The therapeutic landscape for non-small-cell lung cancer (NSCLC) patients that have common epidermal growth factor receptor (EGFR) mutations has changed radically in the last decade. The availability of these treatment options has an economic impact, therefore a budget impact analysis was performed.®) versus first-line osimertinib (Tagrisso®), followed by subsequent treatments. A decision analysis model was constructed in Excel. Scenario analyses and one-way sensitivity analysis were used to test the models’ robustness.A budget impact analysis was conducted from a Dutch healthcare perspective over a 5-year time horizon in EGFR-mutant NSCLC patients receiving first-line afatinib  of 29.1 months versus 24.7 months, quality-adjusted life months (QALMs) of 20.2 versus 17.4 with mean cost of €108,166 per patient versus €143,251 per patient, respectively. The 5-year total budget impact was €110.4 million for the afatinib sequence versus €158.6 million for the osimertinib sequence, leading to total incremental cost savings of €48.15 million.First-line afatinib treatment in patients with EGFR-mutant NSCLC had a lower financial impact on the Dutch healthcare budget with a higher mean ToT and QALM compared to osimertinib sequential treatment.The online version of this article (10.1007/s10198-020-01186-9) contains supplementary material, which is available to authorized users. Lung cancer is the worldwide leading cause of cancer mortality . Non-smaEventually, patients treated with first-line EGFR TKIs develop resistance to treatment. The majority of patients (50–70%) progressing on first- and second- generation TKIs, develop secondary mutations such as the T790M point mutation. For patients with T790M-positive tumors, osimertinib is an approved second-line treatment based on improved PFS compared to standard of care observed in the AURA3 study . ESMO guThere is increasing evidence suggesting that patients treated with first-line afatinib are well suited for subsequent treatment with osimertinib. In a retrospective pooled analysis of data from 34 patients with common sensitizing EGFR mutations treated in the LUX-Lung 3, 6 and 7 studies, the median time on sequential treatment with osimertinib after first-line afatinib was 31.5 months ; the majDue to the high number of life years lost by early death, lung cancer has one of the highest burdens of disease in the Netherlands , 20. The®) followed by second-line osimertinib (Tagrisso®) (T790M positive on progression) or chemotherapy (T790M negative on progression) followed by third-line chemotherapy versus first-line treatment osimertinib followed by second-line chemotherapy. Patients are assumed to go into the health states best supportive care (BSC) or death after failing chemotherapy. The analysis was performed from the Dutch healthcare perspective. The model estimated outcomes and costs for each treatment approach over a 5-year period. This analysis was developed in accordance with the International Society for Pharmacoeconomics and Outcomes Research’s good practices for budget impact analysis [A decision-analytic model was constructed in Microsoft Excel to assess the budget impact of different first-line treatment approaches in advanced or metastatic NSCLC patients with common EGFR mutations. The model compared two treatment strategies Fig. : first-lanalysis .Fig. 1DeThis budget impact analysis represents a base case. One-way deterministic sensitivity analysis and scenario analysis are performed to determine the influence of uncertainty around model inputs.The eligible population included individuals with metastatic NSCLC whose tumors have EGFR deletion 19 or L858R mutations initiating first-line treatment. According to the Dutch Cancer Registration, there were 9175 patients with NSCLC in 2017 [To investigate the effect of treatment sequencing on time on treatment, a survival model with reconstructed individual patient time-to-event data was fitted using digitized PFS curves with data from controlled clinical trials. For afatinib as first-line treatment, patient level data from the LUX-Lung 3 clinical trial were used to fit the PFS curves . In the Eventually the majority of patients will develop resistance to first-line treatment, mostly by developing secondary mutations such as the T790M point mutation. Data from the AURA3  and IMPRThe demographic characteristics of patients included in the RCTs of LUX-Lung 3, FLAURA, AURA3 and IMPRESS (published between 2015 and 2018) were well balanced , 13, 22.To ensure that survival data for patients with similar characteristics were used in the model, the model and analyses were limited to patients with common mutations. A network meta-analysis (NMA) was performed, following a Bayesian framework with two designed and estimated networks. The description of the performed NMA is included in the Supplementary Data. WebPlotDigitizer was used to extract the Kaplan–Meier data from the publications, R version 3.5.1 and the SurvHE package was used to generate pseudo-individual patient-level data . The parTotal time in progression-free disease and post-progression treatment options per treatment plan were calculated using a decision tree combining survival data and prescription data Fig. . Mean suDue to limited availability of overall survival data for the modeled interventions, we have assumed that patients not receiving subsequent therapy following progression will continue to progress and receive best supportive care and/or die.To be able to include adverse events into the budget impact model, disutilities related to specific adverse events in patients with NSCLC  were comComparing the utility in progression-free (PF) patients on first-line treatment with PF patients on second-line treatment resulted in a slightly higher but not clinically relevant mean utility in patients on second-line treatment . One potAn overview of all healthcare costs used in the model is shown in Table The budget impact analysis estimated the costs associated with each treatment approach. Costs were reported as annual total costs for the population and as quality-adjusted life months (QALMs).In accordance with the ISPOR guidelines for budget impact analysis , the robScenario analyses were performed to explore alternative assumptions in line with the suggestion of the ISPOR guidelines for budget impact analysis . A scenaOutcomes survival analysis from the Weibull distribution in decision-analytic model for the various treatment paradigms is shown in Fig. Costs of each first-line treatment strategy were based on number of packages per year . The total budget impact of each treatment sequence is shown in Fig. For the treatment sequence starting with osimertinib, the total budget impact over 5 years was €158.6 million, with total costs per year ranging from €11.34 million in year 1, increasing to €36.98 million for the 3rd year, with lower incremental costs in years 4 and 5. The cost contribution of PDC to total costs was low reaching a maximum of 10% at year 5.The incremental cost savings were €6.06, €12.25 million, €12.26 million, €9.87 million and €7.72 million for years 1, 2, 3, 4 and 5, respectively (see Appendix). Over a 5-year period of time, the incremental budget impact savings of sequential treatment with afatinib versus first-line treatment with osimertinib were estimated to be €48.15 million.Results of the two scenario analysis are presented in Table Figure Over the last decade, various treatment options showed improved PFS data in clinical trials and will support improvement of the burden of disease for lung cancer. The availability of these treatment options has an economic impact, therefore a budget impact analysis was performed to estimate the impact of first-line sequential treatment of afatinib versus the introduction of osimertinib as first-line therapy for NSCLC patients with common EGFR mutations in the Netherlands. The results of this analysis indicated that the incremental budget impact savings of first-line sequential treatment with afatinib in comparison to first-line sequential treatment with osimertinib was €48 million over a period of 5 years. One-way sensitivity analysis showed the model was robust and the variables tested had no substantial influence on the incremental budget impact. As might be expected, the model was most sensitive to the price of osimertinib and afatinib. It is important to note that although there were differences in the tolerability of these agents, the increased frequency and costs of managing adverse events associated with afatinib were not associated with an increased overall treatment cost compared to osimertinib; afatinib had a lower total average cost per patient. Sensitivity analysis also showed that the costs associated with adverse events had little influence on the incremental budget impact.The results of the model were also sensitive to the percentage of patients with T790M mutation-positive disease receiving subsequent treatment, the percentage of patients testing positive for T790M mutations and the percentage of subsequent treatment after first-line therapy with osimertinib. Indeed, the scenario analysis using a higher percentage for the proportion of patients that continued to receive second-line osimertinib following first-line afatinib resulted in smaller incremental budget impact savings due to a longer mean PFS time on second-line osimertinib and therefore increased drug costs. These results highlight the importance of T790M mutation testing, both for patient outcomes and assessment of treatment costs; further research is necessary to confirm the distribution and outcomes of T790M mutation testing. In addition, testing should already have been performed at the first sign of progression on first-line therapy to prevent deterioration of the performance status related to progressive tumor growth. More data on the subsequent treatment options after first-line osimertinib, as alternatives to PDC, are also needed as there is no evidence to support other treatment approaches at this time.To our knowledge, this is the first full budget impact analysis of first-line sequential therapy with afatinib in comparison to first-line osimertinib and was based on the best currently available evidence, a validated budget impact model, and included sensitivity and scenario analyses. No prior analysis has compared the budget impact of afatinib to osimertinib in newly diagnosed patients with metastatic NSCLC whose tumors have EGFR deletion 19 or L858R mutations. Recently, the Dutch Healthcare Institute evaluated the budget impact of first-line osimertinib in NSCLC patients with EGFR mutations in the Netherlands over a 3-year horizon showing an estimated incremental budget impact of €18.6 million to €37.1 million . This isFurther cost-effectiveness analysis is necessary to confirm our cost and quality-of-life assessment comparison between first-line sequential treatment with afatinib versus first-line treatment with osimertinib. The cost-effectiveness of osimertinib has previously been evaluated in Canada , the UniThere are several limitations that should be considered. As no data were available on the efficacy and median PFS of PDC as third-line treatment, data from the second-line setting of the IMPRESS trial were used which likely overestimated the treatment benefit in this treatment arm and also overestimated the additional costs coming from this treatment benefit. To avoid an over- or underestimation on the quality of life of treatments resulting from the exclusion of adverse events for which disutility data were not available, assumptions were made for dyspnea, leukopenia, paronychia and stomatitis. Further research regarding disutilities of adverse events is needed to support these assumptions. The intention of our model was to reconstruct the patients’ time on treatment per first-, second-, and third-line of treatment based on the clinical trials for afatinib, osimertinib and PDC, respectively. As no direct head-to-head studies have compared afatinib versus osimertinib, this model used a mixed treatment model approach. One of the largest differences between patient populations was the presence of the T790-positive mutation in all included EGFR-positive NSCLC patients in the AURA3 trial. The inclusion of these data had to be taken into account in our survival model to be able to reconstruct the effect of second-line treatment with osimertinib. The reason was that in the AURA3 trial the efficacy of second-line osimertinib was evaluated for this specific indication.Even though the included RCTs were overall well balanced, we are aware of potential selection bias due to differences in patient populations such as age, race, smoking history, EGFR mutations status and presence of T790M positive mutation, resulting in potential over- or underestimation for both treatment arms.The model did not include any other second- or third-line treatment options than PDC therapy or second-line osimertinib; it should be recognized that the inclusion of other emerging therapies would alter budget impact and total costs of both treatment strategies. Further research is needed with a head-to-head comparison of osimertinib versus afatinib and other second-generation TKIs in a clinical trial or real-world data setting to support the outcomes of this budget impact model. Finally, compliance was assumed to be 100% for all treatments which may not reflect real-world practice. This may overestimate treatment costs and would also affect the clinical benefits of treatment.In conclusion, the use of afatinib as a first-line treatment approach would have a substantial lower financial impact on the healthcare budget in the Netherlands and would lead to a higher incremental time on treatment of 4.5 months and an incremental QALM of 2.8 compared to a sequential treatment approach starting with osimertinib. The total budget impact over 5 years was €110.4 million for the sequence starting with afatinib versus €158.6 million for the sequence starting with osimertinib, leading to a total incremental cost saving of €48.15 million. Together with clinical data, medicine prices and market access agreements will support governments and healthcare payers to decide how to manage the worldwide leading cause of cancer mortality.Supplementary file1 (DOCX 220 kb)Below is the link to the electronic supplementary material.


Pulmonary neuroendocrine tumors (NETs) are a heterogeneous family of malignancies whose classification relies on morphology and mitotic rate, unlike extrapulmonary neuroendocrine tumors that require both mitotic rate and Ki-67. As mitotic count is proportional to Ki-67, it is crucial to understand if Ki-67 can complement the existing diagnostic guidelines, as well as discover the benefit of these two markers to unravel the biological heterogeneity. In this study, we investigated the association of mitotic rate and Ki-67 at gene- and pathway-level using transcriptomic data in lung NET malignancies. Lung resection tumor specimens obtained from 28 patients diagnosed with NETs were selected. Mitotic rate, Ki-67 and transcriptomic data were obtained for all samples. The concordance between mitotic rate and Ki-67 was evaluated at gene-level and pathway-level using gene expression data. Our analysis revealed a strong association between mitotic rate and Ki-67 across all samples and cell cycle genes were found to be differentially ranked between them. Pathway analysis indicated that a greater number of pathways overlapped between these markers. Analyses based on lung NET subtypes revealed that mitotic rate in carcinoids and Ki-67 in large cell neuroendocrine carcinomas provided comprehensive characterization of pathways among these malignancies. Among the two subtypes, we found distinct leading-edge gene sets that drive the enrichment signal of commonly enriched pathways between mitotic index and Ki-67. Overall, our findings delineated the degree of benefit of the two proliferation markers, and offers new layer to predict the biological behavior and identify high-risk patients using a more comprehensive diagnostic workup. On the other hand, SCLC and LCNEC neoplasms constitute poorly differentiated tumors showing high grade cytologic features, extensive necrosis and mitotic count higher than 10 mitoses per 2 mm2 [Neuroendocrine tumors (NET) are a heterogeneous group of malignancies, which represent around 23% of all lung cancers . Based oer 2 mm2 .In pulmonary NETs, the Ki-67 antigen has been evaluated for its diagnostic, prognostic and grading implications –14. Ki-6Many studies in the literature have shown that the two proliferation markers, mitotic rate and Ki-67 index are strongly correlated , 21–23, The clinical characteristics of patients in the cohort are presented in r = 0.83 . We first examined the association between the two proliferation markers, using the Spearman correlation coefficient, and found a moderate correlation between them (r = 0.55)  . Next, w = 0.55) . The maxFinally, we compared the biological pathways that were associated with the mitotic index and Ki-67. For an FDR < 10%, 311 molecular pathways were enriched using mitotic index, out of which 97 and 214 pathways were positively and negatively correlated with mitotic index, respectively . Similarr = 0.52, between them . Secondly, we found gene-level differences between both the markers, and specifically, the cell-cycle related genes tended to exhibit large variations in the ranking of their correlation strength.For this study, we selected 28 lung NET patients consisting of carcinoids and large cell carcinomas. The proliferation capacity of cancer cells was assessed through two markers, namely, mitotic index and Ki-67 antigen for all the samples. Firstly, we found a strong Spearman correlation between the two proliferation markers  and LCNEC (n = 8). We found moderate correlation  between mitotic index and Ki-67 in carcinoids and in LCNEC, respectively. We observed larger variations in terms of the ranking of cell cycle-related genes in both the subtypes, while the variations were found be larger in the LCNEC group. We hypothesize that these set of proliferation-related genes could potentially be used to characterize the differences or similarities between the two proliferation markers using gene expression data. Using pathway analysis, we were able to show that there is considerable variation in the molecular pathways that were associated with mitotic rate and Ki-67 index across carcinoids and LCNEC. While mitotic index provided a more comprehensive characterization of molecular pathways compared to Ki-67 in carcinoids, Ki-67 elicited a broad characterization of biological pathways compared to mitotic index in the LCNEC group. This reflects that specific pathway properties can explain the inherent biological complexity of these subtypes. Furthermore, to better understand which genes tend to be drive the commonly enriched pathways between mitotic index and Ki-67, we capitalized on the leading-edge genes of a pathway. We found distinct sets of leading-edge genes that drive the biological pathways underpinning the cell cycle kinetics defined by mitotic index and Ki-67 in both the subtypes. Altogether these observations suggest that depending on the histological subtype, either mitotic index or Ki-67 can be used to discover the inherent biological complexity and diversity of these malignancies.Given the disease heterogeneity of lung NET malignancies, it may be difficult to delineate the true extent of benefit of mitotic index and Ki-67 within the histological groups. To investigate this, we examined the association of mitotic index and Ki-67 with the expression profiles across two distinct lung NET subtypes – carcinoids (i) Sample size: due to small sample size of the LCNEC group, the gene-level and pathway-level associations with mitotic rate and Ki-67 index is less robust; ii) Inter-observer variability: there is a considerable interobserver variation in the histopathological characterization of lung NET’s, i.e., in samples with low to medium values of mitotic index [Despite the relative merits of mitotic index and Ki-67, and the degree of correlation between these two biomarkers in different cancer types, less attention has been paid to integrate these two biomarkers in lung NETs. To summarize our findings, we found that mitotic index and Ki-67 markers govern similar set of biological mechanisms (at the pathway-level). Therefore, we hypothesize that integrating both these proliferation indices into the classification framework could potentially be redundant in stratifying lung NET subtypes more effectively. In order to translate these findings into a clinical setting, we will require further validation involving larger cohorts to determine their additive or independent value in a classification setting, which is the focus of future investigations. With regards to the histology-based findings, we hypothesize that either mitotic index and Ki-67 could potentially offer a novel characterization of the biological behavior and identify patients who will benefit from a multi-modal therapeutic regimen. The rational integration of these mutually inclusive proliferation variables within the lung NET subtypes could strengthen the current practices to improve clinical decision making for biologically diverse malignancies. Although our findings are of significant interest from a biological point of view, there were some limitations, which include, ic index . The curhttps://rsr-qc.ca/biobanque/) at the Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ). The cohort included a total of 28 lung neuroendocrine cases. Among these patients, 10 samples were typical carcinoids, 7 samples were atypical carcinoids and 11 cases were LCNEC based on the 2015 WHO classification. The availability of frozen tissue along with the quality and the amount of extracted RNA were assessed. For carcinoids, we selected the cases such that the spectrum of their mitotic index, i.e., of 0–10 mitoses per 2 mm² is covered. All the original H&E slides were reviewed by two thoracic pathologists to confirm the diagnostic, including assessment of the mitotic count and the Ki-67 index. We used the WHO guidelines to classify the tumors, except for cases with 10–20 mitoses per 2 mm2, as we and other studies have shown that they usually or may exhibit carcinoid-like morphology [The study was performed on the cohort from a single pulmonary pathology reference center with the approval of the institutional ethics committee (#21045). Pulmonary resected cases of lung neuroendocrine tumors diagnosed between 2000 and 2016 were reviewed. These samples were part of the Quebec Respiratory Health Network Tissue Bank  using Spearman correlation. This analysis was done to compare and highlight significant genes that are positively and negatively associated with proliferation markers in carcinoids, LCNEC and in all the samples. This analysis would enable us to identify top genes that changed their ranking in terms of the correlation strength with the two proliferation markers.R package [p-values obtained for each molecular pathway were corrected for multiple testing using the false discovery approach (FDR) [R package.The pathway enrichment analysis on the gene expression data was carried out using the gene set enrichment analysis (GSEA) methodology  with tra package . Nominalch (FDR) , with p.To analyze if the same set of genes were driving a pathway enriched by both mitotic index and Ki-67, we performed the leading-edge gene analysis. GSEA method returns a subset of genes, termed as the leading-edge genes, which drives the enrichment statistic in the pathway analysis. The leading-edge genes were obtained from the enrichment score that is defined by the maximum deviation from zero. This set of leading-edge genes are considered to be of high biological interest due to appearing at higher frequencies among the pathway subsets , which c


The disease (COVID-19) novel coronavirus pandemic has so far infected millions resulting in the death of over a million people as of Oct 2020. More than 90% of those infected with COVID-19 show mild or no symptoms but the rest of the infected cases show severe symptoms resulting in significant mortality. Age has emerged as a major factor to predict the severity of the disease and mortality rates are significantly higher in elderly patients. Besides, patients with underlying conditions like Type 2 diabetes, cardiovascular diseases, hypertension, and cancer have an increased risk of severe disease and death due to COVID-19 infection. Obesity has emerged as a novel risk factor for hospitalization and death due to COVID-19. Several independent studies have observed that people with obesity are at a greater risk of severe disease and death due to COVID-19. Here we review the published data related to obesity and overweight to assess the possible risk and outcome in Covid-19 patients based on their body weight. Besides, we explore how the obese host provides a unique microenvironment for disease pathogenesis, resulting in increased severity of the disease and poor outcome. COVID-19 disease is caused by a novel coronavirus SARS-COV-2) that emerged in the Wuhan province of china  that eme–5. Even Here we summarize the available epidemiological data with a particular focus on obesity and its impact on disease severity. We also discuss possible mechanism(s) that make obese host susceptible to severe disease as a result of SARS-CoV-2 infection.2), indicating a high incidence of obesity among patients admitted to intensive care for SARS-COV-2 [2). Out of these 17 (37.8%) showed severe disease. Compared to only 2 (9.5%) non-obese patients that have severe disease. The authors concluded that obesity is a major risk factor for disease severity in COVID-19 patients having MAFLD. A recent review addressed the role of MAFLD in the outcome of COVID-19 patients [2) are at high risk of severe COVID-19. Besides, Obesity (BMI > 30 kg/m2) was strongly and independently associated with the use of invasive mechanical ventilation in patients with COVID-19 [N = 3615) [2 were more than twice likely to be admitted to hospital and develop critical illness compared to patients with a BMI < 30 kg/m2. The likelihood of admission to ICU increased to 3.6 times in patients with severe obesity (BMI ≥ 35 kg/m2) [N = 5279) showed similar results. The authors concluded that after age, obesity was the single most important factor for hospitalized patients with COVID-19 [et. al. reported that obesity predisposed young COVID-19 patients (14–45 Years of age) to the risk of significantly higher mortality [et.al. examined the association of Obesity with the severity of COVID-19 in a designated hospital in Shenzhen, China and concluded that obese patients has increased odds of progressing to severe disease due to COVID-19 [There have been several reports indicating obesity to be a strong factor for becoming seriously ill with COVID-19 –45. A reRS-COV-2 . When coRS-COV-2 . The autpatients . AnotherCOVID-19 . Similar = 3615) . The aut5 kg/m2) . AnotherCOVID-19 . A reporCOVID-19 . The autty BMI ≥  kg/m2 [Nortality . Cai et.COVID-19 . ReportsCOVID-19  an SpainCOVID-19  have alsTable People with obesity have an increased prevalence of diseases like renal insufficiency, cardiovascular diseases, Type 2 diabetes mellitus, certain types of cancers, and a significant degree of endothelial dysfunction. These conditions are major risk factors for disease severity and mortality associated with COVID-19. This makes obesity, particularly ominous in COVID-19. However, there is enough evidence to suggest that obesity is an additional risk factor associated with worse outcomes in COVID-19 patients. Caussy et al. specifically looked at whether obesity was associated with worse outcomes in COVID-19 patients with other risk factors. The authors found that obesity remained a significant factor for poor outcome of patients having other chronic issues like Hypertension, Dyslipidemia, Type 2 diabetes, Cardiomyopathy, Chronic pulmonary diseases, and malignancy. The analysis is shown in Table Therefore, it is reasonable to assume that there are additional factors that make obese host vulnerable to severe disease and worse outcomes as a result of COVID-19 infection.et.al. specifically looked at the role of low inflammation in the severity of COVID-19 disease [Until recently adipose tissue was merely considered to be an inert organ that stored energy in the form of lipids, which could be utilized in the state of fasting/starvation. However, adipose tissue is now being recognized as a key endocrine organ that secretes a plethora of factors  that profoundly impact metabolism and immune system , 62. Nor disease . The autSeveral lines of evidence have strongly indicated that obesity results in significant changes in both innate and adaptive immune response and individuals with obesity are in a state of chronic and low-grade inflammation –82. The Blood cells (both lymphoid and myeloid) lineages are generated from bone marrow-derived pluripotent hematopoietic stem cells. Lymphoid cells undergo further processing in the thymus to generate mature T-Lymphocytes. Mature lymphocytes reside in secondary lymphoid tissues including lymph nodes and spleen, where they take part in immune surveillance and wait for activation by pathogens. Therefore, any change in the lymphoid tissue architecture can adversely affect its functioning resulting in an alteration in the distribution of immune cell populations, impaired T cells activity, and diminished immune defense. Interestingly, Obesity and metabolic syndrome have a profound impact on the functioning of lymphoid tissue , 88. Ectet. al. used triglyceride and glucose index (TyG) as a marker of insulin resistance and showed that TyG index was significantly associated with an increased risk of severe case and mortality in CoVID-19 patients [Multiple lines of evidence suggest that Insulin may be a key regulator of T-cell metabolism and function –99. Insupatients . Althougpatients –113.Besides insulin, leptin the hormone that is secreted from adipocytes exerts profound effects on innate and adaptive immunity. Leptin is a key regulator of metabolic homeostasis and it primarily exerts its effects via Leptin receptors (LEPR) that are highly expressed in POMC neurons in the hypothalamus, which is the epicenter of appetite and energy expenditure regulation. Leptin has also been shown to regulate several other physiological processes in the body. Interestingly, LEPRs are expressed in cells of the immune system and several studies have documents the role of leptin in regulating various aspects of immune cell development and activity –116. Lep. The receptors are expressed on cells in the nose lining, the lungs, pancreas, kidneys and gut, adipose, and in the lining of blood vessels, in the heart muscle, and cells circulating in the blood. It is assumed that increased expression of ACE-2 would boost the entry of the virus into the cells and therefore, cause severe disease with worse clinical outcomes. Emerging evidence indicates that ACE2 expression is increased in individuals who are obese and overweight. Higham et al. have demonstrated increased ACE2 expression in the bronchial epithelium of COPD patients who are overweight or obese compared to lean subjects [Angiotensinogen Converting Enzyme (ACE-2) is required for the entry of COVID-19 into the cellssubjects . The autsubjects . Moreovesubjects . This rasubjects . More imsubjects –128. TheSeveral studies have shown that obesity is associated with a hypercoagulable state and obese subjects have elevated levels of prothrombin factors and reduced levels of anti-thrombin molecules –131. SinObese subjects are at an increased risk of developing pneumonia but ironically, obese patients with pneumonia have a lower mortality as compared to non-obese subjects. This phenomenon is known as “Obesity survival paradox” and has been the subject of several independent studies –136. ObeObesity is a huge healthcare concern because it is associated with several chronic diseases including type 2 diabetes, heart diseases, stroke, and certain types of cancers. Obesity significantly reduces the quality of life and is one of the leading causes of death, worldwide. Recent evidence has shown that obesity weakens the immune system and therefore, making the host vulnerable to infectious diseases. Indeed, Obesity has emerged as a strong risk factor for severe disease in the current pandemic disease, COVID-19. Several independent studies have demonstrated that obese subjects with COVID-19 have a higher risk of severe disease, hospitalization, and increased probability of death. During the 2009 HIN1 pandemic, patients with severe obesity were more likely to require hospitalization, ICU admission, and death due to the disease. Data over the years have indicated that obesity negatively impacts host immune defense making it vulnerable to infectious disease. Excess adiposity is associated with significant changes in the resident immune cell composition of adipose tissue, which disrupts the balance between pro-inflammatory and anti-inflammatory immune cells in favor of the former. This leads to a state of chronic low-grade inflammation. This chronic inflammation is likely amplified by acute inflammation arising out of COVID-19 resulting in a more severe disease phenotype and poorer outcomes. One the other hand excess lipid deposition alters the integrity and architecture of primary lymphoid tissues and thereby impacting the immune cell development and activation. Besides, metabolic changes associated with obesity such as insulin and leptin resistance negatively impact immune cell function. Together these changes have a substantial influence on immune cell growth and proliferation, glucose metabolism, and activation which ultimately results in impairment of host immune defense. Finally, adipose ACE-2 could also play a vital role in the spread of COVID-19 to other tissues but more work is needed to investigate this possibility. Fig.


The COVID-19 pandemic has accelerated the demand for virtual healthcare delivery and highlighted the scarcity of telehealth medical student curricula, particularly tele-critical care. In partnership with the Penn E-lert program and the Department of Anesthesiology and Critical Care, the Perelman School of Medicine (PSOM) established a tele-ICU rotation to support the care of patients diagnosed with COVID-19 in the Intensive Care Unit (ICU). The four-week course had seven elements: (1) 60 h of clinical engagement; (2) multiple-choice pretest; (3) faculty-supervised, student-led case and topic presentations; (4) faculty-led debriefing sessions; (5) evidence-based-medicine discussion forum; (6) multiple-choice post-test; and (7) final reflection. Five third- and fourth-year medical students completed 300 h of supervised clinical engagement, following 16 patients over three weeks and documenting 70 clinical interventions. Knowledge of critical care and telehealth was demonstrated through improvement between pre-test and post-test scores. Professional development was demonstrated through post-course preceptor and learner feedback. This tele-ICU rotation allowed students to gain telemedicine exposure and participate in the care of COVID patients in a safe environment. Telemedicine and virtual care delivery expansion is inevitable, and the COVID-19 epidemic accelerated its implementation ,3,4. CurThe COVID-19 pandemic has been an unprecedented challenge to healthcare systems worldwide ,6. Tele-Medical student involvement in direct patient care was suspended across many institutions early in the COVID-19 pandemic . VirtualThe COVID-19 pandemic demands both innovative methods for delivering care to critically ill patients as well as new training opportunities that provide for the safety of students ,9. In thThe clinical elective, “eICU rotation: COVID-19 & Beyond”, was developed in March 2020 when in-person clinical activities for medical students were suspended for students at the Perelman School of Medicine (PSOM) because of the emerging COVID-19 pandemic. It was designed as a 4-week clinical rotation for post-clerkship students through a collaborative partnership among eICU faculty, curriculum leadership at PSOM and recruited 4th year students. The students took the lead in developing a curriculum that would enable medical students to remotely, safely and meaningfully participate in the care of critically ill COVID-19 patients. The goal of the elective was to enable students to acquire virtual patient care skills and understanding of critical care patient management through using a telemedicine platform and remote patient assessment protocols. Learning objectives for students were to: (i) assess and triage critically ill patients in a virtual setting; (ii) provide clinical care as a part of a remote interdisciplinary care; (iii) reflect on provider well-being in the midst of the pandemic; and (iv) describe the institutional challenges of providing care during a pandemic.Students rotated remotely through a 20-bed medical-surgical ICU in the University of Pennsylvania Health System (UPHS) that at the time only provided care for critically ill patients with a confirmed COVID-19 diagnosis. The remote site was at a UPHS facility in Philadelphia 2.1 miles from the medical center and the medical-surgical ICU. ICU on-site staff included an intensivist physician, a critical care fellow, two advanced practice providers and a respiratory therapist. Tele-ICU staff at the remote location included a 24/7 available intensivist (eMD) and ICU nurse (eRN). Tele-ICU respiratory therapists (eRT), CA-3 anesthesiology residents (eRes) and medical students (eMS) were available on weekdays only. Tele-ICU staff routinely checked in on newly admitted ICU patients and could also be contacted directly for acute issues via an automated system , direct telephone call or emergency alert button located in each ICU room. A camera, video screen and microphone were placed in every ICU room, allowing bidirectional visual and audio communication between on-site ICU staff and tele-ICU staff. Data from the camera, video screen and microphone were not recorded.Students (eMS) were assigned four 5-h shifts per week under the direct supervision of CA-3 anesthesiology residents with supervising faculty on site. There were two students per shift, each following one or two patients. During their clinical shifts, eMS reviewed the electronic health records  of their patients using a checklist developed from University of Pennsylvania Health System clinical practice guidelines  and codeAs students were engaged in remote but direct care of critically ill patients, they participated in weekly debriefing sessions over teleconference led by two emeritus faculty recruited by the PSOM administration. These debriefing sessions allowed students to reflect on patient care and professional and personal challenges encountered during the week. Students on-call at the time of the conferences were excused from clinical duties for the hour. In addition, students participated in small group sessions where they gave a case presentation and a topic presentation each week. These were held in-person at shift change in a large conference room with adequate social distancing. Students were also instructed to post one journal article that had impacted their patient care management plans on an online discussion board and comment on others’ posts. Finally, students were assigned a reflection essay as a capstone assignment for the experience. The reflection essay was intended to summarize key teaching points from the rotation and notable clinical cases. It was also designed for students to reflect on their professional development throughout the rotation.Both students and preceptors were asked to evaluate the rotation using anonymous REDCap-based surveys containing both multiple choice seven-point Likert scale questions and open-ended questions . In addiThis study was approved by the Institutional Review Board of the University of Pennsylvania.The logistics of starting a clinical rotation and educational course during the early surge response delayed the course by one week, leading to a three-week pilot rotation. Five students took the rotation in April 2020. During the three weeks of clinical shifts, the students followed 16 patients, generating 73 notes and 70 contributions to patient management.The patient clinical characteristics are presented in Students initiated a total of 70 clinical interventions, the majority of which were routine (95.6%) rather than urgent. The breakdown of interventions is detailed in Four of the five students evaluated the rotation one week after the rotation ended . Studentbaseline = 15.8 + 2.2 vs. Knowledgepost = 19.8 + 0.3; t[−3.2] = 00; p = 0.023). This assessment was corroborated by subjective agreement in the survey questions “I was able to engage inpatient care at a level consistent with my capabilities” and “this course improved my ability to assess and manage ICU patients”.All eMS reported feeling capable of evaluating and managing ICU and COVID patients after this rotation. The assessment of their knowledge before and after the rotation showed improvement (KnowledgeThe provider post-rotation survey revealed a heterogenous perception of eMS by attendings, residents and fellows. Although both attendings and residents found interactions with eMS valuable, fellows, functioning in-unit in a role similar to that of attendings, were more heterogeneous in their responses. An open-ended prompt “what other feedback would you like to provide about this medical student rotation?” offered insight as the fellows, the group with the lowest scores, explained that they had not been made aware of the initiative or of the expectations on themselves or the students. One fellow stated that, when they did have “time to chat” with the student, they found the eMS’ “clinical reasoning, professionalism, communication skills, and thoughtfulness to be impressive” and suggested that “improving the preparation of preceptors would enhance the experience and interest in participation for preceptors”. The rotation was perceived as innovative by almost all respondents. One attending even remarked that the rotation was “much needed” and “forward-thinking”.This pilot rotation sought to provide a way for students to contribute to direct COVID-19 patient care remotely under supervision while building valuable critical care and telehealth skills. To the best of our knowledge, this is the first report describing a medical student tele-ICU rotation during the COVID-19 pandemic. Given the rise of telemedicine during the pandemic and the growth in telemedicine’s medical student involvement, it is essential to evaluate the educational value of this type of student experience in the critical care setting ,8. This There were several limitations to the pilot rotation. The course was only able to run once with five medical students as the COVID-19 surge resolved earlier than expected and the UPHS healthcare system and the medical school moved forward with post-surge plans. Despite the paucity of participants, the study is a demonstrator of the benefits of medical students participating in a similar program. Medical systems can benefit from utilizing them to reduce the operational backlog. Students gain important expertise in tele-medicine, an essential part of future healthcare. Regarding the quality of data and analysis, several nuances of the data were not communicated clearly to survey respondents. For example, for documented interventions, the proportion of “urgent” interventions is likely underestimated. The routine and urgent variables were not adequately defined prior to the study’s initiation, with respondents defaulting to “routine”. Also, while the survey was intended to capture cases of students receiving teaching from preceptors, this intent was not adequately conveyed, and teaching data is limited. Furthermore, several indirect benefits of the rotation can only be estimated. For example, interventions such as bundling lab draws were not captured by the checklist. Lab bundling limits patient contact and PPE use, increasing efficiency and reducing potential virus transmission.If further surges arise in the future, it is likely that medical students will again be called upon to assist with the care of COVID-19 patients. Alternatively, the rotation can be modified to run outside of the COVID-19 context. One of the tools to provide the student with telemedicine interaction is virtual or augmented reality. These technologies allow for the simulation of almost any healthcare environment. Additionally, virtual and augmented existence may demonstrate conditions where the telemedicine system underperforms providers’ increasing resilience. The need for telemedicine in the delivery of care and UME training in telemedicine will remain long term. Future patients and care settings may also require flexibility, and this initiative can be adapted for those settings. We look forward to iterating our rotation, based on our initial experiences as well as emerging telemedicine literature. There is an unmet need to educate future providers about effective telemedicine utilization.Outstanding questions include the portability of the training based on one digital platform to other software platforms and how this form of clinical engagement affects professional identity development. Due to the virtual nature of the interaction, students could not physically examine or talk to their critically ill and intubated patients. This new type of provider-patient relationship requires further investigation. While we provided support via unstructured debriefing sessions and informal “check-ins”, virtual provider processing and grief must be explored to ensure eMS are adequately supported in their role.


Chronic musculoskeletal pain is a complex medical condition that can significantly impact quality of life. Patients with chronic pain demonstrate attentional biases towards pain-related information. The therapeutic benefits of modifying attentional biases by implicitly training attention away from pain-related information towards neutral information have been supported in a small number of published studies. Limited research however has explored the efficacy of modifying pain-related biases via the internet. This protocol describes a randomised, double-blind, internet-delivered attentional bias modification intervention, aimed to evaluate the efficacy of the intervention on reducing pain interference. Secondary outcomes are pain intensity, state and trait anxiety, depression, pain-related fear, and sleep impairment. This study will also explore the effects of training intensity on these outcomes, along with participants’ perceptions about the therapy.The study is a double-blind, randomised controlled trial with four arms exploring the efficacy of online attentional bias modification training versus placebo training theorised to offer no specific therapeutic benefit. Participants with chronic musculoskeletal pain will be randomised to one of four groups: (1) 10-session attentional modification group; (2) 10-session placebo training group; (3) 18-session attentional modification group; or (4) 18-session placebo training group. In the attentional modification groups, the probe-classification version of the visual-probe task will be used to implicitly train attention away from threatening information towards neutral information. Following the intervention, participants will complete a short interview exploring their perceptions about the online training. In addition, a subgroup analysis for participants aged 16–24 and 25–60 will be undertaken.This study has been approved by the University of Southampton Research Ethics Committee. Results will be published in peer-reviewed journals, academic conferences, and in lay reports for pain charities and patient support groups.NCT02232100; Pre-results. This protocol describes an internet-delivered intervention to explore the efficacy of attentional bias modification training in patients with chronic musculoskeletal pain.The study will recruit a diverse sample of participants in terms of age, socioeconomic status and geographical region.Results will provide important information regarding dose effects, age effects, and participants’ experiences and attitudes using the online intervention.There is limited control over the conditions under which training is completed.Independently verifying participant diagnosis is impossible.Chronic musculoskeletal pain (CMSK) is pain arising from the bones, muscles, ligaments, tendons and/or joints lasting for more than 3 months.Two small randomised controlled trials (RCTs)One small RCT in adolescents with chronic pain randomised participants to either ABM, placebo training or waiting-list groups. No significant differences were found between the three groups in terms of pain, disability, pain catastrophising, anxiety, depression or objective measures of physical functioning , and no evidence was found that ABM changed attentional bias or attentional control compared with placebo and waiting-list conditions.This article presents a study protocol for a randomised, double-blind, internet-delivered ABM intervention. The results of a pilot think-aloud study informing the design of the intervention are also presented. The aim of this RCT is to assess the efficacy of internet-delivered ABM in improving pain and pain-related distress in people aged 16–60 with CMSK, and will report a subgroup by treatment effects using the two age brackets of 16–24 and 25–60. While only limited evidence has been found for age as a moderator of CBM on bias change and symptoms,Participants will be recruited via press announcements, social media and patient organisations throughout the UK. Inclusion criteria will be (1) aged between 16 and 60 years old; (2) experiencing any type of CMSK ; (3) able to sit at a personal computer for 40 min; (4) normal or corrected to normal vision; (5) access to the internet at least twice a week; (6) access to, and familiarity using, a Windows-based computer; (7) successful completion of primary school; and (8) living in the UK. Exclusion criteria will be (1) experiencing malignant CMSK ; (2) a diagnosis of other forms of comorbid chronic pain ; and (3) a diagnosis of any psychiatric disorder, either currently or within the last 5 years. There are no restrictions placed on concomitant care, and participants are not required to make any changes to current treatments they may be receiving.Participant burden of the intervention and outcome measures were assessed using individual interviews and informal feedback from patients participating in two pilot studies.The study is a double-blind RCT with four arms exploring the efficacy of online ABM training versus a placebo training condition theorised to offer no specific therapeutic benefits. The choice of comparator was selected as placebo training closely mimics ABM training, and is frequently used as a comparator in ABM studies eg, refs . The stuThe study design has a 2×2×3 experimental structure, with multiple non-commensurate dependent variables measuring pain intensity and interference, emotional functioning, and pain-related disability. Treatment is a two-level factor , and the number of sessions is a two-level factor , with measures recorded at three points in time . Measures in the 18-session groups (18AMG and 18PTG) will also be taken after session 10.Block randomisation of size four, performed via a randomisation command in the LifeGuide platform,d=0.25) with at least 80% power . The recruitment strategy includes a 20% oversampling to mitigate a loss of power from loss to follow-up.Our previous lab-based, proof-of-concept ABM intervention found reductions in pain intensity and pain interference from pre-ABM to post-ABM were associated with large effect sizes,Interested individuals will contact the researchers on the details provided in study advertisements and will be assessed against the inclusion and exclusion criteria via telephone interview. If eligible, they will receive a copy of the participant information sheet detailing the requirements and procedure of the study, along with a link to the study website which provides further details on ABM and the research team. If the individual consents to take part, they will be required to create an online ABM account. During registration, participants will select their preferred days for training, which will be either (1) Monday/Thursday or (2) Tuesday/Friday.Session 1 is the baseline session, and includes the first assessment visual-probe task measuring attentional biases prior to beginning the intervention, along with the questionnaire battery assessing the primary and secondary outcome measures. Randomisation will take place following session 1, where participants will be informed of the length of their training . Participants randomised to either of the 10-session conditions will complete four pictorial and four linguistic training sessions, while those randomised to either of the 18-session conditions will complete eight pictorial and eight linguistic training sessions (baseline and endline assessment sessions comprise the remainder of the 10/18 sessions). Participants’ attentional biases will be reassessed at endline  using the same assessment version of the visual-probe task  used at baseline and the same questionnaire battery. Participants randomised to either of the 18-session conditions will also have their attentional biases reassessed in session 10 after their training session.Participants’ satisfaction with the online training will also be assessed. Six months after the last session, participants will be invited to again complete the online assessment visual-probe task  and questionnaire battery. Within 2 weeks of the completion of the 6-month follow-up session, participants will be invited to take part in a brief telephone semistructured interview including 15 questions spread across five thematic sections: (1) motivation and expectations about the study; (2) experience of the online study: person, environmental and lifestyle parameters; (3) experience of the visual-probe task; (4) understanding of the process of change; and (5) the visual-probe task as a potential therapeutic tool in pain management. The study flow is presented in To retain as many participants as possible, reminder emails will be sent to participants 24 hours before each scheduled session becomes available, and also at 13:00 on the scheduled session date should the participant not have already logged into their internet-delivered ABMT (iABMT) account. An additional reminder email will be sent 1 week before their 6-month follow-up session is ready. Participants will also be sent encouragement emails informing them when they have reached specific milestones . Participants will also have the option of receiving an SMS (short message service) on their mobile phone at 09:00 on the morning of each scheduled session.The intervention will be hosted using LifeGuide and iSurvey platforms, both developed by the University of Southampton. LifeGuide is an open-source software which allows researchers to create online interventions.Guidance has been informed by research showing attention to be a limited capacity resource,The flow of visual-probe sessions is illustrated in 10.1136/bmjopen-2019-030607.supp1Supplementary data‘p’ or ‘q’) in the location of the neutral stimulus. Participants use corresponding keys on their keyboard to indicate the probe letter as quickly and as accurately as possible. In the standard version of this paradigm completed by PTG groups and used in the assessment sessions, the probe replaces the neutral and threat-related stimulus an equal number of times. The probe-classification version of the visual-prove task is argued to encourage a more even monitoring of the display than the probe-position version , as for the latter participants can adopt biased monitoring strategies favouring one particular region over the other.A separate linguistic visual-probe task will be used in the three assessment sessions, featuring different stimuli to the linguistic training visual-probe tasks. The use of separate assessment and training stimuli is necessary to establish whether training effects generalise to novel stimuli not used in the actual training. The same assessment stimuli will be used in all assessment sessions. The ABM training version of the visual-probe task to be completed by AMG groups includes three main stages per trial . FollowiThe primary outcome measure of pain interference will be assessed by the Brief Pain Inventory-Short Form.10.1136/bmjopen-2019-030607.supp2Supplementary dataA qualitative think-aloud study10.1136/bmjopen-2019-030607.supp3Supplementary dataA full and detailed statistical analysis plan will be written prior to trial closure. In brief, the data analysis will be performed on an intention-to-treat (ITT) basis to provide an unbiased estimate of the treatment effect.Analyses undertaken will include the following:The primary analysis on pain interference will use the initial 2×2×2 structure comprising stage , randomised treatment , placebo) and randomised number of sessions . This comparison will be extended to compare 10AMG and 10PTG after 10 sessions, and to compare 18AMG and 18PTG after 10 sessions.An analysis of pain interference will use the 2×2×3 structure comprising randomised treatment , randomised number of sessions  and stage .An assessment of change in pain interference, both within and between groups, for 18AMG and 18PTG, between the end of session 10 and endline.The four randomised arms compared against one another on pain interference at each of baseline, after session 10, endline and follow-up.An age  subgroup analysis using an age subgroup by treatment effect interaction. These analyses will be an extension of (1), (2) and (3) to incorporate age as a subgroup factor.The same analyses would apply to the secondary outcome measures. The data will be represented descriptively and graphically by arm, and by treatment and age, and standardised effect sizes reported.Linear mixed model with random intercepts will be used to analyse the data with, as appropriate, treatment , number of sessions  and assessment stage as fixed factors. This approach avoids listwise deletion which would apply in a repeated measures analysis of variance approach. The linear mixed modelling approach uses all of the available data and adheres to ITT. As a secondary analysis we will used multiple imputation chained equations to impute outcome dataSimilar to previous studies,For visual-probe data, and as per previous research,Split-half reliability will be computed via a bootstrap procedure, by randomly splitting the total number of trials in two halves, such that each half has the same number of congruent and incongruent trials. Attentional bias scores will be computed for each half and the correlation between them calculated across participants. This procedure will be repeated 100 times, and an average split-half correlation computed.Qualitative analysis will be used to detail participants’ experiences completing the iABMT intervention. Specifically, thematic analysis using inductive coding will be used to identify themes present in the data obtained from the semistructured interviews and the two open-ended questions included in the SOT questionnaire. Guidelines provided by Braun and ClarkeThe study protocol was registered with ClinicalTrials.gov, with a planned start date of September 2020 and a planned end date of September 2022. All data will remain confidential and stored on password-protected systems and databases. LifeGuide and iSurvey servers both use HTTPS (hypertext transfer protocol secure) connections for security purposes. All data will be anonymised prior to dissemination, and personally identifiable information not known to anyone other than the researchers. Participants may withdraw from the intervention at any point by contacting the researchers via email or telephone, or by simply opting not to log into their iABMT account for their scheduled sessions. Participants are also encouraged to contact the researchers should they experience any distress or discomfort completing the intervention. As per university policy, any adverse events, harms or complaints arising from participation in the intervention will be reported to the University of Southampton Research Governance Office. Findings will be published in the most relevant, high-impact, peer-reviewed journals and presented at relevant conferences. Lay reports will be written for interested pain charities and patient support groups.


Cytokine-storm, increased thromboembolic state, deranged overall homeostasis and aggressive medical treatment can cause a variety of lesions in the central nervous system. Interpretation of brain imaging findings will require a thorough understanding of the clinical status of the patient and treatment being offered, keeping in mind the several ways in which the viral pathogen, severe acute respiratory syndrome coronavirus-2 may interact with brain tissue. We present differential diagnosis of a MRI identified solitary lesion in the splenium of the corpus callosum, in a COVID-19 positive patient with altered mental status.Coronavirus infectious diseases (COVID-19) is an emerging infectious disease that has taken a strong grip on the entire global community. The diagnosis  A high propensity for thromboembolic events and a massive release of cytokines are recognized as severe complications of the disease that can lead to deadly complications. Aggressive medical treatment and mechanical ventilation is thereby proposed until dedicated therapies are developed. Patients are treated with multiple drugs such as sedatives, antivirals, antibiotics, anti epileptics and extended prophylactic treatment with anticoagulants is recommended at early stages of the disease.2 Such aggressive treatment may result in several brain parenchymal lesions which may or may not be directly related to SARS-CoV-2. We describe here the CT and MRI findings from a patient with COVID-19 where a lesion in the splenium with subsequent hemorrhage has been identified. This report brings our attention towards difficult differential diagnosis in emerging infections such as COVID-19.On March 11, 2020, the World health organization declared a pandemic outbreak caused by a novel coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV-2).A 73-year-old male presented on March 25, 2020, to the emergency room for a 1-week history of mild influenza like symptoms which rapidly progressed to respiratory distress and high fever (38℃). He had no history of cardiovascular disease, hypertension or diabetes. Because of the constellation of findings in the context of ongoing acute pandemia, the patient was immediately admitted to our intensive care unit for suspected COVID-19).2/s), slight hyperintensity on both T1 weighted imaging, isohypointense on T2 weighted imaging and hyperintense on fluid attenuated inversion recovery images with no gadolinium enhancement  and a normal count of leukocytes and platelets. Nasopharyngeal swab specimen tested using the Real-Time Reverse Transcriptase-Polymerase Chain Reaction assay was positive for SARS-CoV-2 and COVID-19 was diagnosed. Both ferritin and D-dimer levels were elevated. Chest CT was positive for multiple bilateral pulmonary ground glass opacities with interstitial thickening (crazy-paving pattern) . No signancement . The lesSevere hypoxia was treated with bronchial intubation and mechanical ventilation and sedation was achieved with intravenous benzodiazepines, propofol and opioids. The patient did not receive extracorporeal membrane oxygenation therapy. A combination of antiretroviral (Darunavir/Cobicistat), antibiotics and hydroxychloroquine were started. Anticoagulation prophylaxis was introduced with low-molecular weight enoxaparin. Additional supportive therapy such as adequate antipyretic drugs, hydration and intraparenteral nutrition were also provided.3 In fact, an accurate history, a simple blood test and a chest X-ray can easily narrow down the etiology. The ongoing pandemic phase and the presence of SARS-CoV-2 viral antigen in the nasal swab were found to be sufficient to make the diagnosis of COVID-19.Acute respiratory distress syndrome characterized by dry cough, high fever and respiratory distress can be caused by a variety of infectious agents, including influenza viruses . Acute respiratory distress syndrome can also be triggered by non-infectious diseases such as cardiovascular diseases, lung trauma and aspiration pulmonitis to a name a few.4 However, because of increased risk of infection and unstable clinical conditions in the COVID-19 environment, brain imaging may be delayed.Isolated solitary lesions in the splenium of the corpus callosum have diverse etiologies including metabolic disorders, tumors, trauma, demyelinating diseases and stroke. Brain MRI is necessary to reach an appropriate diagnosis.noxa.5 Such lesions, also known as cytotoxic lesion in the splenium of the corpus callosum (CLOCC), are often in the midline and are generally reversible.6,7 CLOCCs have been found in association with influenza virus infections, several metabolic disorders, trauma, variety of pharmaceutical drug toxicity and metabolic disorders.7 From a neurological point of view, splenial lesions are characterized by altered consciousness and seizures that correlated well with our patient’s symptoms.8Isolated splenial lesions that appear hyperintense on diffusion weighted images (DWI) are well-recognized and are an expression of excitotoxic damage to vulnerable splenial nerve fibres due to release of glutamate that is triggered by a variety of endogenous and exogenous 9 COVID-19 positive patients are known to be at high risk of thromboembolic events and stroke has been reported in such patients.10 However, a stroke in the splenium is a rather rare entity. Gradient recall echo T2 weighted imaging did not show any other microhemorrhage or superficial cortical siderosis thereby excluding possible amyloidosis-related hemorrhage. Our patient also had very high levels of ferritin which is considered a proinflammatory cytokine; this may have initiated endothelial damage to vessels in the splenium. We interpreted our findings as a CLOCC that later hemorrhaged due to persistent presence of noxa damaging the blood–brain barrier in an anticoagulated patient, but a splenial artery hemorrhagic stroke cannot be dismissed. Prolonged use of multiple drugs such as propofol with antiepileptic properties could also have contributed to such a lesion.These lesions are readily recognized on MR images as hyperintense on DWI and are generally non-enhancing in the acute phase. This together with the clinical history of the patient is often sufficient to make the diagnosis. However, a DWI hyperintense lesion can also represent a subacute hematoma or a hemorrhagic infarct.After 4 weeks of intensive care therapy, the patient was transferred to a normal ward with continuous monitoring of all vital parameters. Neuroimaging driven patient management included dosage reduction of sedatives, removal of mechanical ventilation and switching to non-invasive ventilation. No episodes of profound hypotension were recorded to warrant use of vasopressors. At 5 week follow-up, the patient was successfully weaned-off of ventilation. Follow-up MR showed the presence of focal residual hemosiderin deposits and myelomalacia in the former region of the hemorrhage .11 Experimental work using mice inoculated intranasally with the 2003 SARS-CoV demonstrated that viral antigens were present in the nucleus ambiguus and in the nucleus of the solitary tract in the medulla of mice but also in the thalamus.12 The authors proposed that the virus invaded the brain via a axonal/synaptin route reaching areas directly connected to the olfactory bulbs such as the hypothalamus, thalamus and the amygdala, a pattern of brain parenchymal hemorrhagic lesions reported recently in a patient with COVID-19.13 Secondly, SARS-CoV, may also invade the brain via angiotensin-converting enzyme 2 receptors that are located principally in the vascular endothelial cells and smooth muscle cells.7 As SARS CoV-2 enters lung host cells via the same receptor on the epithelial cells, it is likely that it uses a similar route of entry to the brain but this has not yet been established.14,15 Thirdly, a massive release of inflammatory cytokines, can cause brain inflammation similar to secondary hemophagocytic lymphohistiocytosis or acute disseminated encephalomyelitis or acute hemorrhagic encephalitis.16,17 More recently, it has been noted that SARS-CoV-2 can cause vasculitis and thromboembolic complications are frequent.18 And last but not the least, the use of multiple drugs in the acute phase, the possible development of vitamin deficiencies, malnourishment, dehydration, high fever, metabolic alterations, prolonged immobility and cerebral hypoperfusion in the severely acute COVID-19 patients, may all contribute to a variety of peripheral nervous system, brain and spine alterations often also seen in other toxic and metabolic diseases.19,20This case provides several reflections for the radiologist/neuroradiologist who may find themselves frontline in the differential diagnosis of brain lesions in patients with COVID-19 on both CT and MRI. Firstly, SARS CoV-2 may enter the CNS, by directly invading the olfactory, trigeminal and the vagus nerves causing symptoms like hyposmia, dysgeusia and perhaps central respiratory depression.10,21 Also a case of acute necrotizing encephalopathy in a patient with COVID-19 has been reported so far, although it is not specific for COVID-19.13,18 Specificity of MR findings will require a large number of cases from different centers across the world in patients and perhaps with RT-PCR positive for SARS-CoV-2 in the CSF.Brain imaging in COVID-19 is still at its earliest stages at the time of writing. A constellation of non-specific MRI findings have been reported in COVID-19 positive patients such as stroke, leptomeningeal enhancement and posterior reversible encephalopathy.The major recognized limitation of this report is that it is a single case. While we want to stay away from reporting every single brain MRI finding in the novel COVID-19 outbreak, the attempt here is to recognize the several mechanisms that might contribute to brain MRI findings in COVID-19 patients and offer medical health professionals in every part of the world a point of reference in interpreting CT and MRI findings in COVID-19 positive patients.COVID-19 is an emerging infection that is being rapidly recognized to affect several organs including the human brain.Similar to influenza viruses, isolated lesions in the splenium is likely to be caused by “cytokine storm” triggered by SARS-CoV-2 and concomitant aggressive supportive therapy, although a wide differential diagnosis must be considered.Neuroimaging must be considered in acute phases of the illness to detect brain lesions that can help guide therapy such as the use of anticoagulants.


One way to enhance quality of life for patients with metastatic sarcoma is to maximize time off chemotherapy—a chemotherapy-free interval. While image-guided ablation of sarcoma metastases may reduce the need for chemotherapy, it remains unknown how long ablation could extend the chemotherapy-free interval. The purpose of our study was to determine the chemotherapy-free interval in comparison to overall survival and progression-free survival in sarcoma patients who undergo ablation procedures. An IRB-approved, single institution, HIPAA compliant database was queried for sarcoma patients who underwent image-guided ablation procedures between 2007 and 2018. Patient demographics, histologic subtype, and other clinical characteristics were recorded. Kaplan-Meier analysis was performed to compute median overall survival, median progression-free survival , and the median chemotherapy-free interval (systemic and cytotoxic) after ablation. Univariate and multivariate analyses were performed using the log-rank test and Cox proportional-hazards model, respectively. A total of 100 sarcoma patients were included in the analysis. The most common histologic subtype was leiomyosarcoma (38%). Median overall survival after ablation of sarcoma metastases was 52.4 months (95% CI: 46.9–64.0 months). The median systemic chemotherapy-free interval following ablation of sarcoma metastases was 14.7 months (95% CI: 8.6–34.3 months). The median cytotoxic chemotherapy-free interval following ablation of sarcoma metastases was 81.3 months (95% CI: 34.3-median not reached). In conclusion, ablation of sarcoma metastases can provide an extended systemic chemotherapy-free interval of greater than 1 year. Ablation of sarcoma metastases may improve patient quality of life by extending the chemotherapy-free interval. Most sarcoma patients are diagnosed with localized disease, which can often be cured through a combination of surgery and radiation therapy. However, some sarcoma patients, particularly those with large primary tumours, presenting initially with localized disease may ultimately experience disease progression at metastatic sites , 2. AlthFor patients that present with primary sarcoma, surgery remains the only curative treatment option . While cAn IRB-approved, single institution, HIPAA compliant database was queried for sarcoma patients who underwent image-guided ablation procedures between 2007 and 2018. All patients over the 11-year period were included in the analysis except for those patients who underwent image-guided ablation for palliative purposes. Patient demographics, tumour size, tumour grade, histologic subtype, whether the patient had failed previous chemotherapy, and the disease-free interval prior to ablation were investigated. Age was defined as the interval from the patient's date of birth to the date of the patient's initial ablation procedure for sarcoma (ablation date). Tumour size was defined as the largest measured transaxial length of the treated tumour; in cases where 2 or more tumours were treated, tumour size was defined as the sum of the largest measured transaxial lengths of the treated tumours. Index tumour grade was defined as the histologic grade of the primary tumour. Failure of previous chemotherapy was defined as having received any systemic chemotherapy (both cytotoxic and noncytotoxic) prior to the ablation date. Disease-free interval was defined as the interval from the date of the patient's most recent surgical resection for sarcoma prior to the ablation date  to the date of the first imaging study thereafter that demonstrated evidence of recurrent disease.Median overall survival, median progression-free survival , and the median chemotherapy-free interval (systemic and cytotoxic) after ablation were computed using Kaplan-Meier analysis. Overall survival was defined as the interval from the ablation date to the date of death. Patients who were not confirmed to have died at the end of the study were censored at the date of last contact. Local progression-free survival was defined as the interval from the ablation date to the date of the first imaging study thereafter that demonstrated evidence of recurrent disease in the ablation cavity or death. Distant progression-free survival was defined as the interval from the ablation date to the date of the first imaging study thereafter that demonstrated evidence of disease elsewhere or death. Patients who were alive and had not experienced local and/or distant progression at the end of the study were censored at the date of the last available surveillance imaging study. The systemic chemotherapy-free interval was defined as the interval from the ablation date to the date of the earliest subsequent documented administration of systemic chemotherapy (both cytotoxic and noncytotoxic). The cytotoxic chemotherapy-free interval was defined as the interval from the ablation date to the date of the earliest subsequent documented administration of systemic chemotherapy that was cytotoxic. Patients whose systemic and/or cytotoxic chemotherapy-free interval was not concluded at the end of the study were censored at the date of last contact.p < 0.05 on log-rank were said to be predictive of the event rate. The Cox proportional-hazards model was used to analyse the independent prognostic value of factors; factors with p < 0.1 on log-rank were entered into the multivariate analysis. For all factors included in the multivariate analysis, hazard ratios with confidence intervals were calculated. Factors with p < 0.05 on multivariate analysis were said to be significantly associated with the time of an event. All statistical analyses were performed using R version 3.5.1 [Univariate and multivariate analyses were performed using the log-rank test and Cox proportional-hazards model, respectively. The end points for both the univariate and multivariate analyses were overall survival, the systemic chemotherapy-free interval, and the cytotoxic chemotherapy-free interval. The log-rank test was used to analyse the effect of each prognostic factor on the event rate; factors with on 3.5.1 .A total of 100 sarcoma patients were included in the analysis. Kaplan–Meier curves for overall survival, progression-free survival  and the chemotherapy-free interval (systemic and cytotoxic) are shown in Figures 1p=0.033). Patients who had not failed previous chemotherapy had a longer median overall survival compared to patients who had failed previous chemotherapy . On multivariate analysis, neither tumour size (p=0.1159) nor failure of previous chemotherapy (p=0.0749) was significantly associated with time of death.Results from the univariate and multivariate analyses of overall survival are shown in p=0.0037). Patients who had not failed previous chemotherapy had a longer median systemic chemotherapy-free interval compared to patients who had failed previous chemotherapy . On multivariate analysis, histologic subtype (p=0.758) was not significantly associated with time of administration of systemic chemotherapy (both cytotoxic and noncytotoxic), but failure of previous chemotherapy (p < 0.0001) was significantly associated with time of administration of systemic chemotherapy (both cytotoxic and noncytotoxic).Results from the univariate and multivariate analyses of the systemic (cytotoxic or noncytotoxic) chemotherapy-free interval are shown in p=0.01). Patients who had not failed previous chemotherapy had a longer median cytotoxic chemotherapy-free interval compared to patients who had failed previous chemotherapy . On multivariate analysis, histologic subtype (p=0.751) was not significantly associated with time of administration of cytotoxic chemotherapy, but failure of previous chemotherapy (p < 0.0001) was significantly associated with time of administration of cytotoxic chemotherapy.Results from the univariate and multivariate analyses of the cytotoxic chemotherapy-free interval are shown in Our results suggest that patients who undergo image-guided ablation of sarcoma metastases are able to remain off systemic chemotherapy (both cytotoxic and noncytotoxic) for approximately 14 months. Despite experiencing postablation recurrence after a median of 6.7 months, repeat ablation allowed patients to remain off systemic chemotherapy (both cytotoxic and noncytotoxic) for an additional 8 months thereafter. While other studies have looked at overall survival and progression-free survival as measures of treatment success in sarcoma patients who undergo ablation procedures , 14–16, Our results are consistent with those of Fonck et al. who showed that thermal ablation of pulmonary metastases resulted in a median chemotherapy-free survival of 12.2 months in patients with metastatic colorectal cancer . The cheA chemotherapy-free interval may be particularly beneficial in younger cancer patients. While sarcomas as a group are rare , they are one of the more common types of cancer in patients aged 15–45 , 24. In Interestingly, our study found that histologic subtype and lack of prior chemotherapy were predictive of the chemotherapy-free interval. Patients with liposarcoma had the longest median systemic chemotherapy-free interval (median not reached) compared to patients with all other histologic subtypes (9.5 months). The extended systemic chemotherapy-free interval seen in patients with liposarcoma may be due to the variable biologic behaviour of this tumour, which ranges from indolent disease to extremely aggressive tumour . PatientThis paper has several limitations. First, it is retrospective in nature. Thus, our results may not be applicable to a prospective cohort of sarcoma patients. We had a wide variety of histologic subtypes, and our conclusions may not be applicable to each subtype individually. We had a relatively small number of patients, and our study may be underpowered. Our sarcoma patients were all patients that were referred to the interventional radiology service, and our cohort may not be representative of sarcoma patients more generally. Deaths were not confirmed to be due to the sarcoma itself. Thus, our calculated overall survival may not accurately reflect the actual disease-specific survival. Certain patients had more than one type of cancer, and our conclusions may not be applicable to patients who have only sarcoma. We were not able to assign a grade to every patient's primary sarcoma. Furthermore, since we often did not have pathologic confirmation of grade of the treated metastasis, in some cases its grade was inferred from the grade of the primary tumour. Thus, we could not accurately assess the predictive value of histologic grade. Finally, several new noncytotoxic chemotherapies were approved during the study period and therefore were not available to all patients in the study; this could alter the calculated chemotherapy-free interval. Future prospective studies will be needed to evaluate if image-guided ablation of sarcoma metastases can extend the chemotherapy-free interval in patients with metastatic sarcoma.In conclusion, ablation of sarcoma metastases can provide an extended systemic chemotherapy-free interval of greater than 1 year. Ablation of sarcoma metastases may improve patient quality of life by extending the chemotherapy-free interval.


We report the effectiveness of automated text messaging for active surveillance of asymptomatic close contacts of coronavirus disease (COVID-19) cases in the Cork/Kerry region of Ireland. In the first 7 weeks of the COVID-19 outbreak, 1,336 close contacts received 12,421 automated texts. Overall, 120 contacts (9.0%) reported symptoms which required referral for testing and 35 (2.6%) tested positive for COVID-19. Non-response was high  and this required substantial clinical and administrative resources for follow-up. The first case of coronavirus disease COVID-19) was notified in Ireland on 29 February 2020 [9 was notAs part of ongoing efforts to control the spread of infection, national and international guidance recommends active surveillance of asymptomatic close contacts of confirmed cases of COVID-19 -7. HowevDuring the study period from 8 March to 23 April 2020 inclusive, cases were defined according to clinical criteria (presence of fever/cough/shortness of breath) and laboratory detection of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) nucleic acid in a clinical specimen [“Do you have new fever or cough or shortness of breath?” Those who responded ‘yes’ were contacted directly by a clinician, assessed over the telephone and, if necessary, referred for priority testing for COVID-19. Those who responded ‘no’ continued with active surveillance until the end of their 14-day follow-up period. Those who responded with details of clinical queries or concerns (instead of responding ‘yes’) were contacted by a clinician or a nurse. Non-responders were sent one follow-up text after 4 h, and were then contacted directly by a clinician or a nurse if they did not respond to the second text.Participants’ mobile telephone numbers were added to an automated text messaging system using text broadcasting software . Asymptomatic close contacts were texted every day from the day following their initial telephone call with the regional DPH until the end of their 14-day follow-up period. Text recipients were asked to provide a yes/no response to the question, Details of all responses to the text broadcast messaging system were exported to Microsoft Excel and collated. Of those who had been tested for COVID-19, positive results were recorded on the Computerised Infectious Disease Reporting system, Health Service Executive COVID-19 tracker, or i.Laboratory Pathology Results Enquiry system. Samples were tested in the National Virus Reference Laboratory in Dublin or in one of the regional microbiology laboratories in Cork/Kerry. Results were verified from daily line listings received from each of these laboratories.All participants provided verbal consent during their initial telephone call with the DPH to receive a daily text message and possible contact by a clinician or nurse. They had the option to withdraw from active surveillance at any time. If requested, they were provided with relevant information pertaining to data protection legislation and compliance with the General Data Protection Regulation. In this study, we present aggregate data with no identifiable information. Thus, ethical approval was not required.There were 1,336 asymptomatic close contacts added to the text-based active surveillance system and 12,421 texts were sent (mean: 9.3 texts per participant). The median age of respondents (or their parents/guardians) was 42 years (range: 10 months to 77 years). In total, 192 respondents (14.4%) required clinical follow-up of whom 104 (54.2%) were female and 88 (45.8%) were male. The majority  were referred for testing, and the results are shown in the Of those who required a clinical call-back, 72 (37.5%) did not meet criteria for testing; they had symptoms which were not deemed to be consistent with COVID-19, or else they sought clinical advice about returning to work, duration of self-quarantine or advice about family members or contacts. During the follow-up period, the national testing criteria for COVID-19 also changed several times as knowledge of COVID-19 and laboratory testing capacity evolved [Overall, the response rate to daily texts was high . Nonetheless, the absolute number of non-responses was large  and this created a substantial workload for DPH clinical and administrative staff.Active surveillance has been recommended for close contacts of other coronavirus infections such as Middle East respiratory syndrome coronavirus (MERS-CoV)  and SARSThe World Health Organization has highlighted the need for robust electronic data capture tools to support efficient contact tracing and active surveillance of close contacts on a large scale . AlthougThe overall effectiveness of any active surveillance system depends on the eligibility criteria applied in testing referrals and may also involve a value judgement over what constitutes an effective yield. To our knowledge, this is the first European study to measure the positive COVID-19 yield from a text message-based active surveillance system. Older people were more inclined to opt out or request follow-up by daily telephone calls rather than by text (data not shown). There was a lack of robust data on this cohort, partly because electronic data capture tools were lacking at the outset. Further analysis of this cohort may have resulted in a greater understanding of the limitations of the text messaging system. Strict national testing criteria were in place at times because of challenges in IT infrastructure, limited laboratory capacity and large backlogs of test results with slow turnaround times owing to difficulties procuring reagents and physical swabs. These practical challenges, and the lack of testing of asymptomatic close contacts, are likely to have reduced the overall yield of positive results. Furthermore, some text recipients indicated that they did not reply to daily texts because doing so involved a cost (if using pay-as-you-go mobile telephones), and this may have impacted on the response rate. At the time of writing, Ireland has implemented testing for all symptomatic and asymptomatic close contacts of confirmed cases of COVID-19. If these criteria had applied during the study period, we may have had a higher yield of SARS-CoV-2 infections among this cohort.Automated active surveillance systems can thus facilitate early identification of symptomatic close contacts and positive cases of COVID-19. However, it requires resourcing with robust IT infrastructure, sufficient laboratory capacity and dedicated clinical and administrative support.


Pattern recognition molecules (PRMs) in the complement system contribute to homeostasis as mediators of complement activation. The contribution of PRMs to primary biliary cholangitis (PBC) is unknown. In the current study, we aimed to assess the association between PRMs and the clinical findings of PBC. A total of 122 PBC patients and 20 healthy controls were enrolled. We measured four different PRMs  using stored sera, and retrospectively analyzed the associations between PRMs and laboratory findings, histological findings, and the development of cirrhosis-related conditions. Ficolin-1 levels were significantly higher in the PBC patients than in the healthy controls , but no significant differences were observed regarding MBL, ficolin-2, and ficolin-3 levels. Ficolin-1 was significantly correlated with alkaline phosphatase (ALP). Low ficolin-1 levels were significantly associated with the development of cirrhosis-related conditions independent for histological stage and ALP levels . Patients with low levels of ficolin-1 (< 77 ng/mL) had a significantly increased rate of developing cirrhosis-related conditions. Low ficolin-1 levels were associated with disease progression independent of histological stage and ALP levels in patients with PBC. Primary biliary cholangitis (PBC) is a progressive autoimmune cholestatic liver disease that predominantly affects women . It is cThe complement system plays important roles in innate immunity; maintaining biological homeostasis and acting as immune surveillance . PatternLiver injury in PBC is initiated by autoimmune reactions based on genetic and environmental factors , and innThis retrospective study enrolled patients who had been diagnosed as having PBC at Fukushima Medical University Hospital  between September 1988 and June 2017. The diagnosis of PBC was defined by the American Association for the Study of Liver Diseases guidelines [This study was conducted in accordance with the principles outlined in the Declaration of Helsinki. The study protocol, including the use of opt-out consent, was approved by the ethics committee at Fukushima Medical University School of Medicine . Written informed consent was obtained from all patients for serum and liver biopsy. Written informed consent was also obtained from all control subjects.We measured MBL, ficolin-1, ficolin-2 and ficolin-3 in the lectin pathway using an ELISA kit according to the manufacturers’ protocols. All ELISA kits were purchased from Hycult Biotech . The diluted serum samples  were used to detect PRMs levels. The measurable concentration ranges in each ELISA kit were as follows: MBL, 0.41–100 ng/ml; ficolin-1, 3.1–200 ng/ml; ficolin-2, 16–1000 ng/ml; and ficolin-3, 8–500 ng/ml.We performed percutaneous liver biopsies with an 18-gauge needle. The biopsy specimens were fixed in formalin and embedded in paraffin. Histological findings were evaluated with hematoxylin and eosin staining, and were determined according to the Scheuer staging system [The development of cirrhosis-related conditions was defined as cirrhosis diagnosed based on biopsy results or at least one of the following events: gastroesophageal varices, ascites, hepatic encephalopathy, hyperbilirubinemia, or hepatocellular carcinoma.Data are presented as median and interquartile range (IQR), and continuous variables were compared using the Mann–Whitney U test or Kruskal–Wallis test. Multivariate analysis was performed using the Cox proportional hazards model to assess predictors of the development of cirrhosis-related conditions. Cumulative survival without development of cirrhosis-related conditions was calculated using the Kaplan-Meier method, and it was compared using the log-rank test. We considered differences of P < 0.05 to be statistically significant. Analyses of data were performed using the Prism 7.0 software  and EZR , a graphical user interface for R software  .The baseline characteristics of the 122 PBC patients at the time of biopsy are shown in The four PRMs in the lectin pathway in both the PBC patients and healthy controls were analyzed . We founNext, we measured ficolin-1 levels in patients with liver diseases other than PBC, such as chronic hepatitis C or autoimmune hepatitis . The ficWe analyzed the correlations among the four PRMs. Both ficolin-2 and ficolin-3 levels were significantly correlated in the PBC patients , although the other PRMs did not show any significant correlations.The correlations of the PRMs with laboratory data were analyzed . MBL levWe analyzed the association between the PRMs and liver histological stages graded according to Scheuer’s classification. Levels of ficolin-3 were negatively correlated with histological stage . No significant correlation was observed between the histological stages and other PRM levels, such as MBL , ficolin-1 , and ficolin-2  .We assessed the association between the PRMs and the development of cirrhosis-related conditions using multivariate Cox proportional hazards models . These mThe results of the present study demonstrate that serum levels of ficolin-1 was associated with the development of cirrhosis-related conditions in patients with PBC. The association between ficolin-1 and the development of cirrhosis-related conditions was independent of histological stage and ALP, which are predictors of prognosis in patients with PBC , 21. AllWe measured levels of PRMs of lectin pathway, MBL, ficolin-1, ficolin-2, and ficolin-3. There have been several reports about the association between PRMs and disease activity of autoimmune diseases. High serum MBL level was reported to be associated with thrombocytopenia and seizure in patients with SLE , and serOn the other hand, Hein et al. reported that serum ficolin-1 in patients with SLE was lower than that in healthy controls, and that serum ficolin-1 is negatively associated with disease activity in SLE patients . Serum fFicolin is a unique lectin with a fibrinogen-like domain that is responsible for carbohydrate recognition . AlthougAlthough the roles of monocytes in PBC are not fully understood, there have been some reports about the association between monocytes and PBC. Shimoda et al. reported that monocytes were detected around injured bile ducts in PBC patients , and MaoInteraction between ficolin-1 and T cells has been reported; the up-regulation of sialic acid expression has been observed on the surface of activated T cells, as has an increase in ficolin-1 binding to activated T cells , which pIn the current study, ficolin-1 was positively correlated with ALP, and low ficolin-1 was associated with poor prognosis independent of ALP levels in multivariate analysis. High ALP has been reported to be associated with poor prognosis in patients with PBC . The serLevels of ficolin-3 were significantly correlated with histological stage, albumin and prothrombin time in patients with PBC in the present study. Although there was no significant association, the ficolin-2 levels in PBC patients with stage 4 were low. Liver fibrosis is associated with a decrease in complement factors, because most complement factors are produced in the liver . FicolinThe current study has some limitations. First, we did not analyze the histological findings of PRM deposition in the liver. We should confirm the presence of ficolin-1 binding to liver tissue or lymphocytes in future studies. Second, we did not investigate the gene polymorphisms of PRMs. Levels of PRMs have been reported to be closely associated with gene polymorphisms . Third, In summary, low ficolin-1 levels were associated with PBC disease progression independent of histological stage and ALP levels, and ficolin-3 levels were negatively correlated with histological stage. These results suggest that there is an association between PRMs and PBC pathophysiology. Elucidation of the contribution of PRMs in the complement system to PBC would help in the understanding of PBC’s pathophysiology.