As COVID-19 vaccinations became available and were proven effective in preventing serious infection, uptake amongst individuals varied, including in medically vulnerable populations. This cross-sectional multi-site study examined vaccine uptake, hesitancy, and explanatory factors amongst people with serious and/or chronic health conditions, including the impact of underlying disease on attitudes to vaccination. A 42-item survey was distributed to people with cancer, diabetes, or multiple sclerosis across ten Australian health services from 30 June to 5 October 2021. The survey evaluated sociodemographic and disease-related characteristics and incorporated three validated scales measuring vaccine hesitancy and vaccine-related beliefs generally and specific to their disease: the Oxford COVID-19 Vaccine Hesitancy Scale, the Oxford COVID-19 Vaccine Confidence and Complacency Scale and the Disease Influenced Vaccine Acceptance Scale-Six. Among 4683 participants , 3813 (81.5%) self-reported having at least one COVID-19 vaccine. Unvaccinated status was associated with younger age, female sex, lower education and income, English as a second language, and residence in regional areas. Unvaccinated participants were more likely to report greater vaccine hesitancy and more negative perceptions toward vaccines. Disease-related vaccine concerns were associated with unvaccinated status and hesitancy, including greater complacency about COVID-19 infection, and concerns relating to vaccine efficacy and impact on their disease and/or treatment. This highlights the need to develop targeted strategies and education about COVID-19 vaccination to support medically vulnerable populations and health professionals. More than one in three people aged 16-years and over have at least one chronic health condition . Once avIn the current pandemic, COVID-19 vaccine hesitancy rates have been reported in up to 50% of the general population, with significant regional variability ,5,9,10. Previously published COVID-19 vaccine hesitancy scales were developed in the general population prior to vaccine approval and widespread use . The aimThis cross-sectional study was implemented at ten health services across four states in Australia, encompassing five metropolitan and five regional areas, across six public and four private settings, with a collective catchment population of 4.9 million. The survey opened at the coordinating site on 30 June 2021 and concluded at all sites on 5 October 2021. During this period, there were varying lockdowns, public health restrictions and vaccine rollout recommendations . The stuParticipants were eligible if they had a past or current diagnosis of a solid organ or haematological malignancy, diabetes, or MS; were aged 18 years and over; and a patient of a participating health service. People with cancer were recruited across nine healthcare services; people with diabetes were recruited at three sites and people with MS at two sites. People with cancer and diabetes who had appointments scheduled in the next six months, and people with MS who attended an appointment in the previous 12 months, were invited to participate via text message invitation  containing a link to participant information and electronic consent. Potential participants with cancer were also invited at their consultations and treatment appointments, and promotional materials were displayed at the health services. ® secure data capture platform. The survey was presented in English. Potential participants who accessed the survey link and gave informed consent were directed to the survey, hosted on the QualtricsThe survey was developed by a panel of clinicians, researchers and patient representatives , and current treatment. Oxford COVID-19 Vaccine Hesitancy Scale: This seven-item scale measures willingness to receive a COVID-19 vaccine. Scores ranged from 7 to 35, with higher scores indicating greater hesitancy. The scale was validated in a UK general population sample of 5114 adults, demonstrating excellent internal consistency  [Oxford COVID-19 Vaccine Confidence and Complacency Scale: This 14-item scale measures confidence and complacency using four factors: collective importance of a vaccine, belief that COVID-19 infection may occur and the vaccine will work, speed of vaccine development, and side-effects  [Disease Influenced Vaccine Acceptance Scale-Six (DIVAS-6): This scale was shown to evaluate aspects of vaccine-associated attitudes emanating from concerns about the patient’s disease and treatment. The Disease Complacency indices, consisting of the first three items, were reverse scored so that higher scores indicate greater vaccine complacency. Higher scores in the Vaccine Vulnerability indices indicate greater perceived disease-related vaccine concerns [concerns . Scores Summary scores were calculated for each scale and subscale scores were calculated for each factor for the Oxford COVID-19 Vaccine Confidence and Complacency Scale and the DIVAS-6. The summary scores and subscale scores were calculated from the sum of all the individual items (coded 1 to 5) for each scale and each factor, respectively. Data cleaning was performed to remove unsubmitted incomplete, duplicate, and ineligible responses. Missing data were not imputed. Socio-demographic, clinical data, and summary and subscale scores were summarised using descriptive statistics. Variables with too few classifications were combined or removed for analysis: this was required for no formal education level and primary education level (combined with secondary as highest education) and non-binary/other gender . p-values < 0.05 were considered significant. Effect sizes were calculated with the phi coefficient (φ) and Cramér’s V (φc) for chi-squared tests, and eta squared (η2) for independent sample t-tests. Assumptions for all the analyses were met. Statistical analyses were performed using SPSS Statistics Version 27.0 . Findings from this study were reported following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies [Differences in demographics and individual scale items (item five ‘intent to vaccinate’ and item 12 ‘likelihood of COVID-19 infection’) between chronic disease type and vaccine uptake (any versus none) were detected with independent sample t-tests and chi-squared tests. Multivariable logistic regression was used to determine whether the scales  predicted vaccination status. Multivariable linear regression was used to assess whether the Oxford scales’ summary and subscale scores predicted DIVAS-6 scores. Time since study commencement and demographic and disease-related variables that were significantly correlated with the outcome variable of interest and had a correlation of r >.10 (using Pearson’s and Spearman’s Rho) were controlled for in hierarchical regression analysis. The covariates were English as a first language and time since cancer diagnosis for the cancer cohort models, and diabetes type and current diabetes treatment for the diabetes cohort models.  studies . Of 8232 responses, 3037 unsubmitted incomplete, 47 duplicate, and 465 ineligible responses were removed. The survey response rate by text message was 21.47% . There were 4683 eligible responses, from 3560 people with cancer, 842 people with diabetes, and 281 people with MS. Socio-demographic characteristics are detailed in Among participants with cancer, the most common types were breast , haematological , genitourinary , gastrointestinal  and lung . 1584 participants (44%) had been diagnosed with cancer in the last two years whereas 880 (24.7%) were diagnosed more than five years previously; 1808 (50.8%) were receiving anti-cancer treatment at the time of survey completion. Most participants with diabetes reported having type 2 , while 252 (29.9%) reported type 1 and 33 (3.9%) reported other/don’t know. The majority  had received their diagnosis more than ten years prior; 827 (98.1%) were receiving treatment including insulin , non-insulin antidiabetic agents  or a combination . Of participants with MS, 203 (72.2%) reported to have the relapsing-remitting type, 30 (10.7%) secondary-progressive; 26 (9.3%) primary-progressive and 22 (7.8%) other/don’t know. Just over half  had received their diagnosis within the preceding ten years, and 224 (79.7%) were receiving current MS treatment. Overall, 81.5% (3813 of 4681) of participants reported having at least one COVID-19 vaccine, comparable to vaccination prevalence in the total Australian population at the corresponding time point (79.9% had received at least one dose by 4 October 2021) . No sign4208 participants (89.8%) reported they had or would definitely/probably accept a COVID-19 vaccine, 271 (5.8%) were unsure, and 203 (4.3%) stated they were unlikely to accept a vaccine. The intent to be vaccinated did not vary significantly between disease types. As expected, there was a significant relationship between vaccine status and intent, with more vaccinated than unvaccinated participants reporting a likelihood to accept vaccination (definitely/have taken or probably) . Of partp < 0.001). More negative attitudes toward COVID-19 vaccines were strongly correlated with greater vaccine hesitancy , Pearson’s r = 0.78, n = 2748, p < 0.001. Participants who were unvaccinated scored higher on the Oxford COVID-19 Vaccine Confidence and Complacency Scale and subscales , signifyOf all participants, 2772 (60.6%) reported they were worried (strongly agree or somewhat agree) about COVID-19 infection and 3191 (69.9%) felt that the vaccine was more important to them due to their underlying disease. 3634 participants (79.8%) endorsed that physician recommendations regarding the vaccine were important to them. 1916 (43.5%) respondents were concerned about vaccine efficacy due to their underlying disease, while 1774 (39.6%) and 1092 (25.7%) reported concerns of vaccine effect on their disease or treatment, respectively . Positive relationships were observed between the DIVAS-6 total and subscale scores and the two Oxford scales of COVID-19 Vaccine Hesitancy and COVID-19 Vaccine Confidence and Complacency, demonstrating convergent validity of the DIVAS-6 with other measures of vaccine hesitancy and attitudes. Overall, unvaccinated participants had higher DIVAS-6 total and subscale scores, indicating greater complacency about potential COVID-19 infection and greater concerns of vaccine efficacy and the impact of vaccination on their disease and/or treatment .In a large cohort of patients with serious and/or chronic morbidity, we found that underlying disease significantly affected attitudes and uptake of COVID-19 vaccination. Interestingly, the level and type of concerns were common across the three major diseases studied. While most participants acknowledged increased apprehension about SARS-CoV-2 infection and the importance of the vaccine due to underlying disease, between a quarter-to-half were worried about vaccine efficacy and/or the effect of the vaccine on their disease. To our knowledge, this is the first study in a medically vulnerable population to use this suite of validated instruments, including a scale to specifically assess disease-related influences on vaccine acceptance. Alongside disease-related concerns, we observed similar explanatory factors of vaccine acceptance to that seen in the general public ,5,9,23, Our study measured concurrently vaccine uptake and hesitancy. The prevalence of vaccine uptake in our cohort was slightly higher than the general population at the time of the survey . Not surVaccine hesitancy is viewed as a continuum which may change with time and co-exist with vaccine compliance. The phenomenon of the ‘vaccinated but hesitant’ is well described . In one Clinical decision making in people with chronic disease is acknowledged to be a multi-layered process, taking into consideration clinical factors, personal values and sociocultural influences . SimilarTo engage medically vulnerable populations, targeted interventions by trusted sources are likely to be crucial and will complement public health campaigns which have largely focussed on broad societal benefits of vaccination. Clinically relevant, evidence-based data need to be delivered promptly to medically vulnerable populations using consistent and simple messaging to alleviate concerns and any misconceptions, consolidate positive attitudes and build confidence in vaccination strategies and health care services. Although there have been information campaigns, often produced by Non-Government Organisations  , there iEducational programs for health care providers are also imperative, based on the high proportion of our participants who valued their physician’s recommendations on COVID-19 vaccines, in line with other studies ,18,29. TIn addition to the use of validated instruments, the strengths of the present study include the broad and diverse sampling of pre-defined, high-risk participants with three disease types within a range of demographics. The three-month recruitment period spanned changing levels of community transmission and social restriction measures, including strict state-wide lockdowns, giving a broader perspective than a short ‘snapshot’ survey. Importantly, data collection commenced at least three months after the availability of vaccines to high-risk groups, allowing sufficient time for vaccination if willing. Finally, the low prevalence of COVID-19 disease in Australia at the time of the study gives insight into attitudes and actions in the setting where there is less immediate threat from COVID-19. Study limitations include recall and misclassification bias inherent in a survey-based study and availability only in English. Only people with cancer, diabetes, and MS were included and of the study population, 76% had cancer. Additionally, people who had a greater interest in COVID-19 vaccinations may have been more likely to respond. These issues should be considered when generalising findings. Given that Australia had one of the highest vaccination rates globally and relatively low community transmission during most of the period studied, results may not be directly translatable to global regions with lower vaccination rates and/or high transmission. However, within one year of the study, a period of extremely high community transmission occurred throughout Australia and with now well-established patterns in this pandemic, understanding attitudes at times of lower community transmission is probably as important as at times of high prevalence. Determinants of vaccine behaviour are likely to evolve over time in the context of changing disease epidemiology, therapeutic options and vaccine characteristics; serial studies are required to assess these dynamics. In a large Australian cross-sectional study in people with cancer, diabetes, and MS, we found high rates of COVID-19 vaccination uptake and positive intent, that importantly, seemed to be influenced by concerns of the impact of SARS-CoV-2 infection on their underlying disease. These concerns were both for the need for vaccination to protect them due to their inherent vulnerability arising from their disease and/or associated treatment, as well as for the potential impact of vaccination on their ability to maintain control of their illness. Our findings highlight the importance of addressing the concerns of medically vulnerable populations, including actively targeted public health communication strategies and health professional training, to optimise COVID-19 vaccine acceptance.


Viscoelastic coagulation tests such as rotational Thromboelastometry (ROTEM) have many theoretical advantages compared to traditional coagulation testing. As a point-of-care diagnostic device, ROTEM results are directly part of treatment decisions. Therefore, it is crucial to know its reliability and precision. Most recommendations for ROTEM S analyses originate from Thromboelastography (TEG), another viscoelastic coagulation assay. However, evidence about how preanalytical and analytical factors, such as sample collection technique, sample handling and the analysis itself, influence ROTEM results is scarce. Due to the absence of a gold standard method, we assessed accuracy with the coefficient of variation and intraclass correlation coefficient and examined the influence of blood collection site, as well as intrarater and in-between device variability, on ROTEM S results of clinically healthy dogs. We found significant changes between ROTEM S parameters from different blood collection sites and significant intrarater and in-between device variability. These findings were most prominent in tissue-factor-activated tests. To ensure patient safety, we therefore suggest running duplicate measurements and to interpret results obtained from tissue-factor-activated tests with caution, since some of their coefficients of variation were moderate to high.Rotational Thromboelastometry (ROTEM) allows for the global assessment of hemostasis in whole blood samples. Preanalytical and analytical factors may influence test results, and data about the reliability and reproducibility of lyophilized ROTEM tests are scarce. Therefore, the objective of this study was to evaluate the influence of blood collection site on ROTEM S parameters and to assess intrarater and in-between device variability. A total of thirty, healthy, staff-owned dogs were included. Blood collection and ROTEM analysis were performed by trained staff according to a standardized protocol. Extrinsically activated , with the addition of cytochalasin for platelet inhibition (Fib-TEM S), and intrinsically activated (In-TEM) analyses were performed. Analysis of our data showed significant variability for various Ex-TEM S and Fib-TEM S parameters from different collection sites and intrarater and in-between device measurements. We conclude that serial monitoring with ROTEM should be performed on the same device, with blood always taken from the same collection site using a standardized blood sampling technique. While In-TEM S, apart from maximum lysis, showed very stable and reliable results, we suggest interpreting especially clotting and clot formation parameters from Ex-TEM S and Fib-TEM S tests with caution and using duplicate measurements to detect outliers and to prevent initiation of incorrect therapies. The methodology of viscoelastic coagulation assays such as rotational Thromboelastometry (ROTEM) or Thromboelastography (TEG) was first described by Hartert more than 50 years ago . Both ROIn veterinary medicine, TEG/ROTEM have been validated for use in horses ,7, dogs In 2014, the “Partnership on Rotational ViscoElastic Test Standardization” (PROVETS) provided guidelines for veterinary use of TEG and ROTEM to improve assay consistency and result interpretation and to allow for the comparison of results between different testing centers and enable further progress in this field ,14.Due to the scarcity of ROTEM studies at this timepoint, most preanalytical recommendations for ROTEM analysis originate from TEG studies. Previous publications from human and veterinary medicine have shown that TEG and ROTEM provide similar but not interchangeable results ,16, thatSmith et al. found that generally good interduplicate coefficients of variance below 20% for Ex-TEM (tissue factor-activated temogram) initiated coagulation, using liquid test reagents provided by the ROTEM manufacturer . To our To the author’s knowledge, there is also no study evaluating the impact of blood collection site for ROTEM analysis in dogs. In cats, jugular venous blood samples analyzed with VCM Vet, another viscoelastic POC device, appear to be more hypercoagulable compared to those taken from the medial saphenous vein .The objective of our prospective observational study was three-fold: to (a) evaluate the impact of blood collection site and technique on viscoelastic test results, to (b) assess the intra- and interrater variability of trained staff using ROTEM delta and to (c) compare ROTEM parameters of the same blood sample that were analyzed on two different ROTEM delta devices. Our null hypothesis was that parameters do not differ between two samples.Healthy, adult, staff-owned dogs were recruited for the purposes of this and another study . The stuDogs weighing <2 kg and dogs showing any signs of stress or struggling during blood collection were excluded. Breed, age, gender and body weight was recorded for every dog.To minimize preanalytical errors, blood collection and analyses were performed according to an institutional standard protocol based on manufacturer’s instructions and international guidelines . Care waVenipuncture was performed by two operators (J.V. and N.W.). For jugular vein sampling, a 22 G needle was connected to a 5 mL syringe and 4 mL of blood was drawn using minimal vessel occlusion and mild aspiration with a vacuum of 1 mL inside the syringe. After removal of the needle, aliquot portions of the blood were immediately transferred into 2 or 3 3.8% sodium citrate tubes , resulting in a 1:9 ratio of citrate with blood. With the minimum possible delay, a second sample was drawn from some of the dogs  from the lateral saphenous vein by the same veterinarian. Again, a 22 G hypodermic needle was used but the blood was allowed to flow directly into 2 or 3 1.3 mL 3.8% sodium citrate tubes. Each tube was inverted carefully several times. The citrated blood was kept at 37 °C, using the analyzer’s designated warming plate or a 37 °C heating chamber, until the tests were run.Rotational thromboelastometry analyses  were performed by the same three experienced veterinarians.Tests performed included Ex-TEM S (extrinsic activation by tissue factor), In-TEM S (ellagic acid activation) and Fib-TEM S . They were performed as previously described  on two RFor the evaluation of the impact of blood collection site on viscoelastic test results, Ex-TEM S, In-TEM S and Fib-TEM S analyses were performed from both jugular and saphenous blood samples at the same time point after blood sampling  on the same ROTEM device by the same operator.For assessment of the intrarater variability of trained staff using ROTEM delta, some of the samples were run in duplicates on the same ROTEM device and by the same operator. Based on the availability of free channels, some samples were additionally simultaneously run on two different ROTEM delta devices (again by the same operator) to assess in-between device variability.All ROTEM tracings were visually evaluated for artefacts by the three operators . If an artefact was suspected, the abnormal parameter or the temogram was excluded.The following parameters were extracted from the ROTEM database and copied into a spreadsheet: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), alpha-angle (α), maximum lysis (ML), maximum clot elasticity (MCE) and G, a calculated measure of total clot strength (G = 5000 × MCF/(100−MCF)). If in any profile MCF did not reach 20 mm, an infinite CFT was defined as 3600 s. For Fib-TEM S, only CT, MCF, MCE and G were analyzed. A green line in the Fib-TEM tracing was defined as a Fib-TEM-MCF of 1 mm.Tracings were categorized as hypo-, normo- or hypercoagulable based on G compared to the reference interval of G .t-tests. Following the approach by Junge et al. [The data were manually transferred from the ROTEM database into an Excel spreadsheet. Afterwards, they were recoded and analyzed with the data analysis programs R  and RStudio . Quantile plots were used to verify that the data were normally distributed. The analyzed variables were for the largely normally distributed. However, there were very few deviations at the tails of the distribution, but this is not surprising given the small sample size. Differences between measurements of the parameter were depicted based on the coefficient of variation (CoV), which was calculated by dividing the standard deviation by the mean times 100. The statistical significance of the differences between the respective first and second measurement was estimated using paired e et al. , we clase et al. . Followie et al. , negativFor the intrarater variability, an ordinary least squares regression model to test whether the person performing the blood sampling or the time of blood sampling had an influence on the repeated measurements was performed. The z-standardized difference between the respective first and second measurements was used as the dependent variable. Person and timing were the dependent variables.n = 3), Chihuahua (n = 2), German Wirehaired Pointer (n = 2) and American Pitbull (n = 2). The remaining dogs (n = 6) belonged to various other breeds, with one individuum per breed.A total of 30 dogs were included. Eighteen dogs (60%) were males  and twelve dogs (40%) were female . The median age of the dogs was 75.5 months  and the median body weight was 22.9 kg . Fifteen dogs were crossbreed, while the most common other breeds were Labrador Retriever , 1/18 In-TEM (normo- to hypercoagulable) and 1/19 Fib-TEM (normo- to hypercoagulable) measurements .Twenty-three duplicate Ex-TEM S measurements, 18 In-TEM S and 21 Fib-TEM S were included. Duplicates were analyzed on the same device. Results of ROTEM measurements assessing intrarater variability are shown in The performance of the In-TEM test showed excellent CoVs for CT (5%), alpha (4%), MCF (1%), MCE (3%) and G (3%). The intraclass correlation coefficient was considered excellent or good for all In-TEM parameters except ML. All In-TEM measurements were within the reference intervals and there was no change in coagulation status .Fib-TEM MCF, MCE and G showed low variability with CoVs of 12%, 12% and 13%, respectively, while ICC was considered good for clot strength parameters. Apart from one measurement of CT, all results were within the reference range. A change of coagulation status was detected in 1/21 cases (normo- to hypercoagulable) .A linear regression model showed that there was no significant influence on CoV by the operator running the tests or by the timepoint after blood sampling  tests were run, while the Ex-TEM test was found to be a significant confounding factor. Compared to an Ex-TEM measurement, the difference between the first and second measurement is 0.74 and 0.67 standard deviations smaller for a Fib-TEM and an In-TEM test, respectively. This means that repeated measurements by both Fib-TEM and In-TEM tests are considerably more reliable than an Ex-TEM test.For Ex-TEM, we ran seven duplicate measurements on device 1 comparing the mean values with the mean value of seven duplicate measurements of the same blood sample tested with device 2. The same procedure was done for six duplicates In-TEM and four duplicate Fib-TEM tests. The results of all measurements investigating the in-between device variability are shown in Inter-device variability was considered low only for Ex-TEM MCF and all In-TEM parameters except ML, while ICC was good to excellent in Ex-TEM MCE, G, IN-TEM CT, CFT and alpha angle. Variability and ICC were inacceptable in Ex-TEM CT, CFT, In-TEM ML and Fib-TEM CT .Coagulation status changed in 1/7 Ex-TEM (normo- to hypocoagulable), 1/4 Fib-TEM (normo- to hypocoagulable) and no In-TEM test .This study investigating the effects of different blood sampling sites, intrarater and in-between device variability on ROTEM S parameters showed significant changes between ROTEM S parameters from different collection sites, duplicate measurements and in-between device measurements.As a POC diagnostic device, ROTEM results are part of a patient’s treatment decisions. It is therefore crucial to know its reliability. The accuracy of a test is assessed by determining how closely the results match the gold standard. Reliability and precision can be investigated with a variability of assays such as CoV, intraclass correlation coefficient, Bland–Altman analysis and various correlation tests among others. Due to the lack of a gold standard method, the coefficient of variation and intraclass correlation were chosen for analysis in order to be able to compare results to previous publications ,23.Previous work about types and frequencies of general laboratory errors has highlighted the occurrence of mistakes primarily in the preanalytical period 61.9%) compared to the analytical (15%) or postanalytical period 23.1%) . Several.1% . Sev1.9% compAnalysis of our data showed significant variability with different collection sites, intrarater and in-between device measurements as well as for specific tests and parameters.Veterinary viscoelastic testing guidelines suggest that blood should be free-flowing and, in small animals, jugular venipuncture is preferable . This reROTEM S analysis comparing jugular and saphenous blood collection sites in our population of healthy dogs resulted in significant differences in several parameters, which is in accordance with a previous study using a viscoelastic method in cats  but not Previous viscoelastic studies in people and dogs report different intra- and interrater variability using duplicate analysis. Anderson et al. reported excellent intrarater coefficients of variation <10% for In-TEM S and Fib-TEM S in human blood but did not investigate Ex-TEM S . AnotherThirteen percent of duplicate samples showed a change in coagulation status when comparing the two measurements based on G. This has to be taken into account when interpreting results from single test results. A linear regression model revealed no significant influence by the operator running the tests, indicating that interrater variability was negligible. Nevertheless, it has to be taken into consideration that our three operators were experienced in performing ROTEM assays, while ROTEM may also be used by less trained personal leading to potentially higher variation.Inter-device variability and ICC showed more variability than intrarater comparison, with Ex-TEM S as well as all Fib-TEM S parameters showing a moderate-to-high variability and poor-to-moderate ICC. Because of the small sample size, significance statements must be interpreted with caution, as distinction between causality and correlation was not reliably possible. A change of coagulation status was observed in 12% of measurements; therefore, current guidelines based on TEG studies recommending serial measurement of tests on the same device  seem to Compared to previous studies investigating TEG or liquid ROTEM test results, specifically the Ex-TEM S and Fib-TEM S tests showed a great variety of values for intrarater and inter-device CoV. We can only speculate about the reasons for this discrepancy. The repeatability of assays may depend not only on pre-analytical factors, which have been eliminated as much as possible in our study setup, but also on the test reagent itself. Since Ex-TEM and Fib-TEM both contain tissue factor as activator, the activator may be responsible for our findings. As suggested before, the concentration of tissue factor in the test reagents may be insufficient for a rapid and adequate thrombin burst. An earlier study has shown that lyophilized Ex-TEM reagents lead to smaller temograms than the liquid Ex-TEM reagents, resulting in lower MCF reference intervals . High acThe judgment of the variability depends on the classification of the CoV, for which we followed the approach of previous studies ,30,31. WParameter wise, we identified considerably higher variability and lower correlation for CT, CFT and ML compared to alpha angle, MCF, MCE and G. This is consistent with the findings of previous studies ,29 but iThis study has some limitations. Due to channel limitations, the sample size is small and not all measurements for the comparison of jugular versus saphenous blood samples were run in duplicates, decreasing the number of comparisons. We also had to exclude some paired jugular-saphenous samples because tests were not run on the same device and the device was shown to have a significant effect on results. Regarding sample size, most analyses were statistically significantly different, indicating enough power for the detection of significant changes in all parameters. An additional limitation could be the multiple pipetting from a tube. Zambruni et al. suggested that repeated sampling from one tube for duplicate measurements should be avoided to prevent artificial hypercoagulability . Since wCT and CFT parameters of Ex-TEM S and Fib-TEM S tests, as well as ML parameters of all three tests, were associated with high CoVs, and low ICC and should be interpreted with caution or measured in duplicates. Apart from these parameters, moderate-to-low variability was investigated for ROTEM S parameters, and In-TEM S showed an excellent performance. We recommend the same device and the same blood collection site for serial measurements. Jugular blood sampling using a syringe may be preferred over a free-flowing lateral saphenous blood sampling technique, as clearly more parameters from jugular venipuncture were within the reference interval.


Following the US Food and Drug Administration’s approval of PD-1 immune checkpoint inhibitors (ICI) for metastatic melanoma, what were the utilization and overall survival associated with ICI in the first-line setting after 2015?In this cohort study of 16 831 patients with metastatic melanoma, first-line immunotherapy use increased from 2010 to 2019, although 38% of patients still were not receiving first-line ICI in 2019. Use of ICI was associated with improvements in survival, even among those with brain metastases.First-line ICI therapy was associated with substantial improvements in overall survival among patients with metastatic melanoma, but rates of use remain suboptimal. This cohort study examines the usage rates of immune checkpoint inhibitors (ICI) and characterizes overall survival associated with first-line ICI use among patients with metastatic melanoma following FDA approval in 2015. In 2015, first-line programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICI) were Food and Drug Administration (FDA)-approved and National Comprehensive Cancer Network (NCCN)-recommended for patients with stage IV melanoma. Few studies have assessed the overall survival (OS) and usage rate associated with first-line ICI following 2015.To determine the rates of ICI use for metastatic melanoma following FDA approval in 2015 and characterize OS associated with first-line ICI use in this patient population.In this retrospective, nationwide cohort study, adult patients (≥20 years of age) with newly diagnosed stage IV cutaneous melanoma from 2010 to 2019 were identified using the US National Cancer Database (NCDB). Data were released by NCDB in March 2022 and analyzed in June 2022.Patients were compared based on first-line ICI receipt vs not.The OS and use of first-line ICI in 2016 to 2019 were assessed using multivariable Cox and logistic regression, respectively. To account for immortal time bias in receiving ICI, landmark time points were used (the 50th and 75th percentile times from diagnosis to ICI initiation).P < .001)—even after adjusting for patient, disease, and treatment factors. Results were similar for the 48-day landmark. This included patients presenting with brain metastases . First-line ICI use varied by patients’ age, insurance status, zip code–level household income, and treating hospital type.Among 16 831 patients with stage IV melanoma, 11 435 (67.9%) of patients were male; 116 (0.69%) were Asian or Pacific Islander, 475 (2.82%) were Hispanic, 270 (1.60%) were non-Hispanic Black, 15 711 (93.55%) were non-Hispanic White, and 145 (0.86%) were other race and ethnicity; the median (IQR) age at diagnosis was 64 (54-73) years. First-line immunotherapy use increased from 8.9% (127 of 1429) in 2010 to 38.8% (685 of 1766) in 2015, and 62.5% (1223 of 1958) in 2019. Median OS improved from 7.7 months  in 2010 to 17.5 months  in 2018. For patients diagnosed in 2016 or later, OS improved with first-line ICI (median OS using the 78-day landmark: 43.7 months  vs 16.1 months  for targeted therapy or chemotherapy; adjusted Following anti–PD-1 approval in 2015, first-line ICI was associated with substantial OS improvements for patients with stage IV melanoma, including those with brain metastases. As of 2019, 38% of patients still were not receiving first-line ICI in the US, with use varying by patients’ socioeconomic factors. In 2011, the United States Food and Drug Administration (FDA) approved the anti–CTLA-4 antibody ipilimumab for patients with stage IV melanoma, followed by the anti–programmed cell death 1 (anti–PD-1) antibodies nivolumab and pembrolizumab in 2014 for the second and subsequent line treatment. With the introduction of ICIs and BRAF/MEK targeted therapies, we and others have shown that the 5-year overall survival (OS) rate for patients with metastatic melanoma has risen from less than 10% to 30% to 50%.11 Currently recommended ICI regimens include anti–PD-1 monotherapy with nivolumab or pembrolizumab and combined anti–PD-l and anti–CTLA-4 therapy with nivolumab/ipilimumab. For patients with BRAFV600-variant melanoma, combination BRAF and MEK inhibitor therapy with either dabrafenib and trametinib, vemurafenib and cobimetinib, or encorafenib and orbinimetinib are recommended first-line regimens.11In 2015, based on several landmark Phase 3 clinical trials demonstrating substantial improvements in objective response and progression-free survival with first-line ICI compared with chemotherapy in patients with stage IV melanoma, the National Cancer Comprehensive Network (NCCN) recommended—and the FDA approved—PD-1 ICI as first-line standard-of-care therapy for such patients.12 Here, we build on that work to examine how first-line ICI use following FDA approval may be associated with the OS of patients with stage IV melanoma in the US, including among patients with brain metastases, liver metastases, and high serum lactate dehydrogenase levels. Furthermore, as a secondary aim, we assessed the use patterns of first-line ICI by patient, socioeconomic, and care setting factors.These newly available therapies have been practice changing. Although there have been multiple randomized studies demonstrating the efficacy of ICI for patients with stage IV melanoma, large-scale analyses examining the association of first-line ICI with survival at a national level have been lacking. We and others have previously reported on the survival benefits for patients with stage IV metastatic melanoma presenting after the FDA’s initial approvals for second-line ICI.STROBE) reporting guideline for cohort studies. This study used the National Cancer Database (NCDB): a hospital-based database that contains information for more than 72% of newly diagnosed cancers in the United States.14 Patients presenting with cutaneous melanomas  from 2010 to 2019 were identified from the NCDB cutaneous melanoma site data set, with 2019 representing the most recent year for which data were available. This NCDB 2019 Participant Use File was publicly released in March 2022 and analyzed in June 2022. Inclusion criteria included adults (aged ≥20 years) with American Joint Committee on Cancer stage IV  cutaneous melanoma, who had no prior history of cancer, and the patient’s data were reported from the treating institution. The NCDB groups all first-line immunotherapies and biologic therapies into a single variable. However, given that in 2016 ICI became the principal NCCN-recommended immunotherapy choice for the standard of care of stage IV melanoma, and that interleukin-2- and interferon-alfa-based regimens were largely relegated to the second- or later-line setting, herein immunotherapy coding was defined as having received ICI.3 Additionally, the NCDB groups all cytotoxic chemotherapies and targeted therapies  into: none, single agent, or multiagent. In this population and timeframe, first-line systemic chemotherapy likely overwhelmingly represented BRAF and MEK inhibitor therapy.This retrospective cohort study was conducted in accordance with the Declaration of Helsinki and was approved by the Mass General Brigham institutional review board. We followed the Strengthening the Reporting of Observational Studies in Epidemiology . In addition to the analysis of survival in all patients with stage IV melanoma, additional prespecified subset survival analyses were conducted for historically challenging melanoma subpopulations: patients with brain metastases, liver metastases, or elevated serum lactate dehydrogenase (LDH) levels. The NCDB excludes survival information for patients diagnosed in the most recent year, which for this data set was 2019. Kaplan-Meier methods were used to estimate OS with 95% CIs and the log-rank test was used for unadjusted OS comparison. To help ensure that first-line immunotherapy represented ICI, we restricted our analyses to patients diagnosed in 2016 to 2019. Variables that could potentially confound the association between first-line ICI and OS were adjusted for in multivariable Cox regression with 99% CIs, including: patients’ age at diagnosis, Charlson-Deyo comorbidity index, first-line targeted therapy and/or chemotherapy, first-line radiotherapy, resection of a nonprimary site, and site of metastasis. The pretreatment (or within 6 weeks of diagnosis) LDH was reported for 22.6% of patients herein and was therefore evaluated separately. The secondary outcome of interest was whether any patient, tumor, or care setting variables were associated with receipt of first-line ICI, which was evaluated using multivariable logistic regression. This analysis additionally included patients’ sex, race and ethnicity, year of diagnosis, insurance status, zip code–level household income (reported by NCDB as quartiles), primary tumor site, primary site surgery, Commission on Cancer classification of hospital type, and hospital geographical location, as previously described.2 Herein, the landmark time points were specified as the 50th and 75th percentiles of time from diagnosis to initiation of ICI: 48 and 78 days, respectively. For the primary analyses, a 2-sided α level of .05 was used, corrected for the 4 hypotheses being tested with the more conservative 78-day landmark: the OS association with first-line ICI vs non–immunotherapeutic systemic therapy in all patients, patients with metastatic brain cancer, patients with metastatic liver cancer, and patients with high LDH stage IV melanoma . For the secondary analysis of first-line ICI use, to reduce the risk of false positives, a 2-tailed P < .001 was designated as significant. Statistical analyses were performed with STATA version 17.1 (StataCorp). Data were released by the NCDB in March 2022 and analyzed in June 2022.To help account for immortal time bias  associated with receipt of ICI in both survival and use analyses, patients were only included if they survived at least until a landmark time point, as we have previously described.Between 2010 and 2019, 16 831 patients presenting with stage IV melanoma met inclusion and exclusion criteria (156 patients were excluded for lacking data about immunotherapy receipt). Among all included patients in this study, 11 435 (67.9%) were male; 116 (0.69%) were Asian or Pacific Islander, 475 (2.82%) were Hispanic, 270 (1.60%) were non-Hispanic Black, 15 711 (93.55%) were non-Hispanic White, and 145 (0.86%) were other race and ethnicity; and the median (IQR) age at diagnosis was 64 (54-73) years. Among these patients, the use of first-line immunotherapy increased from 8.9% (127 of 1429) in 2010 to 38.8% (685 of 1766) in 2015, and to 62.5% (1223 of 1958) in 2019 C. Among P < .001) compared with 16.1 months  among patients who received first-line non–immunotherapeutic systemic therapy . First-line ICI also demonstrated durable OS benefits, with a 53.0% 3-year OS rate  compared with 35.5% for patients with non-immunotherapeutic systemic therapy  from the 78-day landmark.To evaluate the association between first-line ICI and OS, we restricted our analysis to patients with stage IV melanoma diagnosed in 2016 and onward—when anti–PD-1 was FDA approved for the front-line setting. Median (IQR) follow-up in this population was 13.0 (3.4-32.2) months; 3467 patients (59.9%) died. For patients with stage IV cancer diagnosed in 2016 or later who survived at least until the landmark time points, OS significantly improved with first-line ICI—even after adjusting for patient, disease, and treatment factors, and using either landmark time point (eTable in the P = .001) compared with 10.7 months with first-line non-immunotherapeutic systemic therapy  using the 78-day landmark   with brain metastases in 2016 and later, 1544 (50.3%) received first-line ICI, which was associated with an improved median OS of 19.9 months , but differences in ICI use were not observed based on patients’ sex or race and ethnicity. With respect to socioeconomic factors, patients with Medicaid insurance  were less likely to receive first-line ICI compared with patients with private insurance. In addition, patients from zip codes with higher median household incomes were more likely to receive first-line ICI . Melanoma primary site was not associated with ICI utilization, however, metastatic site was: patients presenting with brain involvement were less likely to receive first-line ICI , whereas patients presenting with lung metastasis  or distant lymph node metastasis  were more likely to receive ICI. With respect to patients’ management, those who received first-line non-immunotherapeutic systemic therapy  were less likely to receive first-line ICI . Surgery, either of the primary site or metastases, was not associated with ICI receipt; however, patients who received first-line radiation therapy were more likely to receive first-line ICI . In terms of hospital practice patterns, differences were not observed by geographic location in the US, however, patients diagnosed at comprehensive community hospitals were less likely to receive first-line ICI  as compared with patients at academic or NCI-comprehensive cancer centers. For patients who presented after 2015 and survived at least until the 78-day landmark, the NCDB only reported the reason for a lack of first-line ICI in 210 cases, in which for 55.7% ICI was recommended but refused by the patient, for 20.0% the patient died prior to planned ICI, and for 24.3% ICI was not recommended because it was contraindicated.From 2016 to 2019, 4330 (55.9%) patients received first-line ICI. Notably, among the 691 patients who died less than 48 days after diagnosis , 609 (88.1%) did not receive first-line ICI. Therefore, we also applied the landmark time points to the multivariable logistic regression, to help account for immortal time bias in the receipt of first-line ICI . With reIn this national analysis, we found that use of ICI therapy in the first-line setting for stage IV melanoma has increased substantially in United States, although first-line ICI use continued to lag even after FDA approval in late 2015—particularly for patients who were older, had brain involvement, Medicaid insurance, or were from the lowest quartile of households by zip-code level income. Notably, from 2010 to 2019, the median OS experienced by patients with stage IV melanoma in the US has more than doubled, to an estimated 17.5 months. Following FDA approval, we found first-line ICI use to be independently associated with substantial improvements in OS for patients with stage IV melanoma, including among those with brain metastases. Given the high mortality rate experienced by patients with stage IV melanoma, we incorporated landmark time points in all of our analyses to help account for the immortal time bias associated with the receipt of ICI using both the median and 75th percentile of time from diagnosis to ICI initiation .16 Robert et al17 assessed the efficacy of ipilimumab compared with standard chemotherapy in the first-line setting for patients with metastatic melanoma and demonstrated significantly improved OS even among previously untreated patients . Subsequently, the KEYNOTE-006 and Checkmate-067 studies demonstrated that pembrolizumab or nivolumab monotherapy improved OS compared to monotherapy with ipilimumab.19 Checkmate-067 and 069 also demonstrated improved response rates with combination therapy (nivolumab and ipilimumab) compared with ipilimumab monotherapy.19 Collectively, these studies led to NCCN recommendations  since late 2015 for either anti–PD-1 monotherapy with nivolumab or pembrolizumab or combination anti–PD-1 and anti–CTLA-4 therapy with nivolumab andipilimumab, as the preferred first-line systemic treatments for patients with stage IV melanoma.3 In line with these trials’ efficacy results, we found that first-line ICI after FDA approval was associated with an almost doubling of the median OS compared with patients who received first-line targeted therapy and , and an increase in the 3-year OS rate to 53% from 36%.Following the publication of a phase 3 study that demonstrated an improvement in OS among patients with metastatic melanoma treated with ipilimumab in the second-line setting,BRAFV600-variant metastatic melanoma, targeted BRAF inhibitors and MEK inhibitors have also demonstrated antitumor efficacy and overall survival benefit, the optimal sequencing of ICI vs BRAF and MEK inhibitors remains unclear.20 The recent DREAMseq trial (ECOG-ACRIN EA6134) randomized treatment-naive patients with BRAFV600-variant metastatic melanoma to receive initial ICI or initial BRAF- and MEK-directed therapy, followed by the opposite treatment at the time of disease progression.21 Overall, they found that even among this population of patients with targetable variations, beginning treatment with ICI resulted in a superior overall survival and a longer duration of response than if treatment was started with targeted therapy. Our findings suggest that patients in the US who received single-agent or multiagent targeted therapy or chemotherapy in the front-line setting are less likely to also receive first-line ICI; however, the results of the DREAMseq trial underscore the need for strong consideration for ICI in the first-line management of patients with metastatic melanoma, including those with targetable variations.Moreover, it should be noted that among patients with 19 There has been subsequent work among patients with melanoma brain metastases to better understand the efficacy of ICI among such patients, albeit limited by the small number of patients in these studies, which has been extensively reviewed elsewhere.26 Together, the clinical trials of ICI in melanoma brain metastases illustrated acceptable toxicity, favorable intracranial response rates, and OS improvements. Based on the findings from CheckMate-204, combination nivolumab and ipilimumab is now the standard of care for management of brain metastases.26 We previously demonstrated the OS benefits experienced by patients with melanoma brain metastasis in the US largely in the ipilimumab monotherapy era—results that were extended and confirmed by others.28 Herein, we found that ICI following FDA approval of first-line anti–PD-1 was also associated with extensive OS benefit in patients with intracranial metastases from melanoma, improving median OS to an estimated 20 months among patients who survived at least 78 days. However, first-line ICI use remained disproportionately lower even among patients with brain metastases diagnosed in 2016 to 2019, underscoring persistent gaps in the incorporation of ICI into the management of these patients, although ICI use has likely improved markedly in the years since, given that ChekMate-204’s positive findings with nivolumab and ipilimumab were published in the latter half of 2018. The NCDB unfortunately does not permit distinguishing between anti–PD-1 monotherapy and anti–PD-1/anti–CTLA4 combination therapy.We further evaluated the OS associated with first-line ICI for several subpopulations that were historically challenging to treat. For instance, the practice-changing studies previously described that led to the recommendations for anti–PD-1 ICI in the first-line setting for patients with metastatic melanoma disproportionately excluded patients with brain metastases. More specifically, only 9% of patients in KEYNOTE-006 and 3% of patients in Checkmate-067 and -069 had brain metastases, and subanalyses pertaining to just patients with intracranial disease were not reported, thereby limiting the applicability of these efficacy data to patients with intracranial disease.31 Herein we found that first-line ICI use has increased to 63% of newly diagnosed patients with stage IV melanoma in 2019, from 9% in 2010 and 39% in 2015 . In order to investigate the patient, socioeconomic, and care setting factors associated with underutilization of first-line ICI, we also incorporated landmark time points into our analysis to help account for the immortal time bias associated with receipt of ICI, in which early mortality would preclude patients who would otherwise receive first-line ICI from doing so. Following FDA approval of anti–PD-1, we found that first-line ICI was underutilized among older patients and patients with brain metastases, although this has likely improved since the data from CheckMate-204 were reported. Furthermore, patients with Medicaid insurance or from the poorest zip codes (by median household income) were less likely to receive ICI, suggesting that some financial barriers may hinder access to first-line ICI. Finally, although improvements have been made across cancer program times in ICI use, comprehensive community cancer programs continued to have disproportionately lower use of ICI in the first-line setting compared with academic or NCI-designated comprehensive cancer centers.As a secondary aim, we evaluated the factors associated with underutilization of first-line ICI following the publication of NCCN recommendations and FDA approval for front-line anti–PD-1 in late 2015. We and others have previously analyzed ICI use patterns for patients with advanced melanoma primarily in the ipilimumab era, when anti–PD-1 use was likely restricted to clinical trial or off-label use.36 For example, data regarding limited  vs distant  metastatic disease were not granularly reported by the NCBD; however, we included resection of a nonprimary lesion in our multivariable analyses to help account for resectability. The NCDB additionally does not report the use of corticosteroids—an especially pertinent consideration in the brain metastasis setting, which increasingly has been shown to compromise the efficacy of ICI.40 Third, the NCDB does not report data relating to progression-free survival or objective response assessment.This study has some limitations. First, the NCDB does not report details regarding the specific agents, doses, schedules, duration of treatment, or associated toxicities for immunotherapy or targeted therapy or chemotherapy; nor does the NCDB report treatments used beyond the first-line setting. Consequently, we could not distinguish anti–PD-1 monotherapy from combined anti–PD-1 and anti–CTLA-4. Second, the NCDB lacked details regarding localized treatment of metastases, which play a crucial role in many melanoma treatment settings, especially brain metastases.In this national-level cohort study, we found a substantial increase in the use of ICI in the first-line setting for patients with metastatic melanoma, associated with improvement in their OS. These benefits were also seen in patients presenting with brain involvement. However, despite the steady increase in use over the last decade, an estimated 38% of patients diagnosed with metastatic melanoma in the US still did not receive ICI in the first-line setting in 2019—with use lagging for older patients and patient with brain metastasis, but also varying by patients’ socioeconomic statuses and care settings—indicating a need for ongoing efforts to increase the use of these important therapies.


This case series demonstrates how COVID-19 infection might affect the heart in the context of acute myocardial infarction. Atrioventricular (AV) block might appear as one of the significant cardiac complications of acute MI in patients who tested COVID-19 PCR positive regardless of the presence of CVOID-19 infection symptoms. In our series, conduction disorders as a complication of acute inferior STEMI are more common in patients who tested positive for the COVID-19 infection. 11 patients out of 18 inferior STEMI patients who have tested positive for the COVID-19 infection have atrioventricular block disorders. Coronavirus disease 2019 (COVID-19) is a viral infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It first emerged in Wuhan, China, in December 2019 [Multiple studies have shown that elders, especially those with chronic underlying diseases, including chronic pulmonary disease, heart diseases, and diabetes mellitus, are more susceptible to COVID-19 complications . VariousMultiple studies have shown both increased susceptibility in patients with underlying cardiovascular disease to COVID-19 and severe cardiovascular complications in COVID-19 infected patients, including acute myocardial injury, thrombotic events, arrhythmias, and shock with challenges in acute management , 9, 10.The type and severity of atrioventricular (AV) block associated with COVID-19 have not been described. We aimed to evaluate the incidence of the AV block as a complication, angiographic findings, and clinical outcome in the setting of acute inferior STEMI in patients with COVID-19 infection. We noted that the incidence of atrioventricular block as one of the complications of acute inferior STEMI is higher in patients who were tested as COVID-19 positive versus COVID-19 negative cases.COVID-19 infection was confirmed with reverse transcription-polymerase chain reaction assays (PCR). Inferior STEMI was defined based on the presence of typical cardiac symptoms associated with at least 1 mm ST-segment elevation in inferior leads.A total of 44 patients were admitted with acute inferior STEMI between May 1, 2020 and June 15, 2020. All patients met the definition criteria of STEMI with localized ST-elevation, and all were treated in the setting of emergent activation. 18 patients (40.9%) had tested positive for the COVID-19 infection, while 26 patients (59.1%) had tested negative for the COVID-19 infection (59.1%). No complications related to atrioventricular conduction disorders were documented in non-COVID-19 infection patients who presented with acute inferior STEMI (0%). While 11 out of 18 positive COVID-19 infection patients had atrioventricular block (AV) disorders (61%), 8 patients had a high degree of atrioventricular block (44.5%), and 3 patients developed first-degree AV block (16.6%). Although all patients shared the same basic characteristics, including age, gender, race, demographic distribution, and risk factors, conduction disorders were significantly higher in inferior STEMI with positive COVID-19 infection tests.In this special case series, we are going to present all cases of high-degree atrioventricular block (AV) and one of the three cases of first-degree AV block as the one with the longest PR interval. This data was collected from Qatar cardiovascular COVID-19 registries. It was approved by the Institutional Review Board in Hamad Medical Corporation, and all performed procedures were following institutional guidelines and recommendations. Due to the nature of the study, written informed consent was not required. The authors declare that all supporting data are available within the article.A 48-year-old male complained of chest pain associated with dizziness, subsequently, he shortly lost consciousness and injured his face. He was taken by his colleagues to the peripheral hospital, upon arrival, he was bradycardic and hypotensive, but he was conscious, and both bradycardia and hypotension responded well to IV fluid and atropine. 12 leads electrocardiography (ECG) showed acute inferior STEMI complicated with 3 : 1 high-grade atrioventricular (AV) block . He was A 55-year-old male has type 2 diabetes mellitus. He was admitted as case of symptomatic upper urinary tract infection; while he was in the emergency unit, he developed severe chest pain associated with hypotension. ECG showed sinus rhythm with acute inferior STEMI and first-degree AV block, subsequently; he developed complete heart block with signs of RV involvement in serial ECGs .He underwent thrombus aspiration and successful primary percutaneous coronary intervention (PPCI) to severe thrombotic stenosis from proximal to mid-RCA with DES Figures . BesidesAdvanced AV block was resolved after IV fluids and inotropes while transferring him to catheterization laboratory. COVID-19 PCR test came positive without COVID-19 infection related symptoms.A 57-year-old man without positive cardiac or medical history presented with severe chest pain for 2 hours associated with dizziness and sweating. He has no history of fever or cough, but he has a history of general weakness for one week prior to the current event. On admission, vital signs were remarkable for a blood pressure of 89/56 mmHg, heart rate of 30 bpm, and oxygen saturation at 90% on room air, which improved to 97% with a nonrebreather mask. Initial ECG demonstrated sinus bradycardia with third-degree AV block and ST-segment elevation in inferior leads . CoronarThe cardiothoracic team was involved in the early stage for possible CABG once his medical condition is allowed, but he developed SARS-CoV-2 pneumonia associated with multiorgan failure in the background of active cardiac ischemia, he was intubated, and he was started on inotropes along with SARS-CoV-2 antiviral agents. COVID-19 pneumonia made his hospital course very challenging with many complications related to SARS-CoV-2 pneumonia like acute respiratory failure, disseminated intravascular coagulation DIC, severe sepsis, and septic shock with a superimposed bacterial infection. AV block was recovered over one week of admission, but due to the significant multiorgan failure, he was arrested and died after 3 weeks of admission.A 45-year-old gentleman presented with chest pain for more than 24 hours. Initial ECG showed ST-segment elevation with deep Q waves in inferior leads, which represented late presentation inferior. When he arrived in coronary care unit (CCU), he was hemodynamically stable without chest pain, subsequently, telemetry showed episodes of escape junctional bradycardia, isorhythmic AV dissociation . SubsequA 50-year-old gentleman without significant medical history was brought by EMS with severe chest pain for 5 hours. Initial ECG showed ST-segment elevation in inferior leads with complete heart block which was resolved with 1 mg IV bolus atropine. Repeated ECG at emergency room still showed acute inferior STEMI with new right ventricular infarction.Urgent coronary angiography demonstrated moderate stenosis in left anterior descending (LAD) and left circumflex (LCX) and totally thrombotic occlusion of midright coronary artery. Successful PPCI to mid-RCA with DES deployment without immediate complications Figures . COVID-1A 36-year-old male without significant cardiac history is a smoker, one pack per day. He was brought by EMS due to central chest heaviness radiated to the left arm and associated with and profuse sweating. ECG showed escape junctional rhythm with complete heart block and acute ST-segment elevation in inferolateral leads. He was initially managed with atropine, IV fluid, noradrenaline IV infusion, and transcutaneous temporary pacing then transferred for PPCI.Coronary angiography revealed 100% thrombotic stenosis in proximal RCA. Successful PPCI to ostial to proximal RCA with DES was done without immediate complications Figures ). BradycA 52-year-old male presented to the health center with sudden onset of chest pain for 2 hours. He was clinically stable, heart rate at 43 per minute, and blood pressure at 120/80 mmHg. Initial ECG showed sinus bradycardia, and ST-segment elevation in inferior leads associated with third-degree AV block . He was A 49-year-old man with a history of hypertension presented with severe chest pain for 3 hours. He denies any history of fever or cough. Initial ECG demonstrated sinus rhythm with ST-segment elevation in inferior leads. On the way to the cath lab room, he developed hypotension and sinus bradycardia with complete heart block, which was responded to one dose of IV atropine 0.5 mg and IV fluid. Coronary angiography revealed severe three-vessel diseases with moderate distal left main stem stenosis. He underwent PPCI to thrombotic stenosis in proximal and distal RCA with 2 overlapping drug-eluting stents DES Figures . After cA 57-year-old man with a history of uncontrolled type 2 diabetes mellitus was recently discharged from COVID-19 infection facility as a noncomplicated COVID-19 infection to continue the home quarantine. He presented with severe chest pain for 3 hours duration. ECG showed sinus rhythm with first-degree AV block PR interval of 340 milliseconds with ST-segment elevation in inferior leads , but he Coronary angiography demonstrated severe large burden thrombotic stenosis in mid-RCA, thrombus aspiration was done, followed by successful PPCI to the mid-RCA with 2 overlapping DES without immediate complications Figures .First-degree AV block showed gradual regression and PR interval normalized during the stay in COVID-19 infection facility.Atrioventricular blocks are relatively common as a complication of acute myocardial ischemia; despite the marked improvements in the management of acute coronary syndromes, complete (AV) block can still be seen in the context of acute myocardial infarction (MI), especially inferior STEMIs.The incidence rates of third-degree AV block in patients with inferior/posterior wall AMI were twice compared with patients with anterior wall AMI. Third-degree AV block in context of acute inferior wall STEMI is usually transient, supra-Hisian in origin, narrow QRS escape junctional rhythm, and usually the risk of mortality is low. Anterior wall infarctions, on the other hand, are usually infra-Hisian, have a wide QRS escape rhythm, and carry a much higher mortality rate because of the wide extension of myocardial damage .In the prethrombolytic era, both Goldberg RJ et al. and Rathore SS et al. reported that the overall incidence of second- or third-degree AV block was recorded in 5% to 7% of patients presenting with acute MI , 13 and In the current modern era of primary percutaneous coronary intervention, the incidence and in-hospital mortality rate of complete atrioventricular block in patients with STEMI who underwent primary PCI was reduced compared to the data from the thrombolytic era, and the incidence of complete atrioventricular block (CAVB) dropped to 3.2 and 4.6%  and 3.2%COVID-19 outbreak has introduced new clinical and logistical challenges in the treatment of STEMI and related complications. We still have no clue about conduction abnormalities as one of the complications of STEMI in patients who tested positive for the COVID-19 infection regardless of COVID-19 infection symptoms.All patients who presented with inferior MI without evidence of viral infection did not develop any type of atrioventricular block, while all documented cases with complications related to conduction abnormalities in the settings of inferior MI have tested positive for the COVID-19 infection.Some STEMI patients were presented to the hospital later than usual; this could be due to the new policies that took place over the country to minimize the risk of COVID infection transmission and spread like the lockdown areasPatient fears of getting the COVID-19 infection if they seek medical help, assuming that the risk of infection is higher in places that provide health care like hospitals. It is known that stress and anxiety can trigger cardiovascular problems like heart attacks. It is no doubt that the COVID-19 outbreak carries lots of social and financial negative impacts that could lead to an increase in the risk of cardiovascular events and related complications in generalThe COVID-19 infection itself might be associated with larger MI extension, high burden clots, and more active inflammatory process, which can be measured by elevated CRP, ferritin, and IL6High burden clots also could be a potential factor. Four patients (22%) underwent thrombus aspiration despite the current international guidelines do not support the routine thrombus aspiration in the context of acute STEMI. It is worldwide accepted that thromboembolic events and pulmonary embolism are common in very critical COVID-19 patients. Most of the current regimens encourage the use of anticoagulation as part of management protocols with antiviral agents, especially in the high-risk patients The factors that can stand behind the high incidence of AV block (61%) are theoretically due to:We also noted that patient's age was lower than what was watched previously in Meine et al. study  even allOnly one patient  died because of multiorgan failure caused by COVID-19 infection complications in the context of acute inferior STEMI.Based on our findings, the incidence of atrioventricular blocks is higher than the incidence of AV block even in the prethrombolytic era. In almost 24 months of COVID-19 outbreaks worldwide, we are still lacking understanding of the aspects of COVID-19 behavior. While more recent studies provide more details of how the infection invades body organs in general, the cardiac manifestations of COVID-19 infections are still unclear, especially those related to the conduction system. The higher rate of patients with inferior STEMI who tested positive for COVID-19 infection developed conduction system abnormalities, even double the incidence of such a complication in the prethrombolytic era. Further studies with larger numbers are recommended to clarify why the incidence of AV blocks is higher in COVID-19 infection patients.


Hepatocellular carcinoma (HCC) is the most common primary liver neoplasm, and its incidence has doubled over the past two decades owing to increasing risk factors. Despite surveillance, most HCC cases are diagnosed at advanced stages and can only be treated using transarterial chemo-embolization (TACE) or systemic therapy. TACE failure may occur with incidence reaching up to 60% of cases, leaving patients with a financial and emotional burden. Radiomics has emerged as a new tool capable of predicting tumor response to TACE from pre-procedural computed tomography (CT) studies. This data report defines the HCC-TACE data collection of confirmed HCC patients who underwent TACE and have pre- and post-procedure CT imaging studies and available treatment outcomes . Clinically curated segmentation of pre-procedural CT studies was done for the purpose of algorithm training for prediction and automatic liver tumor segmentation.  The rates of HCC have doubled over the past two decades and are anticipated to continue to increase owing to increasing risk factors such as liver cirrhosis, steatohepatitis, and obesity4. Despite close HCC surveillance, 70%–80% of HCC cases are diagnosed at advanced stages when they are unresectable. Treatment of unresectable HCC includes transarterial chemo-embolization (TACE) and systemic sorafenib therapy7.Hepatocellular carcinoma (HCC) is the most common primary liver neoplasm, with an incidence of 42,810 newly diagnosed cases in the United States in 20205. The Barcelona Clinic Liver Cancer (BCLC) staging system is recommended for HCC patient stratification and treatment selection. It includes patient performance status, severity of the underlying liver disease using clinical and laboratory markers of liver synthetic performance (Child Pugh Grading [CPG]), and extent of tumor including its size, number of tumor foci, metastasis, and vascular invasion8. Candidates for TACE therapy include BCLC stage B patients (with intermediate HCC) and patients waiting for a liver transplant who underwent TACE as bridging therapy. The median survival duration of patients with HCC is 16 months from diagnosis for intermediate cases, which decreases to 6–8 months for advanced cases10.TACE selectively delivers chemotherapy to targeted liver tumors, taking advantage of the fact that HCC primarily receives its blood supply from the hepatic artery, while the liver parenchyma primarily receives its blood supply from the portal vein. This technique spares the healthy liver parenchyma from being damaged by the chemotherapy13. Clinical models are being developed for the prediction of TACE outcomes and the selection of patients who will benefit from the procedure. However, the high variability in TACE response has encouraged researchers to develop complicated predictive models using histological tumor markers like vascular endothelial growth factor, biological markers like alpha-fetoprotein, or a combination of both17. However larger patient sample sizes are needed to validate their prognostic value. In addition, poor detection rate of alpha-feto protein in patients with small residual size tumor after TACE may limit its prognostic significance18. Artificial intelligence (AI) and its sub-classes, deep learning, machine learning, and radiomics, have been used in imaging for various tasks including classification, segmentation, and detection. Prediction is an important task that has been shown to be best solved by AI. This includes prediction of disease severity, prediction of treatment response, and prediction of disease progression22. AI-based prediction models are usually not included in reports from large multi-center randomized trials, limiting the development of widely used predictive models. Furthermore, most of the in-house-developed models lack generalizability to other institutions or even with different datasets. Therefore, external validation of AI models is an integral step for the model to be widely used in day-to-day clinical practice26. Although large imaging datasets have been made available to the public to be used in further research steps or in re-generating the original results, treatment-related datasets are scarce owing to the complexity of various treatments and the variability in tumor grading and treatment selection. Recent advances in patient de-identification and image registration have allowed for the creation of different imaging databases within The Cancer Imaging Archive (TCIA) that may offer a better opportunity for treatment response validation28.TACE is an invasive procedure with several potential adverse effects, including treatment failure, organ failure, and even death. In addition, studies have shown that up to 60% of patients with HCC who undergo TACE do not benefit from the procedure in spite of multiple sessions, causing financial and emotional burdens for the patient30. The open access to this data allows for inter-institutional comparisons of non-randomized patient, treatment, and outcome data, in addition to the development of new architectures and models with higher performance and the external validation of other developed models using our patient cohort.Here, we present the HCC-TACE collection, a single-institution collection of 105 patients with confirmed HCC treated at The University of Texas MD Anderson Cancer Center from 2002 to 2012. The HCC-TACE collection integrates de-identified, comprehensive clinical data with diagnostic imaging and its manual segmentation and makes these data publicly available to researchers. Unique to this dataset is the inclusion of TACE procedure details, imaging before and after the procedure, manual segmentation , radiological measures of treatment response by experts in abdominal imaging, as well as patient outcomes after the procedure in the form of overall survival (OS) and time-to-progression (TTP). These data were used in prior publications, which evaluated prediction of TACE procedure outcomes using pre-procedural imaging and proposed convolutional neural network architecture for segmentation of HCC and automation of the prediction processTo develop this dataset, the MD Anderson Cancer Center institutional database was searched for patients with HCC treated from November 2002 to June 2012. Inclusion criteria were patients with HCC who (1) underwent TACE as the sole first-line therapy or initial bridging therapy, (2) had available multi-phasic contrast-enhanced CT images with liver protocol obtained prior to TACE , (3) had available multi-phasic contrast-enhanced CT images with liver protocol obtained within 14 weeks from the TACE procedure , and (4) had CT images of acceptable quality with no obvious artifacts. Patients undergoing TACE who had more than one HCC focus were excluded, so that calculation of OS and TTP depends only on one tumor and with no confounders. This study was approved by our institutional review board; written informed consent was waived due to the retrospective nature of the study. Pre-procedural CT images were obtained 1–12 weeks prior to the first TACE session (average 3 weeks).31, Okuda score32, TNM staging system33, and BCLC staging system34. In addition, performance status according to the Eastern Cooperative Oncology Group (ECOG) scale, CPG, alpha-fetoprotein level, and tumor extent  were reported.The final patient cohort identified in our institutional database (N = 105) was 68 male patients  and 37 female patients . Risk factors for development of HCC were reported for each patient, including hepatitis, smoking, alcohol use, diabetes, cirrhosis, and family history of either liver disease or cancer. Multiple grading systems were recorded for our cohort to enhance the usage of our dataset: CLIP scoreAll patients underwent contrast-enhanced CT of the abdomen, with liver protocol on 16–, or 64–detector row CT scanners . A pre-contrast scan was obtained, followed by an arterial phase scan 17 seconds after peak enhancement (using bolus tracking) of the aorta after injection of contrast medium. The porto-venous phase was scanned at 60 seconds. Images were acquired with the following scanner parameters: CT tube voltage of 120–140 KVp; Tube current of 150–630 mA; slice thickness of 0.63–5 mm; Pitch of 0.9–0.98; revolution time of 0.40–0.80 seconds; table speed of 18.75–39.38 mm/gantry rotation and field of view of 360–460 mm. The injection rate of contrast medium was 3–5 ml/sec. Standard image reconstruction algorithm was used in all cases. A total of 621 CT series  from 105 patients were examined.Tumor response to TACE was assessed using European Association for the Study of the Liver (EASL), Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, and modified RECIST (mRECIST) guidelines. All pre-and post-procedural studies were reviewed by three different board-certified radiologists , each with more than 20 years of experience in abdominal imaging. They independently measured tumors in both pre- and post-procedural studies, taking into consideration tumor viability and enhancement in the arterial phase. EASL measurements were recorded by reader 1 only, RECIST 1.1 and mRECIST measurements were recorded by all the three readers.Patients undergoing TACE were administered one of the following chemotherapy regimens: (a) doxorubicin in 20- to 100-mg drug-eluting beads  or (b) cisplatin, doxorubicin, and mitomycin C . Details about the TACE procedure were missing in 17 patients. The patient cohort was monitored longitudinally with post-procedural CT. Each lesion was monitored for progression based on radiology reports. The TTP was defined as the number of weeks from the treatment (TACE) to the date of radiological evidence of progression according to mRECIST criteria. Lesions were considered as censored if (a) there was no progression by the study date, (b) the patient was lost to follow-up, either due to not appearing or died in the meantime, (c) the date of death was before the date of tumor progression, or (d) treatment was changed to something other than TACE. In our previous studies, we divided patients into TACE-susceptible and TACE-refractory groups with a cutoff TTP of 14 weeks. TACE-susceptible patients are those who do not show radiological progression at follow-up CT, while TACE-refractory patients show radiological progression of the tumor.The AI approach for building a neural network or machine learning model is to extract imaging features from sub-volumes in the study. Segmentation of CT studies has been the main obstacle in creating such models from publicly available datasets as acquiring well-curated data is usually a time-consuming and labor-intensive process that requires dedicated personnel. In order to build our model, segmentation of the tumor (both viable and necrotic volumes) and background liver was done. The porto-venous phase of pre-procedural CT studies was used to simplify lesion assessment, and CT studies were exported in DICOM format and subsequently converted into Neuroimaging Informatics Technology Initiative (NIFTI) format to preserve orientation information and pixel spacing, with simpler headers than standard DICOM format. For each patient study, pre-contrast, arterial, and port-venous images of the pre-procedural scans were registered and re-sampled to the port-venous phase images. Segmentation of intra-hepatic vessels and the abdominal aorta was done as well. Manual segmentation was done using semi-automated segmentation tools available in AMIRA software  by three different radiology residents  and reviewed by a body imaging radiologist with 20 years of experience (K.M.E.).35. Image registration was done using affine transformation and linear interpolation. All images manipulation, and STAPLE image production were performed using the Convert3D medical image processing tool available with the ITK-SNAP software package36. To enhance the generalizability of the dataset, segmented NIFTI files have been converted to DICOM-SEG using the DICOM for Quantitative Imaging (dcmqi) library for Quantitative Image Informatics for Cancer Research (QIICR) in the 3D-Slicer software package38. The process of data curation and processing is demonstrated in Fig. The three different segmentations were validated and combined together to produce a single image using the STAPLE algorithm to produce the ground truth segmentation. The STAPLE algorithm uses the different segmentations as an input and generate a binary image of each voxel being the “true” segmentation. This process is achieved on each label29 was to automate the treatment response prediction process by automating segmentation of the liver and both viable and necrotic tumor. Two back-to-back convolutional neural networks (CNNs) were constructed for that purpose. The first CNN (CNN1) was built to segment liver tissue from the background using axial images of port-venous phase CT scans; this network was trained on the axial CT images and corresponding liver segmentations from the Medical Image Computing and Computer Assisted Intervention Society Liver Tumor Segmentation (or LiTS) challenge 39. CNN2 was built to segment HCC from the output of CNN1, and it was trained separately on the manual segmentation of our cohort . Both CNNs follow the U-Net architecture41. The output of CNN1 is a CT image with binary classification of the liver tissue; this image serves as input to CNN2, which segments the tumor from the liver mask. Each convolution operation uses a 3 × 3 kernel size and is followed by batch normalization. The rectified linear unit activation function was also used. A dropout (P = 0.5) was used before each convolution in the up-sampling limb of the U-Net. Our CNN architecture and codes can be found in our GitHub repository (https://github.com/fuentesdt/livermask).Our original workOur dataset consists of (a) 51,832 DICOM files from 621 series and 210 studies collected from 105 patients; (b) 105 DICOM-SEG files, each containing segmentation of the liver, tumor (viable and necrotic), intra-hepatic vessels, and aorta of pre-procedural CT images; and (c) a single spreadsheet file including all of the demographic, clinical, and diagnostic data, as well as EASL, RECIST, and mRECIST readings of each pre- and post-procedural CT images.42.There are total of 203 series of pre-contrast phase, 204 series of arterial phase, 210 series of porto-venous phase, and 4 series of delayed phase. Of note, there are 48 series that have combined phases in one series owing to technical errors export of DICOM files from our PACS system to a separate research folder for de-identification. Detailed description for each series is found in supplementary table 28.Patient’s DICOM files were de-identified using curated clinical trial protocol (CTP) developed by medical imaging resource center (MIRC) recommended by radiological society of North America. The program removes all protected health information (PHI) from all DICOM files metadata. It also replaces study, series and image unique identifiers (UIDs) with hashed version so we ensure complete de-identification of the images in accordance with the Health Insurance Portability and Accountability Act (HIPAA)https://github.com/UAMS-DBMI/PosdaTools. For further detail on the curation of DICOM CT and SEG files using POSDA Tools within TCIA, please refer to https://posda.com.The POSDA Tools used by TCIA for technical validation of this DICOM collection. These tools are openly available, and contributions from the research community are encouraged: To support validation of this collection, the capabilities of POSDA Tools were extended in the following way: extract each 3D-slicewise segmentation from a DICOM-SEG file, convert it to a set of 2D contours, and display those contours superimposed on the referenced CT slice for a (non-radiologist) curator’s eye to confirm reasonable alignment and file linkage. Every CT file and CT file referenced by Unique Identifier in the SEG files was confirmed to exist and checked to ensure data completeness; this capability was added in response to a missing CT file error, which affects one segmentation series for Patient ID HCC_001. This missing file corresponds to image slice far from liver, tumor and their masks, so clinical interpretation should be unaffected by this discrepancy.https://qiicr.gitbook.io/quantitativereporting-guide/. For the full list of the available software, please visit dcmqi documentation for instructions at: https://dicom4qi.readthedocs.io/en/latest/results/seg/.Multiple open-source software can be used to visualize the DICOM-Seg files; we highly recommend using the latest stable version of 3D-Slicer for data visualization after installing “quantitative reporting” extension. Step-by-step guidance for installation and guidance can be found in: Detailed description of each CT series uploaded to TCIA