID and discusses the underlying pathophysiological mechanisms that include viral persistence, mucosal and systemic immune dysregulation, microbial dysbiosis, insulin resistance and metabolic abnormalities. Due to the complex and potentially multifactorial nature of this syndrome, rigorous clinical definitions and pathophysiology-based therapeutic approaches are warranted.

Overlapping Presentations of HELLP Syndrome and COVID-19.

Introduction: Haemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome is a leading cause of maternal mortality. The emergence of coronavirus disease 2019 (COVID-19) has led to challenges in diagnosing HELLP syndrome due to overlapping clinical and laboratory presentations. We report a case of HELLP syndrome complicated by COVID-19 infection. Case Description: An otherwise healthy pregnant 31-year-old woman presented with fever, myalgia and headache. She was found to be COVID-positive with laboratory signs of HELLP syndrome. Symptoms and laboratory findings trended toward normal after delivery confirming the diagnosis of HELLP syndrome. Discussion: A prompt diagnosis of HELLP syndrome is essential to avoid maternal and fetal complications. Clinicians should be aware of the similarities in presentation between HELLP syndrome and COVID-19 for timely diagnosis and treatment. LEARNING POINTS: SARS-CoV-2 preferentially binds to ACE2 which is expressed in extrapulmonary tissue including placental tissue.COVID-19, HELLP syndrome and preeclampsia may have similar characteristics including elevated blood pressures, liver dysfunction, cardiopulmonary complaints and hypercoagulability.The temporal relationship of symptomatic improvement with delivery and after delivery may better differentiate HELLP syndrome from COVID-19.

Automatic deep learning-based consolidation/collapse classification in lung ultrasound images for COVID-19 induced pneumonia.

Our automated deep learning-based approach identifies consolidation/collapse in LUS images to aid in the identification of late stages of COVID-19 induced pneumonia, where consolidation/collapse is one of the possible associated pathologies. A common challenge in training such models is that annotating each frame of an ultrasound video requires high labelling effort. This effort in practice becomes prohibitive for large ultrasound datasets. To understand the impact of various degrees of labelling precision, we compare labelling strategies to train fully supervised models (frame-based method, higher labelling effort) and inaccurately supervised models (video-based methods, lower labelling effort), both of which yield binary predictions for LUS videos on a frame-by-frame level. We moreover introduce a novel sampled quaternary method which randomly samples only 10% of the LUS video frames and subsequently assigns (ordinal) categorical labels to all frames in the video based on the fraction of positively annotated samples. This method outperformed the inaccurately supervised video-based method and more surprisingly, the supervised frame-based approach with respect to metrics such as precision-recall area under curve (PR-AUC) and F1 score, despite being a form of inaccurate learning. We argue that our video-based method is more robust with respect to label noise and mitigates overfitting in a manner similar to label smoothing. The algorithm was trained using a ten-fold cross validation, which resulted in a PR-AUC score of 73% and an accuracy of 89%. While the efficacy of our classifier using the sampled quaternary method significantly lowers the labelling effort, it must be verified on a larger consolidation/collapse dataset, our proposed classifier using the sampled quaternary video-based method is clinically comparable with trained experts' performance.

Circulating Dickkopf1 Parallels Metabolic Adaptations and Predicts Disease Trajectories in Patients With COVID-19.

CONTEXT AND AIMS: Coronavirus disease 19 (COVID-19) trajectories show high interindividual variability, ranging from asymptomatic manifestations to fatal outcomes, the latter of which may be fueled by immunometabolic maladaptation of the host. Reliable identification of patients who are at risk of severe disease remains challenging. We hypothesized that serum concentrations of Dickkopf1 (DKK1) indicate disease outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals. METHODS: We recruited hospitalized patients with PCR-confirmed SARS-CoV-2 infection and included 80 individuals for whom blood samples from 2 independent time points were available. DKK1 serum concentrations were measured by ELISA in paired samples. Clinical data were extracted from patient charts and correlated with DKK1 levels. Publicly available datasets were screened for changes in cellular DKK1 expression on SARS-CoV-2 infection. Plasma metabolites were profiled by nuclear magnetic resonance spectroscopy in an unbiased fashion and correlated with DKK1 data. Kaplan-Meier and Cox regression analysis were used to investigate the prognostic value of DKK1 levels in the context of COVID-19. RESULTS: We report that serum levels of DKK1 predict disease outcomes in patients with COVID-19. Circulating DKK1 concentrations are characterized by high interindividual variability and change as a function of time during SARS-CoV-2 infection, which is linked to platelet counts. We further find that the metabolic signature associated with SARS-CoV-2 infection resembles fasting metabolism and is mirrored by circulating DKK1 abundance. Patients with low DKK1 levels are twice as likely to die from COVID-19 than those with high levels, and DKK1 predicts mortality independent of markers of inflammation, renal function, and platelet numbers. CONCLUSION: Our study suggests a potential clinical use of circulating DKK1 as a predictor of disease outcomes in patients with COVID-19. These results require validation in additional cohorts.

Interferon gamma runs interference on persistent COVID-19.

COVID-19 represents a collection of disease endotypes stemming from infection with SARS-CoV-2 and thus requires precision medicine approaches to target specific viral variants and stages of illness. In this issue, van Laarhoven et al.1 describe five immunocompromised patients with prolonged COVID-19 successfully treated with interferon gamma (IFNγ).

Outcomes for emergency department patients with suspected and confirmed COVID-19: An analysis of the Australian experience in 2020 (COVED-5).

OBJECTIVE: The aim of the present study was to describe the characteristics and outcomes of patients presenting to Australian EDs with suspected and confirmed COVID-19 during 2020, and to determine the predictors of in-hospital death for SARS-CoV-2 positive patients. METHODS: This analysis from the COVED Project presents data from 12 sites across four Australian states for the period from 1 April to 30 November 2020. All adult patients who met local criteria for suspected COVID-19 and underwent testing for SARS-CoV-2 in the ED were eligible for inclusion. Study outcomes were mechanical ventilation and in-hospital mortality. RESULTS: Among 24 405 eligible ED presentations over the whole study period, 423 tested positive for SARS-CoV-2. During the 'second wave' from 1 July to 30 September 2020, 26 (6%) of 406 SARS-CoV-2 patients received invasive mechanical ventilation, compared to 175 (2%) of the 9024 SARS-CoV-2 negative patients (odds ratio [OR] 3.5; 95% confidence interval [CI] 2.3-5.2, P < 0.001), and 41 (10%) SARS-CoV-2 positive patients died in hospital compared to 312 (3%) SARS-CoV-2 negative patients (OR 3.2; 95% CI 2.2-4.4, P = 0.001). For SARS-CoV-2 positive patients, the strongest independent predictors of hospital death were age (OR 1.1; 95% CI 1.1-1.1, P < 0.001), higher triage category (OR 3.5; 95% CI 1.3-9.4, P = 0.012), obesity (OR 4.2; 95% CI 1.2-14.3, P = 0.024) and receiving immunosuppressive treatment (OR 8.2; 95% CI 1.8-36.7, P = 0.006). CONCLUSIONS: ED patients who tested positive for SARS-CoV-2 had higher odds of mechanical ventilation and death in hospital. The strongest predictors of death were age, a higher triage category, obesity and receiving immunosuppressive treatment.

Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice.

Increasing age is the strongest predictor of risk of COVID-19 severity and mortality. Immunometabolic switch from glycolysis to ketolysis protects against inflammatory damage and influenza infection in adults. To investigate how age compromises defense against coronavirus infection, and whether a pro-longevity ketogenic diet (KD) impacts immune surveillance, we developed an aging model of natural murine beta coronavirus (mCoV) infection with mouse hepatitis virus strain-A59 (MHV-A59). When inoculated intranasally, mCoV is pneumotropic and recapitulates several clinical hallmarks of COVID-19 infection. Aged mCoV-A59-infected mice have increased mortality and higher systemic inflammation in the heart, adipose tissue, and hypothalamus, including neutrophilia and loss of γδ T cells in lungs. Activation of ketogenesis in aged mice expands tissue protective γδ T cells, deactivates the NLRP3 inflammasome, and decreases pathogenic monocytes in lungs of infected aged mice. These data establish harnessing of the ketogenic immunometabolic checkpoint as a potential treatment against coronavirus infection in the aged.

Sensitive detection and quantification of SARS-CoV-2 in saliva.

Saliva has significant advantages as a test medium for detection of SARS-CoV-2 infection in patients, such as ease of collection, minimal requirement of supplies and trained personnel, and safety. Comprehensive validation in a large cohort of prospectively collected specimens with unknown SARS-CoV-2 status should be performed to evaluate the potential and limitations of saliva-based testing. We developed a saliva-based testing pipeline for detection of SARS-CoV-2 nucleic acids using real-time reverse transcription PCR (RT-PCR) and droplet digital PCR (ddPCR) readouts, and measured samples from 137 outpatients tested at a curbside testing facility and 29 inpatients hospitalized for COVID-19. These measurements were compared to the nasal swab results for each patient performed by a certified microbiology laboratory. We found that our saliva testing positively detects 100% (RT-PCR) and 93.75% (ddPCR) of curbside patients that were identified as SARS-CoV-2 positive by the Emergency Use Authorization (EUA) certified nasal swab testing assay. Quantification of viral loads by ddPCR revealed an extremely wide range, with 1 million-fold difference between individual patients. Our results demonstrate for both community screening and hospital settings that saliva testing reliability is on par with that of the nasal swabs in detecting infected cases, and has potential for higher sensitivity when combined with ddPCR in detecting low-abundance viral loads that evade traditional testing methods.

Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy.

BACKGROUND AND AIMS: COVID-19 is associated with liver injury and elevated interleukin-6 (IL-6). We hypothesized that IL-6 trans-signaling in liver sinusoidal endothelial cells (LSECs) leads to endotheliopathy (a proinflammatory and procoagulant state) and liver injury in COVID-19. METHODS: Coagulopathy, endotheliopathy, and alanine aminotransferase (ALT) were retrospectively analyzed in a subset (n = 68), followed by a larger cohort (n = 3,780) of patients with COVID-19. Liver histology from 43 patients with COVID-19 was analyzed for endotheliopathy and its relationship to liver injury. Primary human LSECs were used to establish the IL-6 trans-signaling mechanism. RESULTS: Factor VIII, fibrinogen, D-dimer, von Willebrand factor (vWF) activity/antigen (biomarkers of coagulopathy/endotheliopathy) were significantly elevated in patients with COVID-19 and liver injury (elevated ALT). IL-6 positively correlated with vWF antigen (p = 0.02), factor VIII activity (p = 0.02), and D-dimer (p <0.0001). On liver histology, patients with COVID-19 and elevated ALT had significantly increased vWF and platelet staining, supporting a link between liver injury, coagulopathy, and endotheliopathy. Intralobular neutrophils positively correlated with platelet (p <0.0001) and vWF (p <0.01) staining, and IL-6 levels positively correlated with vWF staining (p <0.01). IL-6 trans-signaling leads to increased expression of procoagulant (factor VIII, vWF) and proinflammatory factors, increased cell surface vWF (p <0.01), and increased platelet attachment in LSECs. These effects were blocked by soluble glycoprotein 130 (IL-6 trans-signaling inhibitor), the JAK inhibitor ruxolitinib, and STAT1/3 small-interfering RNA knockdown. Hepatocyte fibrinogen expression was increased by the supernatant of LSECs subjected to IL-6 trans-signaling. CONCLUSION: IL-6 trans-signaling drives the coagulopathy and hepatic endotheliopathy associated with COVID-19 and could be a possible mechanism behind liver injury in these patients. LAY SUMMARY: Patients with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection often have liver injury, but why this occurs remains unknown. High levels of interleukin-6 (IL-6) and its circulating receptor, which form a complex to induce inflammatory signals, have been observed in patients with COVID-19. This paper demonstrates that the IL-6 signaling complex causes harmful changes to liver sinusoidal endothelial cells and may promote blood clotting and contribute to liver injury.

Automatic deep learning-based pleural effusion classification in lung ultrasound images for respiratory pathology diagnosis.

Lung ultrasound (LUS) imaging as a point-of-care diagnostic tool for lung pathologies has been proven superior to X-ray and comparable to CT, enabling earlier and more accurate diagnosis in real-time at the patient's bedside. The main limitation to widespread use is its dependence on the operator training and experience. COVID-19 lung ultrasound findings predominantly reflect a pneumonitis pattern, with pleural effusion being infrequent. However, pleural effusion is easy to detect and to quantify, therefore it was selected as the subject of this study, which aims to develop an automated system for the interpretation of LUS of pleural effusion. A LUS dataset was collected at the Royal Melbourne Hospital which consisted of 623 videos containing 99,209 2D ultrasound images of 70 patients using a phased array transducer. A standardized protocol was followed that involved scanning six anatomical regions providing complete coverage of the lungs for diagnosis of respiratory pathology. This protocol combined with a deep learning algorithm using a Spatial Transformer Network provides a basis for automatic pathology classification on an image-based level. In this work, the deep learning model was trained using supervised and weakly supervised approaches which used frame- and video-based ground truth labels respectively. The reference was expert clinician image interpretation. Both approaches show comparable accuracy scores on the test set of 92.4% and 91.1%, respectively, not statistically significantly different. However, the video-based labelling approach requires significantly less effort from clinical experts for ground truth labelling.

COVID-19 vaccines for patients with cancer: benefits likely outweigh risks.

Less than a year since the start of the COVID-19 pandemic, ten vaccines against SARS-CoV-2 have been approved for at least limited use, with over sixty others in clinical trials. This swift achievement has generated excitement and arrives at a time of great need, as the number of COVID-19 cases worldwide continues to rapidly increase. Two vaccines are currently approved for full use, both built on mRNA and lipid nanotechnology platforms, a success story of mRNA technology 20 years in the making. For patients with cancer, questions arise around the safety and efficacy of these vaccines in the setting of immune alterations engendered by their malignancy and/or therapies. We summarize the current data on leading COVID-19 vaccine candidates and vaccination of patients undergoing immunomodulatory cancer treatments. Most current cancer therapeutics should not prevent the generation of protective immunity. We call for more research in this area and recommend that the majority of patients with cancer receive COVID vaccinations when possible.

Perforated Appendicitis: An Unintended Consequence During the Coronavirus-19 Pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had major clinical impact across the globe. Delayed presentation for medical emergencies has been noted by the medical community. There has been limited reporting on the impact for the care for emergent surgical conditions. We sought to describe the effect of the global pandemic on the presentation and outcomes for the most common urgent general surgery disease process, acute appendicitis. METHODS: We performed a retrospective review of patients admitted to the United States Naval Hospital Okinawa during the COVID-19 pandemic, from January 2020 to May 2020 (COVID cohort), and compared them to a historical cohort (pre-COVID cohort) over the prior 2 years. Demographics, clinical presentation data, and interventions were collected. RESULTS: Of the 80 patients with appendicitis, 20% presented perforated. Most patients were male (71%), presented with 1 day of symptoms and had a length of stay of 1 to 2 days. Comparing groups, 13% of the pre-COVID group vs. 31% of the COVID cohort presented perforated (P = .04), with a symptom duration of 1.6 vs. 2.7 days before presentation (P = .075), respectively. CONCLUSIONS: The COVID-19 pandemic and the global systematic response has impacted unrelated medical and surgical conditions. At our overseas military hospital with minimal disease burden, we observed a delay in presentation for acute appendicitis with a higher incidence of perforation. Patients should be empowered to continue to seek care for urgent and emergent medical and surgical conditions so that they are not harmed by fear of COVID-19 rather than by COVID-19 itself.

Point-of-care lung ultrasound in the assessment of patients with COVID-19: A tutorial.

The adoption of point-of-care lung ultrasound for both suspected and confirmed COVID-19 patients highlights the issues of accessibility to ultrasound training and equipment. Lung ultrasound is more sensitive than chest radiography in detecting viral pneumonitis and preferred over computed tomography for reasons including its portability, reduced healthcare worker exposure and repeatability. The main lung ultrasound findings in COVID-19 patients are interstitial syndrome, irregular pleural line and subpleural consolidations. Consolidations are most likely found in critical patients in need of ventilatory support. Hence, lung ultrasound may be used to timely triage patients who may have evolving pneumonitis. Other respiratory pathology that may be detected by lung ultrasound includes pulmonary oedema, pneumothorax, consolidation and large effusion. A key barrier to incorporate lung ultrasound in the assessment of COVID-19 patients is adequate decontamination of ultrasound equipment to avoid viral spread. This tutorial provides a practical method to learn lung ultrasound and a cost-effective method of preventing contamination of ultrasound equipment and a practical method for performing and interpreting lung ultrasound.

AGA Clinical Practice Update on Management of Inflammatory Bowel Disease During the COVID-19 Pandemic: Expert Commentary.

The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update was to rapidly review the emerging evidence and provide timely expert recommendations regarding the management of patients with inflammatory bowel disease during the coronavirus disease 2019 pandemic. This expert commentary was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely perspective on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Gastroenterology.