The benefits of intravenous immunoglobulin administration are controversial for critically ill COVID-19 patients.We analyzed retrospectively the effects of immunoglobulin administration for critically ill COVID-19 patients. The primary outcome was 28-day mortality. Inverse probability of treatment weighting (IPTW) with propensity score was used to account for baseline confounders. Cluster analysis was used to perform phenotype analysis.Between January 1 and February 29, 2020, 754 patients with complete data from 19 hospitals were enrolled. Death at 28 days occurred for 408 (54.1%) patients. There were 392 (52.0%) patients who received intravenous immunoglobulin, at 11 (interquartile range (IQR) 8, 16) days after illness onset; 30% of these patients received intravenous immunoglobulin prior to intensive care unit (ICU) admission. By unadjusted analysis, no difference was observed for 28-day mortality between the immunoglobulin and non-immunoglobulin groups. Similar results were found by propensity score matching (n = 506) and by IPTW analysis (n = 731). Also, IPTW analysis did not reveal any significant difference between hyperinflammation and hypoinflammation phenotypes.No significant association was observed for use of intravenous immunoglobulin and decreased mortality of severe COVID-19 patients. Phenotype analysis did not show any survival benefit for patients who received immunoglobulin therapy. Since March 2020, when the WHO declared the COVID-19 outbreak a global pandemic, the infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has led to 173,674,509 confirmed cases and 3,744,408 deaths to date , Huangshi (Hubei Province), Shenzhen (Guangdong Province), and Jiangsu Province. We screened all adult patients with COVID-19 who were admitted to intensive care units (ICUs) of the participating hospitals between January 1 and February 29, 2020. Inclusion criteria were the following: 1) >18 years of age; 2) laboratory-confirmed diagnosis of COVID-19 ; 3) seveDemographic data, chronic comorbidities, vital signs, and laboratory results obtained within the first 24 h after ICU admission were extracted from electronic medical records. Treatment and outcome data were also recorded. Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were calculated to assess the severity of illness. The main exposure of interest was the administration of IVIG therapy. All data were collected by using a case record form modified from the standardized International Severe Acute Respiratory and Emerging Infection Consort. The primary outcome was 28-day mortality.Values were presented as the mean (SD) or median (interquartile range (IQR)) for continuous variables as appropriate and as percent for categorical variables. Comparisons between groups were made using the chi-square test or Fisher’s exact test for categorical variables and Student’s t-test or the Mann–Whitney U test for continuous variables, as appropriate.Propensity score matching (PSM) was performed to reduce bias by adjusting for the following 15 variables: age; sex; history of hypertension, diabetes, and chronic heart disease; chronic kidney disease, solid malignancy, connective tissue disease, and chronic obstructive lung disease; and vasopressor, invasive mechanical ventilation on ICU admission, APACHE II, disease onset days, and use of glucocorticoids. PSM was implemented with a nearest-neighbor strategy. IVIG and non-IVIG patients were paired according to the propensity scores using exact matching with a caliper size of 0.02 and a paired ratio of 1:1.During the matching process, a considerable proportion of patients were lost. Thus, inverse probability of treatment weighting (IPTW) using the propensity score analysis was also performed to estimate the causal treatment effects including all eligible patients .The balance of covariates was evaluated by estimating standardized mean differences (SMD) before matching, after matching, and after IPTW adjusted, and a small absolute value less than 0.1 was considered successful balancing between IVIG and non-IVIG patients.Logistic regression and Cox proportional hazards regression were performed to assess an association between IVIG therapy and 28-day mortality. Baseline variables of clinical relevance and significance at the univariable level (p < 0.20) were the following: use of glucocorticoids, APACHE II scores, age, sex, and history of hypertension, diabetes, cardiovascular disease, chronic kidney disease, and chronic obstructive lung disease. The same baseline covariates with IVIG therapy were adjusted in the Cox model. All statistical analyses were performed using R .According to Sinha et al., clinical data such as vital signs and laboratory measurements may enable phenotype identification based on machine learning in acute respiratory distress syndrome (ARDS) . As a reIn this study, we included 754 critically ill patients, of whom 392 (52.0%) received IVIG therapy. The days from illness onset to ICU admission were longer in the non-IVIG group compared with the IVIG group  vs. 12 , p = 0.009). More patients in the non-IVIG group than in the IVIG group required vasopressin on ICU admission . Differences in baseline and clinical characteristics are listed in We did not consider the dose and course of IVIG, although most patients were administered with a conventional dose of 0.5 g/kg/day. The patients in the IVIG group received IVIG at 11 days from illness onset Table 1.The overall cohort 28-day mortality was 54.1%. There were no significant differences between the groups in the number of deaths by 28 days Table 1.The PSM resulted in 253 patients who received IVIG matched to 253 patients who did not receive IVIG. More participants received IVIG than those who did not receive it; thus, 139 IVIG patients were unmatched in contrast to 109 non-IVIG patients. Inverse probability of treatment weighting (IPTW), assessed from patients with complete covariate data included in the propensity analysis, also resulted in between-group balance on baseline characteristics (n = 731). All baseline variables had SMD values of less than 0.1. We found by consensus k means clustering models based on clinical data and inflammatory markers that a 2-class model was the optimal fit for the two distinct phenotypes of COVID-19 patients Figure 2In this retrospective cohort study, we did not find IVIG therapy for COVID-19 associated with a lower risk of 28-day mortality compared with the absence of IVIG. This finding was consistent across analytic approaches and different COVID-19 phenotypes.As noted by Tang et al., patients with severe COVID-19 are prone to have high concentrations of pro-inflammatory cytokines . IVIG isAccording to Osuchowski et al. , SARS-CoOne strength of our study was that it included a multicenter cohort of more than 700 patients with severe COVID-19. The data were collected during the early phase of the COVID-19 outbreak in China. We used robust statistical methodologies such as propensity score matching and inverse probability of treatment weighting to compare 28-day mortality of patients treated or not treated with IVIG. Assessment of IVIG treatment effect was limited in most previous studies because of small sample sizes (<100 participants). The retrospective cohort study conducted by Liu et al. mentioned earlier had a sample size comparable with that of our study . HoweverOur study also had some limitations. Because of its observational design, unmeasured confounders and residual measured confounders may have influenced the results despite effective propensity score matching and inverse probability of treatment weighting. We did not consider the dose and course of IVIG treatment because the IVIG regimen protocol was not available during the period of COVID-19 disease represented by our cohort; most patients were administered with 0.5 g/kg/day. Also, confounders such as the allocation of medical resources during the emergency may have been associated with mortality but difficult to measure quantitatively in our cohort. Subtle phenotypes may have been missed because of a lack of plasma biomarkers such as interleukin-6 and ferritin. In addition, the safety and tolerance of IVIG therapy were not recorded, although Ferrara et al. have reported minor adverse reactions .Among severe patients with COVID-19, IVIG therapy was not associated with the lower risks of 28-day mortality, compared with the control group. Phenotype analysis also showed no survival benefits in patients who received IVIG therapy. A randomized clinical trial is needed for the estimation of the benefits of IVIG treatment on COVID-19.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The Ethics Committee of Jin Yin-tan Hospital approved this study (KY-2020-10.02). Patient-level informed consent was not required because this study was retrospective.Among the authors in the list JX, WW, SL, YH, MH, JL, ZT, HQ and BD had the idea for and designed the study; ZT, BD and HQ supervised the study; LW and YC did the statistical analysis. All authors contributed to acquisition, analysis, or interpretation of data. YC, LW, and BD wrote the manuscript. All authors revised the report and approved the final version before submission.This work was supported, in part, by grants from Ministry of Science and Technology of China (2020YFC0843700 and 2020YFC0841300).The funding sources had no role in study design, data collection, data analysis, data interpretation, or writing of the manuscript. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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This study evaluated total knee arthroplasty (TKA) outcomes for an Existing-TKA versus New-TKA from the same manufacturer.TKA outcomes for 752 with Existing-TKA versus 1129 subjects with New-TKA were followed through 2 years using patient-reported outcome measures (PROMs). Responders were assessed per Outcome Measures in Rheumatology-Osteoarthritis Research Society International criteria. Kaplan-Meier implant survivorship was estimated. Radiographs had an independent radiographic review.P = 0.005; pain: 88.9 versus 87.1, P = 0.019; symptoms: 84.1 versus 82.2, P = 0.017; Sport/Rec: 63.9 versus 58.8, P = 0.001; and QOL: 77.0 versus 73.5, P = 0.003), Patient's Knee Implant Performance , Oxford Knee Score , and EQ5D-3L . Two-year responder rates using WOMAC were 93.9% versus 90.6% (P = 0.018) for New-TKA versus Existing-TKA. Independent radiographic review showed that tibial and femoral radiolucencies ≥2 mm were similar (P ≥ 0.05) or favored New-TKA. Implant survivorship was similar between groups (log-rank P = 0.9994).Two-year follow-up was 84.6% (636/752) for Existing-TKA and 82.5% (931/1129) for New-TKA. Two-year PROMs mean outcomes for New-TKA versus Existing-TKA at 2 years were: Knee Injury and Osteoarthritis Outcome Score (ADL: 89.0 versus 86.8, New-TKA versus Existing-TKA demonstrated slightly better PROMs with similar radiographic and implant survivorship outcomes. However, up to 30%5678910 of patients reported dissatisfaction with the outcome of their surgery. New-TKA implants and surgical processes are intended to improve performance, particularly from a patient perspective. Infrequently, there are accompanying data to document relative clinical performance of newly released implants. The goal of this study was to evaluate clinical, patient-reported, implant survivorship, adverse events, and radiographic outcomes of an implant widely used for decades (Existing-TKA), compared with a new implant (New-TKA) from the same manufacturer. As a matter of surveillance, we wanted to confirm that there was no evidence of worsened outcomes with the new implant and, at the same time, to determine whether we could detect any improvements in outcomes in the short term, as recommended by Callaghan.11Total knee arthroplasty (TKA) has evolved into highly successful surgery, providing excellent implant survivorship,This was a prospective, nonrandomized multicenter clinical study of two total knee arthroplasty (TKA) implant systems, an Existing-TKA (PFC SIGMA) and a New-TKA (ATTUNE), both from the same manufacturer (DePuy Synthes Joint Reconstruction). The New-TKA is similar to the Existing-TKA design with some design modifications, including expanded size range, modified J-curve with gradually reducing femoral radii (versus multiradius) designed to improve AP kinematics, narrower and thinner anterior flange, proportional intracondylar box that allows for less bone removal in smaller patients, finer increments of patellar thickness, an extended trochlear groove, and 1-mm increments in polyethylene inserts. Approval was granted from each participating center's institutional review board or ethics committee, and written informed consent was provided by all study subjects before their enrollment. To avoid potential bias, neutral language was used in the consent forms when describing standard-of-care implants in both cohorts.12 Both cohorts included all four TKA configurations . Study investigators were trained on the New-TKA before enrollment and most attended cadaveric-based training. Most of the investigators were assigned to implant one configuration, consistent with their standard of care, with several exceptions where surgeons also subsequently enrolled in an additional configuration to help the team complete enrollment. All surgeons followed their preferred surgical technique for anterior/posterior referencing, femur first versus tibia first, gap balancing versus measured resection, cement choice, cementing technique, and patella resurfacing.This study was a post hoc comparison of two separate trials in the United States, United Kingdom, Australia, and New Zealand. From October 2011 to March 2015, 27 surgeons at 19 sites consecutively enrolled 752 subjects with Existing-TKA. Between November 2012 and May 2015, 32 surgeons at 23 sites (of which 19 surgeons at 18 sites had enrolled Existing-TKA) consecutively enrolled 1,129 subjects with New-TKA. Subjects from sites which participated in both studies comprised 625 of 752 (83.1%) of Existing-TKA enrollment and 789 of 1,129 (69.9%) of New-TKA enrollment. The mean, minimum , and maximum  enrollment across Existing-TKA sites was 39.6, 9 (1.2%), and 77 (10.2%), and across New-TKA sites, it was 47.0, 4 (0.4%), and 100 (8.9%). At a given site, enrollment was nonoverlapping: Each site completed their Existing-TKA enrollment before commencing enrollment of New-TKA. In both cohorts, “consecutive enrollment” meant that all subjects who met eligibility criteria, including consent, were enrolled. Eligibility was identical in both cohorts: age 22 to 80 years, noninflammatory degenerative joint disease, informed consent, willing/able to follow protocol-defined clinic visits; exclusion criteria were if pregnant or lactating, contralateral knee in this study, contralateral amputation, prior knee arthroplasty  patellectomy or high tibial osteotomy in the study knee, bedridden, current radicular pain from spine, enrolled in IDE/IND clinical investigation within past 3 months, involved in personal injury litigation or medical-legal or worker's compensation claims, drug or alcohol abuser, fibromyalgia being treated with prescription medication, neurological or musculoskeletal disorders that may affect gait or weight bearing , inflammatory arthritis, or less than 2 years of life expectancy. Subjects were not compensated for their participation. The first 10 New-TKA learning curve cases that each surgeon implanted were included in this study and have also been analyzed separately to explore the technically demanding skills associated with New-TKA adoption.14 (enables WOMAC scoring), Oxford Knee Score,15 Patient's Knee Implant Performance,17 and EQ5D-3L.18 The original American Knee Society Score (AKS)19 was collected for Existing-TKA, and the 2011 AKS21 was collected along with the original AKS pain score  for New-TKA; range of motion (ROM) defined as flexion minus extension was collected for both. Because of tibiofemoral alignment differences between original and 2011 AKS questionnaires, the alignment component of the AKS score was taken from the independent laboratory radiographic assessments for both Existing-TKA and New-TKA cohorts instead of the clinical examination alignment collected by investigators. The PROMs data were also analyzed using responder analysis. Responders were assessed at 2 years according to the Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI)23 using both WOMAC and KOOS outcomes, where high responders were those who demonstrated at least a 50% and 20-point improvement on either pain or function score, and moderate responders were those who demonstrated at least a 20% and 10-point improvement in 2 of 3 scores: pain, function, or quality of life.Subjects were evaluated preoperatively and postoperatively at regular intervals. The postoperative intervals were <1 year (1—303 days), 1 year (304—668 days), and 2 years (669—1763 days) after surgery. Data collection included a broad range of patient-reported outcome measures (PROMs): Knee Injury and Osteoarthritis Outcome Score (KOOS)24 by a fellowship-trained musculoskeletal radiologist using a detailed radiographic analysis protocol. The bone-cement and the implant-cement interfaces were evaluated across zones consistent with Knee Society recommendations24 based on implant geometry. Based on the timing of observation, an index radiolucent line (RLL) was one that was observed on immediate postoperative radiographs and would be most likely the result of surgical process challenges, such as poor cement interdigitation into the sclerotic bone26 because bone resorption would not be expected immediately after surgery. In this study, index RLLs were defined as interface gaps and could be later classified as a RLL if the width increased at subsequent intervals. By zone, the width of each RLL was recorded in millimeters and progression over time was assessed. RLLs were tallied by subject according to width: 0 to <1 mm, ≥1 mm to < 2 mm, and ≥ 2 mm. If a study subject had a RLL in more than one zone, the knee was only counted once, for the widest RLL. Final data for this study were collected in August 2018.Subjects were only counted once for each respective AE, even if they reported the AE more than once, and percentages of subjects who experienced local adverse events were compared. Radiographs were prospectively collected in the New-TKA cohort . For the Existing-TKA cohort, a pragmatic sample approach was used; all sites were asked to retrospectively provide their standard-of-care radiographs, but not all sites were able. Each site that was able, submitted all available standard-of-care radiographs that included 497 provided preop radiographs; 312 provided minimum 2-year radiographs. Radiographic evaluation of both cohorts was done by an independent core laboratory  per the Knee Society recommendationst-test. Because of multiple comparisons of these many continuous outcomes, a P value threshold of 0.01 for statistical significance was used for identifying differences that favored New-TKA. The large sample sizes in this study  were sensitive to small effects; an effect size of 0.18 would have been detected with a 2-sided alpha of 0.01 and 80% power. The Fisher exact test was used to compare complication rates, responder rates, and the percentage of subjects with radiographic findings. Implant survivorship was estimated with Kaplan-Meier (KM) methodology and compared across cohorts with a log-rank P value, where a revision was defined as the removal of any TKA implant for any reason (KM1), and the implant was considered to be surviving if it had not been revised. For subjects who were revised, the time to revision was the date of revision minus the date of primary TKA. The time to censoring for subjects who were not revised was defined to be the time of the last clinical study visit, death, or study withdrawal minus the date of primary TKA. KM methodology was also used to evaluate and compare implant survivorship with three other definitions of revision: the removal of any implant for any reason other than infection (KM2), the removal of metal implants for any reason (KM3), and the removal of any metal implants for any reason other than infection (KM4).Statistical summaries and analyses were conducted with all available data at respective time points for all enrolled subjects. Data imputation methods were not used in cases of missing data. PROMs, AKS, and ROM comparisons were conducted with a 2-sided independent samples Demographics and follow-up summaries are presented in Table P values less than 0.01  and high responder rates favored New-TKA with P values < 0.05  are presented in Table P = 0.0235), and symptomatic crepitus, which was higher for Existing-TKA (P = 0.0057), the distribution of local AEs was similar between cohorts.Table Radiographic outcomes are presented in Table It is well documented that TKA can reduce pain and improve function, but a notable percentage of patients are incompletely satisfied. Newer implants are designed to improve these suboptimal outcomes. This study was designed to carefully document a wide array of outcomes, with a focus on PROMs, of one specific, newer TKA design using the same manufacturer's predecessor implant as a control. Using the same surgeons to implant both Existing-TKA and New-TKA was an effort to minimize outcome differences and bias due to differences in surgical technique, patient populations, pain management, etc.27 It can be difficult to determine whether these small differences in outcomes signify clinical significance, and for that reason, we performed the OMERACT-OARSI23 responder analysis to further enhance the interpretation of the results. Approximately 3% to 6% more of the New-TKA subjects were responders compared with Existing-TKAs, inclusive of both responder criteria. Whether this is clinically significant and remains to be seen, but in the short term, we can safely conclude that the new implant shows equivalent, if not somewhat better clinical outcomes. Health economic literature focused on cost-effectiveness modeling evidence, which shows that even small improvements in PROMs can markedly raise cost-effectiveness favorability when translated into gains in quality-adjusted life years, provided that the improvement is sustained over long periods of time.28Postoperatively, subjects in both cohorts reported statistically significant improvements in PROMs compared with preoperative baseline. At both 1 and 2 years postoperatively, PROMs showed small differences favoring New-TKA compared with Existing-TKA. These differences were modest in magnitude, and although statistically significant, they were less than any recognized minimum clinically important differences for these PROMs. This is expected because TKAs, in general, have been shown to have a positive effect on patients' quality of life.P = 0.9994) between cohorts and were similar to 3-year estimates for the New-TKA and the class of TKAs from national joint registries30 and similar to the 97.68% implant survivorship estimate from the Michigan Arthroplasty Registry31 and the recent Kaiser Registry presentation.32 The reasons for revisions in the two cohorts in this study were similar at this time point. There were slightly more revisions for stiffness in New-TKA versus Existing-TKA, and these seven cases were across six different study sites, with no apparent pattern. Furthermore, the aseptic loosening rate in both cohorts was low and similar, which complements two RSA studies that showed no difference in maximum total point motion versus SIGMA in one study33 and maximum total point motion consistent with published criteria in the other study.34 These study data provide a large data set on New-TKA with which to understand a robust, short-term device survivorship estimate.The 3-year KM implant survivorship rates  demonstrated no statistically significant difference  subjects from these same two studies that was reported separately.36; thus, this study provides a broader view of the available implant survivorship information for this new product beyond what is currently available in published registry reports.29The strengths of this study include prospective data collection with fairly large sample sizes, consecutive enrollment, and multicenter data coming from experienced surgeons/clinical researchers who included all consecutive knees starting with their first New-TKA implanted. Additional strengths include the use of multiple validated PROMs to better understand the patient's perspective; utilization of knee-specific PROMs that included more advanced activities, such as KOOS Sports and Recreation, and a newer PROM (Patient's Knee Implant Performance) that included questions related to underlying reasons associated with functional outcomes, such as confidence and stability when performing activities. An independent radiographic core laboratory reviewed both cohorts of radiographs using an identical protocol, and 12 sites in the New-TKA cohort have elected to continue follow-up to 15 years thus providing opportunity to follow a portion of this original cohort long term. Approximately half of the subjects in both cohorts come from the United States, which currently does not have product-level reporting in their registryThe weaknesses of this study included nonrandomized enrollment, which was balanced by the fact that most of the sites participated in both cohorts to minimize biases associated with institutional practices. A potential for temporal bias was observed because Existing-TKA enrollment preceded New-TKA enrollment at sites which participated in both studies; however, all implants were placed over a fairly similar time frame, so it is unlikely that any new protocols or surgical techniques influenced the outcomes. Incomplete radiographic review of Existing-TKA was observed, and implementation of the AKS 2011 required a conversion to compare with the previous AKS outcomes.Although improvements out to 2 years that are demonstrated with the New-TKA in this study are subtle, we are encouraged that the new design has resulted in PROMs that are moving in a positive direction. With many examples of implant “improvements” in the orthopaedic industry leading to poorer performance, these data show that collaboration between clinicians and industry to improve outcomes in TKA can produce positive results. The early PROMs and radiographic outcomes of the New-TKA have produced encouraging results with modest improvement in most PROMs while maintaining the low level of radiolucency of the Existing-TKA, which suggests satisfactory long-term implant survival.37 and including a variety of PROMs to carefully assess performance from a patient perspective and radiographic/adverse event data to characterize the safety profiles. A longer term follow-up is ongoing for many of the study sites who have chosen to join the noted ongoing 15-year New-TKA study.The authors recommend that new implants that are introduced undergo similar levels of scrutiny using multicenter surveillance evaluation as recommended by several landmark articles


Alveolar echinococcosis (AE) is an orphan zoonosis of increasing concern in endemic areas, including Europe. It frequently presents in an advanced, inoperable stage, that requires life-long parasitostatic benzimidazole therapy. In some patients, long-term therapy leads to negative anti-Em18 antibody ELISA and PET. It is disputed, whether these patients are truly cured and treatment can be safely discontinued. Our aim was to retrospectively assess long-term outcome of 34 patients with inoperable AE who participated in a previous study to determine feasibility of benzimidazole treatment cessation.Retrospective analysis of medical charts was undertaken in all 34 AE patients who participated in our previous study. Of particular interest were AE recurrence or other reasons for re-treatment in patients who stopped benzimidazole therapy and whether baseline clinical and laboratory parameters help identify of patients that might qualifiy for treatment cessation. Additionally, volumetric measurement of AE lesions on contrast-enhanced cross-sectional imaging was performed at baseline and last follow-up in order to quantify treatment response.12 of 34 patients stopped benzimidazole therapy for a median of 131 months. 11 of these patients showed stable or regressive AE lesions as determined by volumetric measurement. One patient developed progressive lesions with persistently negative anti-Em18 antibody ELISA but slight FDG-uptake in repeated PET imaging. At baseline, patients who met criteria for treatment cessation demonstrated higher lymphocyte count and lower total IgE.Treatment cessation is feasible in inoperable AE patients, who demonstrate negative anti-Em18 antibody ELISA and PET on follow-up. Close monitoring including sectional imaging is strongly advised. Echinococcus multilocularis, which behaves similar to a malignant tumor with mostly infiltrative growth and occasional metastatic spread. Without adequate treatment, AE leads to death in 90% of patients within 10 years. Cure can be achieved through radical surgery, but frequently AE presents in an advanced, inoperable stage, that requires life-long drug therapy. Fortunately, these drugs are very effective. In fact, since their introduction in the mid 1970s, life expectancy of patients with inoperable AE has nearly reached that of the normal population. This leads to the question, whether the parasite has died and treatment can be stopped. Two biomarkers that reflect disease activity are the PET-CT and anti-Em18 antibody. Using these two parameters, we could previously show, that 1/3 of patients might have quiescent disease that allows treatment cessation. In our current study, we provide long-term follow-up of this patient cohort, including lesion size measurements at baseline and last visit. We demonstrate that 11 of 12 patients who stopped therapy show stable disease over a median of 131 months. These results consolidate our approach to a structured treatment interruption in AE.Alveolar echinococcosis (AE) is a zoonosis of the liver caused by the larval stage of the fox tapeworm Echinococcus multilocularis. This parasite is predominantly perpetuated in a wildlife-cycle with canines as definitive and small mammals as intermediate hosts. In Switzerland, approximately a 30–70% of the rural or urban fox population are infected, leading to an increase in cases since the new millenium [E. multilocularis eggs [Alveolar echinococcosis (AE) is an orphan zoonosis caused by the larval stage of the fox tapeworm illenium ,2. Humanris eggs . Mainstaris eggs . In inopris eggs .in-vivo parasite viability.Benzimidazoles, mainly albendazole and mebendazole, are efficacious in slowing parasite growth and stabilizing the disease . Since tplus antibody ELISA [Three studies have addressed the issue of treatment cessation in AE systematically. In their study, Reuter et al. used metabolic activity in PET-imaging after 1 hour as the sole criterium to determine parasite vitality and thereby identify inoperable AE patients that might qualify for treatment cessation . Howeverdy ELISA . Both stdy ELISA ,15. Our dy ELISA ,17.In the current study, the aims were to determine a) if all patients that stopped treatment showed no disease progression after an extended follow-up, b) how often and why treatment was restarted in these patients, c) if additional patients could stop treatment and d) to identify additional parameters, such as lesion morphology and size, age, sex, treatment type and duration, blood count and chemistry, as well as total immunoglobulin E (IgE), that might help to determine which patients might qualify for treatment cessation.Ethical approval for this study was obtained from the local ethics committee (EC) in Zurich . Patients still followed-up at our clinic provided written consent. For those that had died or were lost to follow-up written consent was waived.All 34 patients who participated in the previous study were included in our current retrospective cohort . The diaIn case patients were no longer followed up at our clinic, they or their family physicians were contacted to arrange a follow-up visit at our clinic or by phone. Complete follow-up included existing current patient history, imaging report , serology, blood analysis until last contact or study closure date by March 2021. AE-recurrence in patients that stopped treatment was defined as new lesions and/or progression of known lesions on cross sectional imaging with a positive anti-Em18 antibody ELISA or positive PET-CT. Patients who had had to continue benzimidazole treatment during the previous study, were evaluated for possible treatment discontinuation during extended follow-up. Baseline characteristics were acquired from entry into the previous study . The preData was acquired through the electronic medical records of the University Hospital Zurich. In case patients were followed-up at a different center, available records were obtained through the local treating physician. In particular, age at diagnosis and screening, PNM classification and stagIn our previous study, the metabolic activity of AE lesions was assessed solely 1 hour after flourodeoxyglucose (FDG) administration. Since then, due to the findings of Caoduro et al.  protocolTo determine the disease course, volume of the AE lesions was determined as the surrogate marker in addition to Em18 serology. When available at baseline and follow-up, contrast-enhanced cross-sectional imaging was used to measure the volume of the AE lesions. In case of retreatment, last follow-up imaging before re-initation of medical therapy was used. For this, one board certified radiologist , who was blinded to the clinical information, performed volumetric measurements of all hepatic AE lesions on contrast-enhanced MRI, CT or PET-CT studies in the portal venous phase for each patient using dedicated software . All hepatic lesions were delineated slice by slice using a free-hand region of interest (ROI) tool. Baseline and follow-up exams of the same patient were evaluated side by side in the same session. Cystic and calcified parts of all hepatic AE lesions were included in the volumetric measurements.Statistical analysis was performed using Graphpad Prism 8  Version 8.0.0 (224). To compare non-parametric, unpaired, numerical data the Mann-Whitney U-test was used. For unpaired, categorical data the Fisher’s exact or Chi Square test was applied. A tow-tailed p-value <0.05 was regarded as statistically significant.Age at diagnosis and at screening, sex, stage of AE, prior surgery, lesion size at study inclusion, benzimidazole type and duration of therapy did not differ significantly between the group that initially met criteria for treatment cessation versus the group that did not . InteresMedical records of all patients were reviewed. At the end of follow-up four patients in the discontinuation group and five in the treatment continuation group died . Cause oOf the group that continued therapy, 5 of the 13 patients, who had not met treatment cessation criteria due to positive anti-Em18 antibody ELISA result, demonstrated delayed anti-Em18 antibody negativity and underwent repeat PET-CT scanning to determine metabolic activity . Two of Of the 12 patients, with discontinued treatment for more than 60 months, 10 demonstrated AE lesions that could be measured. One of the other two patients demonstrated only very small calcifications in the liver, which were not suitable for volumetric measurement. The other patient was followed-up at a different center with ultrasound imaging only. Median follow-up time for cross-sectional imaging was 118 months, ranging from 61–172 months . Over thOf the 21 patients that continued benzimidazole therapy throughout the entire study period, 12 had received contrast-enhanced cross-sectional imaging at baseline and at some timepoint throughout extended follow-up, which was available for volumetric measurement. Median follow-up for cross-sectional imaging was 108 months, ranging from 55–200 months . All patThe primary aim of this study was to evaluate the currently still disputed structured approach to treatment cessation in patients with inoperable AE by retrospective analysis of the extended follow-up of all patients included in our previous study . To the Our analysis shows, that almost all patients who met the criteria for treatment cessation showed a favorable outcome after a median of 10.9 years off benzimidazole therapy. This is underlined by our finding, that 11 of the 12 patients showed a stable or decreasing AE lesion volume and persistently negative anti-Em18 antibody ELISA results. Only one patient demonstrated an increase of the AE lesion size. It is important to note, that in between treatment cessation and last follow-up for the current study, this patient chose to have follow-up ultrasound at a center without a specialist in AE for 9 years. Repeated anti-Em18 antibody ELISA was persistently negative but repeated PET imaging showed very slight FDG-uptake  only after 3h. Accordingly, the patient was restarted on benzimidazole therapy.plus antibody ELISA may be used alternatively, as it has been shown to also reflect disease activity [In conclusion, the selection of patients with inoperable AE for treatment cessation after at least two years of benzimidazole therapy and negative anti-Em18 antibody ELISA and PET on follow-up is feasible. Depending on the local availability of serological markers and AE center experience, anti-Em2activity ,21. Whenactivity . On the activity ,16. We tIt is also important to note that in our previous prospective study, PET imaging reported measurement of FDG-uptake only after 1 hour. As shown by Caoduro et al., delayed PET imaging after 3 hours is more sensitive for the detection of perilesional metabolic activity in AE than after conventional 1 hour . HoweverThe secondary aim of this study was to find further clinical and/or laboratory parameters that might help to distinquish AE patients that might qualify for treatment cessation. At baseline, only total IgE and lymphocyte count differed significantly between those who met criteria and those who did not. The role of periphal blood lymphopenia in AE has not been evaluated systematically. In cancer, lymphopenia has been associated with poorer prognosis and survival ,23. As iNaturally, there are some limitations to this study. In particular, the retrospective nature of data analysis, the lack of a predetermined surveillance protocol, some patients being lost to follow-up and some lacking contrast-enhanced sectional imaging that could be used for volumetric measurements. However, data on the most important group, being those that discontinued benzimidazole therapy, was mostly complete.Cessation of benzimidazole therapy in inoperable but metabolically (PET) and serologically (anti-Em18 antibody ELISA) quiescient alveolar echinococcosis is possible with a favourable outcome, but careful follow-up with regular cross-sectional imaging in a specialist center for AE treatment is mandatory.


The COVID-19 pandemic has resulted in a huge number of deaths from 2020 to 2021; however, effective antiviral drugs against SARS-CoV-2 are currently under development. Recent studies have demonstrated that green tea polyphenols, particularly EGCG, inhibit coronavirus enzymes as well as coronavirus replication in vitro. Herein, we examined the inhibitory effect of green tea polyphenols on coronavirus replication in a mouse model. We used epigallocatechin gallate (EGCG) and green tea polyphenols containing more than 60% catechin (GTP60) and human coronavirus OC43 (HCoV-OC43) as a surrogate for SARS-CoV-2. Scanning electron microscopy analysis results showed that HCoV-OC43 infection resulted in virion particle production in infected cells. EGCG and GTP60 treatment reduced coronavirus protein and virus production in the cells. Finally, EGCG- and GTP60-fed mice exhibited reduced levels of coronavirus RNA in mouse lungs. These results demonstrate that green tea polyphenol treatment is effective in decreasing the level of coronavirus in vivo. The COVID-19 pandemic has resulted in millions of deaths from 2020 to 2021 due to the high mortality of SARS-CoV-2 [Green tea has been consumed for thousands of years, and many beneficial effects of green tea have been reported ,4. RecenBecause green tea is a very popular beverage, there has been attempts to evaluate the correlation between average green tea consumption and COVID-19 morbidity/mortality, and countries with higher rates of green tea consumption showed less morbidity/mortality than those with lower green tea consumption . RecentlCoronaviruses are classified into alpha, beta, gamma, and delta coronaviruses, and only alpha and beta coronaviruses are reported to infect humans . Seven cRD and HCT8 cells were maintained in MEM  containing 10% fetal bovine serum  and 1% penicillin-streptomycin solution (Welgene). RD cells were infected with HCoV-OC43, as described previously . The HCo7 PFU/mL) through intranasal injection [2) euthanasia, and samples were collected.Male C57BL/6 mice (3-week-old) were obtained from DBL  and housed with wood chip bedding, clean-air rooms with a 12-h light–dark cycle, and a relative humidity of 50%. Mice were infected with 10 μL of HCoV-OC43 virus . After dehydration, the cells were air-dried using a vacuum desiccator. Cells were coated with platinum, and images were captured using a Carl Zeiss SEM SUPRA 40 microscope .t-test using Excel software, Excel 2016 . Statistical significance was set at p < 0.05.The results of Western blotting and quantitative RT-PCR were evaluated by a 2-tailed Student’s To examine the coronavirus infection on the surface, we infected RD and HCT8 cells with HCoV-OC43 strain. Three days after infection, we used a scanning electron microscope (SEM) to analyze the infected cells. The mock-infected control cells showed a smooth surface, and coronavirus infection resulted in coronavirus virion particles on the cell surface A–F. We aWe examined the effect of green tea polyphenols on coronavirus replication in mice and produced the coronavirus in RD and HCT8 cells. As HCoV-OC43 virus produced in HCT8 cells results in efficient infection in mice, we performed the experiments with the coronavirus produced in HCT8 cells. We examined the inhibitory effect of EGCG on coronavirus infection in HCT8 cells and found that EGCG treatment effectively decreased virus production and surface projection in HCT8 cells A. In addNext, we examined the effects of green tea polyphenols on coronavirus replication. We used green tea polyphenols containing more than 60% catechin (GTP60), and SEM analysis demonstrated that GTP60 treatment decreased coronavirus-induced virus particle production and surface projections in HCT8 cells A as wellWe also confirmed the reduction in coronavirus replication by examining coronavirus infectivity upon EGCG or GTP60 treatment. RD cells were infected with HCoV-OC43 and treated with EGCG or GTP60. After the media change, the infected cells were incubated for 72 h, and the conditioned media was used to infect uninfected cells A. CoronaAfter we showed the inhibitory effect of EGCG and green tea polyphenols on coronavirus replication in vitro, we performed a mouse experiment to examine their inhibitory effect in vivo. Mice were infected with HCoV-OC43 virus, which was produced in HCT8 cells by intranasal infection, and the coronavirus RNA was evaluated by quantitative RT-PCR. We found that coronavirus RNA was readily detected in the mouse lung after two weeks A,B. HoweMounting evidence indicates that green tea polyphenols such as EGCG inhibit coronavirus replication in vitro; however, experiments using mouse models have not yet been performed . To the In this experiment, we used two types of compounds as a source of green tea polyphenols. One was EGCG, a major green tea polyphenol, and the other was a green tea extract from lab reagent suppliers (Sigma-Aldrich). Because the composition of green tea extract can be diverse based on the extraction methods, we used a standard green tea extract. Therefore, a similar experiment can be repeated by other researchers. In addition, we used the HCoV-OC43 virus for mouse experiments as a surrogate for SARS-CoV-2. Due to strict regulations, it is difficult to perform experiments with SARS-CoV-2. However, both SARS-CoV-2 and HCoV-OC43 are beta coronaviruses, and HCoV-OC43 is a good alternative for SARS-CoV-2 . FurtherInitially, we attempted to infect mice with HCoV-OC43 virus, which was produced in human RD cells; however, successful infection was not obtained with repeated trials. For this reason, we tested several other cell lines and found that the human HCT8 cell line was suitable for the production of HCoV-OC43 virus for infecting mice. Although we detected the replication of HCoV-OC43 in mice lungs, we did not observe any mouse death due to coronavirus infection, and we did not observe weight loss due to infection (data not shown). The effect of HCoV-OC43 infection on mice was mild and we did not observe any other external differences between the uninfected group and infected group. This is probably due to the pathological differences between humans and mice, and it is the limitation of animal experiments. To validate the effect of EGCG or green tea on coronavirus, further human clinical study should be conducted.In this experiment, we evaluated the mouse intake of EGCG and GTP60 based on daily water consumption and reagent concentration . As the There are many reports supporting the efficacy of green tea against coronavirus. Green tea polyphenols, including EGCG, have been reported to inhibit several coronavirus proteins . Moreove


Background: Cardiac injury is common and associated with poor clinical outcomes in COVID-19. Data are lacking whether high-dose intravenous vitamin C (HIVC) could help to ameliorate myocardial injury in the pandemic.Methods: The retrospective cohort study included consecutive severe and critically ill COVID-19 patients with cardiac injury receiving symptomatic supportive treatments alone or together with HIVC. Troponin I and inflammatory markers were collected at admission and day 21 during hospitalization from the electronic medical records.Results: The patients (n = 113) were categorized into the ameliorated cardiac injury (ACI) group (n = 70) and the non-ameliorated cardiac injury (NACI) group (n = 43). Overall, fifty-one (45.1%) patients were administered with HIVC, the percentages of patients with HIVC were higher in the ACI group than those in the NACI group. Logistic regression analysis revealed that HIVC was independently associated with the improvement of myocardial injury. Further analysis showed that inflammatory markers levels significantly decreased at day 21 during hospitalization in patients with HIVC therapy compared to those administered with symptomatic supportive treatments alone. Meanwhile, similar results were also observed regarding changes in inflammatory markers levels from baseline to day 21 during hospitalization in the patients treated with HIVC.Conclusions: HIVC can ameliorate cardiac injury through alleviating hyperinflammation in severe and critically ill patients with COVID-19. Coronavirus disease 2019 (COVID-19) caused by a novel coronavirus named SARS-CoV-2 poses a worldwide healthcare issue with the increasing number of infected individuals . A growiGiven the background, it is urgently needed to study new therapeutic options to suppress hyperinflammation for ameliorating cardiac injury and reducing fatality. At present, managing COVID-19 is challenging as there is lack of antiviral agents against SARS-CoV-2. Symptomatic supportive treatment is still the current main therapeutic strategy in the pandemic. Clinical efforts focus on repurposing already approved drugs for treatment of the disease. Vitamin C is significant to human body and potentiates the ameliorative effect of inflammatory-induced tissue damage. Additionally, the use of intravenous vitamin C arises from experimental evidence of its anti-inflammatory properties . A recenA retrospective, observational cohort analysis was carried out from February 1 to March 10, 2020. The study subjects consisted of COVID-19 pneumonia with myocardial damage who consecutively admitted to Tongji Hospital of Huazhong University of Science and Technology , and were diagnosed as positive for SARS-CoV-2 infection by performing RT-PCR assay on samples from nasal and pharyngeal swab, and were in severe and critically ill condition. Identification of disease condition was achieved in accordance with the criteria in Chinese management guidelines for COVID-19 on February 4, 2020  . The excThe study complied with the ethical principles of the World Medical Association’s Declaration of Helsinki and received the ethical approval from the Medical Ethics Committee of the hospital. The oral, not written informed consents were obtained from patients underwent HIVC therapy owing to observational nature of the research and isolation precautions of the rapidly evolving pandemic.The screening exam comprised patient’s demographics details and baseline clinical characteristics available in the hospital’s electronic medical records system for analysis. The following information was recorded for each patient: age, gender, smoking status, pulse, blood pressure, comorbidity , time from illness onset to admission, as well as presenting clinical symptoms. Simultaneously, we collected the laboratory examinations on complete blood counts, haemoglobin, serum biochemical indicators, N-terminal pro-B-Type natriuretic peptide (NT-proBNP) at baseline. The parameters of inflammation including high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, and hs-cTnI were obtained at admission and repeated day 21 during hospitalization.hs-cTnI, NT-proBNP and inflammatory markers determinations were conducted in the central laboratory of Union Hospital. A blood sample was acquired at admission (defined as day 1) and finally beyond day 20 to discharge . All procedures were carried out following standard operating procedures.On admission, all subjects were initiated on symptomatic supportive treatments based on the requirements of each individual patient. As suggested in the guideline,  symptomaThe clinical spectrum of COVID-19 ranges from mild, common, severe to critically ill cases. Severe illness was considered in the presence of one or all three of the following criteria: (i) dyspnea with respiratory rate ≥ 30 breaths/min; (ii) arterial oxygen saturation ≤ 93% at a rest state; (iii) the ratio of arterial partial pressure of oxygen/fractional inspired oxygen < 300 mm Hg . Patientt test was applied to analyze differences between the ACI group and the NACI group; otherwise, the Mann-Whitney U test was conducted. The assumption of normal distribution of the data was determined using the Shapiro-Wilk test. Proportions for categorical variables were compared using chi-square test or Fisher's exact test where appropriate. The independent association between medications and cardiac injury was studied using univariate and multivariate logistic regression analysis accounting for HIVC as well as other symptomatic supportive treatments. The results were described as odds ratio (OR) and 95% confidence interval (CI). A forest plot was created base on logistic regression analysis results. Hypothesis tests were performed using two-tailed test with P value of < 0.05 indicating statistical significance. All statistical analysis was performed using SPSS (version 16.0) and GraphPad Prism 5.0.We expressed continuous variables as median with interquartile range  or categorical variables as number with percentage to characterize the study cohort. When continuous variables conformed to a normal distribution, 2-sample independent group The detailed analysis of baseline characteristics in our study cohort was described in P = 0.734]. In contrast, the concentrations of hs-cTnI at day 21 during hospitalization appeared significantly lower in the ACI group compared with the NACI group .As shown in 2 = 4.432, P = 0.035; 2 = 4.336, P = 0.049), mechanical ventilation , and renal replacement therapy  were also statistically significant between the two cohorts  cases were administered with symptomatic supportive treatments alone and 51 (45.1%) received administration with HIVC in addition to symptomatic supportive treatments. The percentages of subjects with HIVC therapy were 52.8% (n = 37) in the ACI group and 32.5% (n = 14) in the NACI group, respectively; and the proportions were significantly different  and renal replacement therapy . Thus, HIVC seemed to show a beneficial effect in improving myocardial damage among patients with SARS-CoV-2 infection in severe and critically ill condition.To investigate the independent effect of HIVC on cardiac injury in more detail, logistic regression analysis was performed with variables entered in the model including HIVC and other medications during hospitalization. The result revealed that administration of HIVC infusion was correlative with the improvement of cardiac injury . However, the levels of inflammation parameters at day 21 during hospitalization among cases receiving HIVC therapy significantly decreased compared to those administered with symptomatic supportive treatments alone . Furthermore, changes in inflammatory markers levels displayed a tendency of significant decrease at day 21 during hospitalization related to baseline in patients receiving HIVC therapy .We subsequently investigated changes in parameters of inflammation from admission to day 21 during hospitalization. As described in The pandemic of COVID-19 continues to spread worldwide with a serious threat to human life, there are not yet effective treatments that target SARS-CoV-2, it is urgent to find new preventive and therapeutic strategies as soon as possible to potentially protect from the virus or to alleviate its effects once caught. One such medication that is being touted in the media is HIVC. However, the efficiency of HIVC in the management of SARS-CoV-2 infection is still controversial , 13. In There is a high prevalence of myocardial injury in the form of elevation in hs-cTnI at high risk for severe disease and death . A largeTo better understand the cardioprotective mechanism of HIVC, we assessed the impact of HIVC therapy on inflammatory markers levels in the subjects. We measured inflammatory markers levels of the cases underwent symptomatic supportive treatments alone or in addition to HIVC at admission and day 21 during hospitalization. The results indicated that patients administered with HIVC exhibited a significant decrease of concentrations of inflammation parameters compared with those receiving symptomatic supportive treatments alone. In addition, the changes in inflammation parameters levels displayed a tendency of significant decrease at day 21 during hospitalization related to baseline in patients treated with HIVC. On all these counts, we demonstrated the elevated levels of inflammatory markers that might result in hyperinflammation significantly decreased in patients administered with HIVC, which indicated that HIVC may be helpful in improving cardiac injury through mitigating hyperinflammation. As shown by the data available, COVID-19 frequently encounters conditions in which hyper-inflammatory response characterized by a cytokine storm results from an exaggerated response of the systematic inflammation in patients infected with SARS-CoV-2 . MoreoveLimitations to the present study include a single center experience with a relatively small sample size. It was not possible to perform a valid calculation of the sample size due to the critical condition of the ongoing pneumonia in our hospital. Also, the study was a nonrandomized observational study and hence suffered from potential selection and ascertainment biases. The determinations of parameters of inflammation should be very detailed at additional time points during and following treatment, but we only collected hs-CRP, IL-6, IL-8, and TNF-α at baseline and day 21 during hospitalization, it was thus uncertain whether HIVC may have an effect on other inflammatory markers levels. Furthermore, medications such as corticosteroids usage may affect levels of inflammatory markers. Importantly, we had no standardized protocol for HIVC, the dosage of HIVC used in this study may be insufficient for optimal care of SARS-CoV-2 infection. Further research on vitamin C dosages and longer administration time may need optimization.In this retrospective cohort study, our analysis of data from the patients treated with HIVC along with our tests of inflammatory markers showed the novel information that HIVC therapy may be potential benefit in ameliorating myocardial injury by alleviating hyperinflammation in the form of elevated levels of hs-CRP, IL-6, IL-8, and TNF-α. Therefore, our study supports the hypothesis that HIVC can ameliorate myocardial damage by alleviating hyperinflammation, it has shown promise as an adjunct therapeutic strategy for myocardial injury in the clinical management of COVID-19 pneumonia.


The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic necessitated rapid local public health response, but studies examining the impact of social distancing policies on SARS-CoV-2 transmission have struggled to capture regional-level dynamics. We developed a susceptible-exposed-infected-recovered transmission model, parameterized to Colorado, USA‒specific data, to estimate the impact of coronavirus disease‒related policy measures on mobility and SARS-CoV-2 transmission in real time. During March‒June 2020, we estimated unknown parameter values and generated scenario-based projections of future clinical care needs. Early coronavirus disease policy measures, including a stay-at-home order, were accompanied by substantial decreases in mobility and reduced the effective reproductive number well below 1. When some restrictions were eased in late April, mobility increased to near baseline levels, but transmission remained low (effective reproductive number <1) through early June. Over time, our model parameters were adjusted to more closely reflect reality in Colorado, leading to modest changes in estimates of intervention effects and more conservative long-term projections. However, widely used national-level models might not capture regional heterogeneity. The coronavirus disease (COVID-19) outbreak in Colorado, USA, has been the subject of numerous discrepant projections from the Institute for Health Metrics and Evaluation and other modeling groups  and the efficacy of current and future intervention measures, providing time-sensitive data to policy-makers  model calibrated to statewide COVID-19 case and hospitalization data to estimate changes in the contact rate and the RThe first SARS-CoV-2 case was reported in Colorado on March 5, 2020, and a rapid succession of policies to control transmission followed . The Colhttps://emresource.juvare.com). Because EMResource appeared to underreport COVID-19 hospitalizations during March, we inferred COVID-19 hospitalizations by using CEDRS before April 8.Hospitalization data are a robust indicator of transmission trends compared with reported case data because reported case data are sensitive to testing capacity. However, because COVID-19 hospitalization data were sparse early in the epidemic, we initially fit models to reported COVID-19 cases from the Colorado Electronic Disease Reporting System (CEDRS). We fit models to the daily number of symptom onsets to reflect a biologically meaningful process (report date can be sensitive to testing lags). Missing onset dates were imputed as report date minus 7 days, the median onset-to-report lag. In May, we began fitting models to the daily number of hospitalized COVID-19 patients because we suspected that reported cases captured a variable proportion of infections over time because of increases in testing capacity. Daily hospital census records were obtained from EMResource (>60 years of age) to estimate key model parameters and project the number of COVID-19 hospitalizations. In the model, we assume a single virus introduction event occurring on January 24, a date extrapolated from the first reported cases in Colorado.We used a deterministic age-structured SEIR model with 3 age groups . We defined contacts as interactions that could enable spread of infections from an infected person to a susceptible person. The term social distancing is used to encompass all contact-reducing behaviors and policies, including working from home, school closures, maintaining physical distancing, socializing outdoors (vs. indoors), and increased hygiene. Social distancing was modeled in phases coinciding with major events and policy measures . Phase 1We added mask wearing to the model in May (fits 3 and 4) in response to increasing evidence that masks are effective for controlling transmission  from the model output. We additionally estimated the overall number of hospitalizations prevented as a result of decreasing contacts by comparing the fitted model on June 16 with a reference scenario assuming no reduction of the contact rate .Because of the median 7-day lag between symptom onset and reporting, on April 3 (fit 1), we included cases that had a symptom onset date through March 26 for model fitting, which enabled us to generate a preliminary estimate of phase 1 social distancing. On April 16 (fit 2), we included cases that had an onset date through April 9 for model fitting, which enabled us to refine estimates of social distancing during phase 1 and generate preliminary estimates of social distancing during phase 2. We generated a preliminary estimate of phase 3 social distancing on May 15 (fit 3) and then re-estimated on June 16 (fit 4), when social distancing during phase 4 was estimated. We estimated the proportion of the population wearing masks in fits 3 and 4 with the effectiveness assumptions defined and estimated the effective reproduction number  data to examine changes in mobility in Colorado from March through June. Specifically, we used an aggregated and anonymized measure of time away from home reported at the census block group. We calculated changes in mobility as a percent decrease in time away from home relative to pre-epidemic baseline: January 29‒February 15 (mean 2.3 hours).We used SafeGraph  to avoid conflating parametric assumptions with changes in observed mobility, nor changes to any other aspects of the model.e decreased from 5.3 to 2.4 , we re-estimated phase 1 and phase 2 parameters, which indicated transmission reduction had been more moderate initially , and greater for phase 2 . On May 15, which was 18 days after the end of the stay-at-home order, there was no evidence of an increase in hospitalizations or contact rate due to decreased restrictions, noting that because of the ≈13-day lag between infection and hospitalization, this estimate reflects transmission through May 2. A month later on June 16 (fit 4), a greater decrease in transmission was estimated for phase 3 , and the estimated decrease in contact rates during safer-at-home (phase 4) was 90%. Estimated Re decreased to 0.6 during phase 4.On April 3 (fit 1), we generated a preliminary estimate of social distancing during phase 1, which equated to a ≈45% decrease in the contact rate , and Re 3 to 2.4 . BecauseAs of June 16, a total of 5,272 COVID-19 hospitalizations in Colorado had been reported to CEDRS, and EMResource data strongly suggested underreporting of COVID-19 hospitalizations to CEDRS during April and May. Using CEDRS and EMResource data, we found that the SEIR model estimated a cumulative of 5,344 COVID-19 hospitalizations in Colorado by Jun 16 , panel DWe provide projected hospitalizations  and ICU Residents of Colorado decreased activity outside the home starting in early March , panel Ae well below 1, in agreement with other studies of nonpharmaceutical interventions to decrease SARS-CoV2 transmission .–Mobility, assessed by using mobile-device data, generally reflected state-level policy during March‒June but mirrored transmission only in the early months of the pandemic. Mobility decreased rapidly in March in concert with early transmission control policies and the statewide stay-at-home order, and mobility increased as social distancing policies were relaxed. Consistent with our findings, others have found that US population mobility was reactive to policy during March: greater perceived disease prevalence and governmental stay-at-home orders resulted in less mobility and social interaction (Mobility data can be used to estimate when and where persons are congregating, a precondition for transmission, but do not sufficiently capture behaviors such as mask wearing, physical distancing, or moving activities outside. Those individual behaviors can play a critical role in spreading infections, and understanding what drives those behaviors can improve epidemic response. Public perception of and reaction to perceived risk is multifactorial, and, although clearly influenced by policy, in a time of heightened fear, local policy probably plays only a partial role in determining risk-reducing behavior. Rapid and frequent introduction of COVID-19‒related policy measures and public communication by government officials at the national, state, and local scales probably increased fear and public risk perception regarding COVID-19 transmission, and contributed to adoption of transmission-reducing behaviors before the start of and beyond the end of stay-at-home orders (Real-time estimation of contact reduction enabled us to respond to urgent requests to actively inform rapidly changing public health policy amidst a pandemic. In early stages, the urgent need was to flatten the curve (A key challenge we faced was generating projections of hospital and critical care needs with limited data and rapidly evolving science. Early model estimates were imprecise because data were sparse and poor quality, leading projections to overestimate hospital needs. Estimates and, consequently, projections improved with greater data quantity and quality. Another challenge was the need to generate estimates under extreme time constraints. We designed a preliminary model in a matter of days and adapted it regularly to accommodate new data streams and science. The need for efficiency led to tradeoffs: for example, we did not account for age-specific contact rates (The model findings were provided weekly to decision-makers in Colorado by written reports and briefings. These collaborative interactions provided an opportunity to review findings and define projection scenarios useful for decision-making. The rapidly developed, locally calibrated transmission model provided timely evidence of a moderate decrease in transmission in Colorado after an early transmission control policy began and a substantial decrease in the contact rate after stay-at-home orders that persisted after these policies were partially relaxed. Decreases in transmission mirrored changes in mobility through the end of stay-at-home, at which point mobility ceased to be a clear proxy for transmission. Locally calibrated models have local credibility and can be used to provide time-sensitive, tailored information to policymakers to assist their decision-making.Additional information on estimating the impact of statewide policies to reduce spread of severe acute respiratory syndrome coronavirus 2 in real time, Colorado, USA.


Substance use is a risk factor for COVID-19 infection and adverse outcomes. However, reasons for elevated risk for COVID-19 in substance users are not well understood.The aim of this study was to evaluate whether alcohol or other drug use is associated with adherence to Centers for Disease Control and Prevention (CDC) guidelines for COVID-19 mitigation. Preregistered analyses tested the hypothesis that greater use of alcohol and other drugs would be associated with lower CDC guideline adherence. A secondary objective was to determine whether substance use was associated with the likelihood of COVID-19 testing or outcome.A cross-sectional web-based survey was administered to a convenience sample recruited through Amazon’s Mechanical Turk platform from June 18 to July 19, 2020. Individuals aged 18 years or older and residing in Connecticut, Massachusetts, New Jersey, New York, or Rhode Island were eligible to participate. The exposure of interest was past 7-day use of alcohol, cigarettes, electronic cigarettes, cannabis, stimulants, and nonmedical opioids. The primary outcome was CDC guideline adherence measured using a scale developed from behaviors advised to reduce the spread of COVID-19. Secondary outcomes were likelihood of COVID-19 testing and a positive COVID-19 test result. All analyses accounted for the sociodemographic characteristics.The sample consisted of 1084 individuals (mean age 40.9 [SD 13.4] years): 529 (48.8%) men, 543 (50.1%) women, 12 (1.1%) other gender identity, 742 (68.5%) White individuals, 267 (24.6%) Black individuals, and 276 (25.5%) Hispanic individuals. Daily opioid users reported lower CDC guideline adherence than nondaily users  and nonusers . Daily alcohol drinkers reported lower adherence than nondaily drinkers . Nondaily alcohol drinkers reported higher adherence than nondrinkers . Daily opioid use was related to greater odds of COVID-19 testing, and daily stimulant use was related to greater odds of a positive COVID-19 test.In a regionally-specific, racially, and ethnically diverse convenience sample, adults who engaged in daily alcohol or opioid use reported lower CDC guideline adherence for COVID-19 mitigation. Any opioid use was associated with greater odds of COVID-19 testing, and daily stimulant use was associated with greater odds of COVID-19 infection. Cigarettes, electronic cigarettes, cannabis, or stimulant use were not statistically associated with CDC guideline adherence, after accounting for sociodemographic covariates and other substance use variables. Findings support further investigation into whether COVID-19 testing and vaccination should be expanded among individuals with substance-related risk factors. The use of alcohol, tobacco, and other drugs has been identified as a risk factor for infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the COVID-19 pandemic . First, Emerging data indicate changes in substance use and related problems in the United States during the pandemic. In a Centers for Disease Control and Prevention (CDC) survey, 13% of US adults reported initiating or increasing substance use to deal with COVID-19–related stress . AnotherThe CDC recommends several behaviors to mitigate the spread of SARS-CoV-2, including avoiding close contact with others outside the household, handwashing, and wearing a face covering . States The objective of this study was to investigate links between use of specific substances and behavioral adherence to CDC guidelines in a sample of US adults surveyed in June and July 2020. Our main hypothesis predicted that greater substance use would be associated with lower CDC guideline adherence after accounting for demographic and contextual factors that have been associated with CDC guideline adherence or related health behaviors in previous studies, such as age and income -19. GiveThis study was a deidentified, web-based, cross-sectional survey with a nonprobability sample. Participants were recruited using Amazon’s Mechanical Turk (MTurk) platform. MTurk is a crowdsourcing platform with a built-in survey administration system that allows researchers access to a pool of >200,000 potential respondents, producing data of quality equal to or better than professionally sourced panels . Our stuEligibility criteria were as follows: ≥18 years of age, residing in an eligible state , and holding an active MTurk account. Quotas based on age, gender, race, and ethnicity were used to ensure a diverse sample. Black and Hispanic individuals were oversampled owing to overwhelming evidence that such individuals have been disproportionately affected by the pandemic -30. RaceDemographic characteristics included age, sex, gender identity, highest level of education, annual household income, and home ownership. These variables have demonstrated associations with adherence to COVID-19 prevention/mitigation behaviors in US adults in previous research -18 asideThe primary outcome was measured using a self-report questionnaire that we developed from the CDC’s recommendations for behaviors in which the public should engage to mitigate COVID-19 transmission see . ParticiCOVID-19 testing and test results were the secondary outcomes. Testing history was assessed by asking “Have you been tested for the novel coronavirus or COVID-19?” (yes/no/not sure). Answering “yes” prompted these follow-up questions: “Have you had a nose swab test for the virus that causes COVID-19?” and “Have you had a blood test to see if you already had the virus (“serology”)?” Each of these were followed with the question, “If yes, what was your result?”Substance use was recorded using the Timeline Followback method  for the t tests compared daily use to 1-6 day and no use categories and 1-6 days of use to no use. Adjusted 2R and 2ΔR evaluated the proportion of variability in CDC guideline adherence accounted for by variables included in the models.The analytic plan was preregistered and can be accessed online . A descrt tests for continuous variables and Pearson χ2 tests for categorical variables. A subset analysis among those who reported a COVID-19 test evaluated the likelihood of a positive test result . Covariates that were not related to COVID-19 testing or COVID-19 test results in omnibus Type III sums of squares tests were removed and models retested.A secondary set of logistic regression models tested associations of covariates and substance use variables with the likelihood of COVID-19 testing and results. An initial logistic model evaluated the likelihood of COVID-19 testing . Differences in testing likelihood according to substance use frequency prompted post hoc analyses on possible explanatory factors. The post hoc analyses used independent two-sided Of the 3849 individuals who were assessed for eligibility, 1185 completed the entire survey see . Data seR2=0.071, adjusted R2=0.057). Unadjusted relations of substance use variables with CDC guideline adherence scores are provided in Table S2 in R2=0.129, adjusted R2=0.120), where the covariate model reported above had accounted for 7.1% of the variance in CDC guideline adherence. Thus, when considering influences on CDC adherence, alcohol and opioid use contributed nearly as much to understanding adherence as did the combination of gender, ethnicity, essential worker status, income, and COVID-19 test.Covariates tested for inclusion are reported in The relation of CDC guideline adherence with COVID-19 testing was also evaluated and found to be not statistically related. Of the covariates in t tests showed no difference in this count of medical conditions between daily users versus nonusers  or between nondaily users versus nonusers . Second, we asked whether engagement in medication-assisted treatment (MAT) for opioid use disorder was associated with a higher likelihood of receiving a COVID-19 test. In the total sample, MAT was endorsed by 61% (28/46) of daily opioid users, 32.2% (58/180) of nondaily opioid users, and 2.1% (18/858) of nonusers. Among opioid users, 40.7% (57/140) of opioid users not engaged in MAT received a COVID-19 test, whereas 79% (68/86) of opioid users engaged in MAT received a COVID-19 test. This difference was significant . In summary, MAT engagement was associated with higher rates of COVID-19 testing in nondaily and daily opioid users. The likelihood of a positive result was evaluated among the subset who received a COVID-19 test. The following Following the finding that daily and nondaily opioid users were more likely to receive a COVID-19 test, we conducted 2 post hoc analyses on factors that might plausibly lead to higher testing rates in opioid users. First, we asked whether opioid users had significantly higher rates of comorbid medical conditions known to increase the risk of COVID-19 in their households by comparing the count of how many of the following conditions were endorsed by the participants: autoimmune disease, cardiovascular disease, cerebrovascular disease, chronic lung disease, diabetes, immune compromise, or kidney disease. Independent This study tested the hypothesis that heavier substance use would be associated with lower adherence to CDC guidelines to reduce the spread of COVID-19. Our geographic focus was 5 states that had experienced the highest rates of COVID infection and deaths at the time of the survey . Our hypUse of some substances was related to the likelihood either of receiving a COVID-19 test or of receiving a positive test. The odds of COVID-19 testing were 3.35 times as large for daily opioid users as for nonusers and 2.08 times as large for nondaily opioid users as for nonusers. Post hoc analyses showed that opioid users did not have significantly higher rates of comorbid medical conditions than nonusers, but they did report high rates of engagement in MAT for opioid use disorder. In turn, MAT was associated with significantly higher rates of COVID-19 testing in opioid users. Although speculative, it is possible that engagement in MAT increased contact with the health care system and thereby increased testing rates in opioid users. In addition, among those who received a COVID-19 test, odds of a positive test were significantly higher in daily stimulant users than those who used stimulants less frequently or not at all. There is a large body of research linking the use of amphetamine, methamphetamine, and other stimulants to HIV transmission, largely through risky sexual behavior -38. AlthCigarette use was associated with CDC guideline adherence in unadjusted analyses; yet, this variable became nonsignificant after adjusting for sociodemographic characteristics and other substance use. This pattern suggests that other characteristics or behaviors associated with cigarette use are driving the finding. Null results observed for e-cigarette, cannabis, and stimulant use should be interpreted within the limits of the study design and sample size. The prevalence of nondaily or daily e-cigarette, cannabis, and stimulant use was less than 6%. For these substances, the study may not have had sufficient power to detect differences in CDC adherence scores.In the final model, gender, income, and COVID-19 test history were the demographic covariates that remained significant after the inclusion of substance use variables. Women reported higher adherence than men and those with other gender identities, and income showed a positive linear association with adherence. These findings are consistent with previous research ,17. PartSubstance use is a known risk factor for COVID-19 infection . HoweverInterestingly, individuals who drank 1-6 days per week reported higher CDC guideline adherence relative to nondrinkers and daily drinkers who did not differ statistically from each other. This finding may be in line with other observational research linking moderate or occasional alcohol consumption to health behaviors such as physical activity ,41. ThisThe limitations of this study include the use of a nonrepresentative convenience sample, self-report data, and a novel CDC adherence scale that has not yet been validated. The survey did not explicitly assess the number or timing of COVID-19 tests that participants had received. Absence of data on the timing of testing is a significant limitation particularly with regard to understanding the relation with substance use. Analyses accounted for frequency but not quantity of substance use or specific patterns of polysubstance use, both of which are potentially important factors that warrant attention in future research. Our findings may not generalize to the US population as a whole. For effects with large confidence intervals, findings should be interpreted as informing directionality for future research rather than representing a reliable estimate of their magnitude in the sampled population.In a convenience sample of adults living in the northeastern United States, we found that daily use of alcohol or opioids was significantly associated with lower adherence to CDC guidelines for reducing the spread of COVID-19, after accounting for sociodemographic characteristics and other substance use. However, use of cigarettes, e-cigarettes, cannabis, or stimulants was not associated with adherence. We also found that daily use of nonprescribed opioids was associated with higher odds of COVID-19 testing and that daily use of stimulants was associated with higher odds of a positive COVID-19 test result. The strengths of this study include the calendar-based assessment of several common classes of substances and the racial, ethnic, and age diversity of the sample. The findings of this study point to a need for public health efforts to support behavioral adherence and to expand COVID-19 testing and vaccination in individuals with high levels of alcohol, opioid, or stimulant use.


Prostaglandin E-major urinary metabolite (PGE-MUM) and C-reactive protein (CRP) are useful biomarkers in patients with ulcerative colitis. However, whether changes in endoscopic scores over time are reflected in the values of these biomarkers has not been verified. This prospective observational study aimed to assess the relationship between changes in biomarker levels and endoscopic scores in patients with ulcerative colitis. A total of 100 colonoscopy intervals of patients with ulcerative colitis were enrolled. The relationship between variations in the Mayo endoscopic subscore over time and the accompanying changes in biomarker values were investigated. PGE-MUM levels showed a significant rise in the increased endoscopic score group (P = 0.007) and a decrease with reduced endoscopic score group (P = 0.023). CRP levels showed a significant decline with lower endoscopic values (P < 0.001); however, there was no corresponding increase with higher endoscopic scores (P = 0.141). Biomarker levels remained unchanged with stable endoscopic scores (P = 0.090 and P = 0.705). PGE-MUM levels varied significantly, and corresponded to the mucosal healing state (P = 0.019 and P = 0.009). The correlation between changes in PGE-MUM and the endoscopic score was stronger than that for CRP . PGE-MUM reflected changes in endoscopic scores more accurately than CRP. Initially, the primary goal of medical therapy for UC was to achieve stable clinical remission. However, with the development of various evaluation and treatments methods, the current objective is to achieve mucosal healing (MH), which has been proven to improve the prognosis of UC6. Although endoscopic evaluation is typically required to determine the state of MH, several biomarkers have been reported to be effective alternatives. C-reactive protein (CRP) is a common long-standing inflammatory biomarker. Although CRP is not disease-specific, it is widely used for monitoring UC in clinical practice because it is easy to measure12.Ulcerative colitis (UC) is a chronic idiopathic inflammatory bowel disease (IBD) characterized by symptoms such as diarrhoea, abdominal pain, and haemorrhagic stools17, and the faecal immunochemical test (FIT) has been described to be reflective of the mucosal state in patients with UC23. The usefulness of serum leucine-rich alpha-2 glycoprotein (LRG) has also been reported and LRG is used in clinical practice24. Using biomarkers to evaluate UC disease activity may reduce the number of colonoscopies (CS) performed, as well as minimize CS-related complications, such as bowel perforation. Additionally, fewer colonoscopies may also prevent infectious diseases, such as the coronavirus disease (COVID-19), from being transmitted during endoscopic examination25.Faecal calprotectin (FC) has recently been reported as an extremely significant biomarker that reflects endoscopic scores26. PGE-MUM is sourced from urinary specimens27 and has been reported to be useful in paediatric patients with UC28. Additionally, PGE-MUM may be efficient in distinguishing between chronic enteropathy associated with the solute carrier organic anion transporter family member 2A1 (SLCO2A1) gene and Crohn's disease29. Compared with FIT, PGE-MUM is particularly effective in patients with long-term UC30 and predicts possible relapse31.Prostaglandin E-major urinary metabolite (PGE-MUM) has been reported as a novel and effective biomarker for UC23. However, studies investigating changes in PGE-MUM in relation to changes in endoscopic scores of UC patients have yet to be reported.Multiple cross-sectional studies have examined the correlation between biomarkers and endoscopic scores in patients with UC. The receiver operating characteristic curves for the prediction of achieving MH with certain biomarkers have been analysed. However, only a few longitudinal observational studies have investigated the changes in biomarkers in relation to the endoscopic scores of patients with UC. If the exacerbation or improvement of colon inflammation can be confirmed using biomarkers, an appropriate treatment plan can be selected accordingly. Hiraoka et al., demonstrated that a variation in precedent and subsequent endoscopic scores resulted in significant variations in FIT and FCIn this study, changes in endoscopic scores and accompanying variations in the PGE-MUM and CRP values of UC patients were longitudinally analysed.The characteristics of the patients with UC that were enrolled at precedent CS N = 100) are shown in Table 00 are shIn Cohort 1, variations in PGE-MUM and CRP values between the precedent and subsequent CS in the 3 MES subgroups were analysed  with changes in PGE-MUM (ΔPGE-MUM) and CRP (ΔCRP) from the precedent to the subsequent CS were also analysed Fig. . A signi31. This study aimed to examine whether longitudinal changes in PGE-MUM corresponded with changes in endoscopic scores of patients with UC.When examining the utility of a biomarker for UC, it is critical to ensure the following: (1) reflection of endoscopic scores in cross-sectional evaluations; (2) prediction of clinical relapse; and (3) longitudinal variations in the endoscopic score. PGE-MUM has been proven to reflect endoscopic scores and predict clinical relapse in patients with UC27. PGE-MUM has been reported to reflect the endoscopic scores in paediatric patients with UC28. As PGE-MUM is present in urine, it possesses the advantages of hospital sample collection and submission, as well as unlikely detection failure by urinalysis. However, its levels may be elevated in cigarette smokers, patients with chronic lung disorders, and patients with cancer; hence, adequate care should be taken during analysis of such cases37.PGE-MUM, a stable product of the metabolism of prostaglandin E2 (PGE2), is produced by the inflamed colon and is metabolized in the urine. The utility of PGE-MUM as a biomarker for UC was initially reported by Arai et al.41. In our previous cross-sectional study, MES 0, 1 was defined as MH, and receiver operating characteristic analysis of PGE-MUM to predict MH showed that the cut-off value was 30.9 μg/g·Cr and the area under the curve was 0.644 (95% CI 0.523–0.765), with a sensitivity of 48.5% and specificity of 78.0%26. However, most previously reported studies were cross-sectional studies, and only a few longitudinal observational investigations focused on endoscopic exacerbations of MH using MES. Although previous studies have used biomarkers for clinical trials or investigations with a focus on novel drugs, only a handful of analyses on biomarkers reflected endoscopic exacerbations. Endoscopic exacerbation of UC contributes significantly to its prognosis, and secondary treatment is recommended even in clinical remission. Therefore, determining MH by tracking the changes in PGE-MUM during UC treatment may be more beneficial than measuring CRP levels. Although data are not whown in Result section, we analyzed the correlation with the precedent CS data. The correlations of CAI with PGE-MUM and CRP were significant . Although the correlations of MES with PGE-MUM and CRP were also significant, the correlation coefficient was greater for CRP than for PGE-MUM . However, since the biomarker values vary from UC patients to patients, we consider it important that the endoscopic findings and biomarker values fluctuate in parallel as shown in this study. The correlation plots diagram in Fig. In this study, PGE-MUM and CRP values showed significant changes that were parallel to the Cohort 1 of the MES-increase and MES-decrease subgroups. In Cohort 2, PGE-MUM values showed a significant increase and decrease in the Cohort 2 subgroups of remission phase to active phase and active phase to remission phase, respectively. In contrast, CRP values only showed a significant decrease with a decrease in endoscopic score . Therefore, we concluded that PGE-MUM reflects endoscopic scores with greater accuracy than CRP does, especially during exacerbations (increase in endoscopic score). Some studies reported the usefulness of CRP as a biomarker for UC; these studies defined MES 0 or 1 as MH, similar to the findings of our study42. However, biomarkers may better reflect inflammation of the entire colon, which can be measured by S-MES. The S-MES possesses a broad range of scores, displaying variations in the inflammatory status with increased precision. A previous study reported that FC displayed a stronger correlation with S-MES  than with the conventional MES 43. PGE-MUM has also been proven to display a stronger correlation with S-MES than with MES 26.Scoring indices, such as the MES and UC endoscopic index of severity employed in clinical practice only indicate the lesion displaying the most severe inflammationIn this study, PGE-MUM values displayed significant parallel changes in Cohort 3 of the S-MES-increase and S-MES-decrease subgroups from the precedent to the subsequent CS. A significant correlation was also observed between changes in S-MES and changes in PGE-MUM values. In the conventional MES alone, the range was smaller at 0–3; however, in the S-MES, the range was as wide as 0–15. Thus, the S-MES may reflect a more detailed change in the endoscopic score than the conventional MES.27. Subsequent research should focus on comparing the utility of PGE-MUM as a biomarker with FC and histological findings in patients with UC.This study has several limitations. First, the investigation was conducted at a single centre with a limited number of enrolled patients. Second, PGE-MUM and CRP were the only biomarkers considered for comparison with the endoscopic scores of patients with UC. PGE-MUM was found to be superior to CRP in reflecting changes in endoscopic scores; however, FC, which has recently been employed in clinical practice and trials, was not incorporated into this study. In addition, biological data including FIT, leukocyte, platelet count, and serum albumin level was also insufficient. Third, as tissue healing has been regarded as a significant therapeutic goal for patients with UC in recent years, a comparative analysis between PGE-MUM and histological findings should have been done. Arai et al., examined the effectiveness of PGE-MUM as a biomarker by comparing it with histological scores in patients with UCIn conclusion, variations in PGE-MUM values corresponded to changes in the endoscopic score of in patients with UC. In addition, the varying mucosal state of the colon was reflected more accurately by PGE-MUM levels than by CRP levels. Evaluation using PGE-MUM was considered to be a useful reflection of endoscopic exacerbations during the treatment of UC while aiming for MH.This study’s the protocol was reviewed and approved by the Ethics Committee of Hamamatsu University School of Medicine (number 18-228) prior to research commencement. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All enrolled patients provided written informed consent to participate in the study.37. The study participants were those for whom colonoscopy had been performed for routine surveillance or for clinical relapse of UC activity.A total of 60 patients with UC who underwent CS at the Hamamatsu University School of Medicine between April 2015 and October 2020 were enrolled in this study. Out of these, 40 patients were evaluated using three CS records  and the remaining 20 patients were evaluated using two CS records ; there were 100 intervals in total. The patients enrolled were diagnosed with UC based on a typical history, clinical features, and endoscopic and histological findings as per recent guidelines. Patients with IBD who were diagnosed with non-UC ailments, such as indeterminate colitis or unclassified IBD, as well as those with cigarette smoking habits, chronic fibrosing interstitial pneumonia, or malignant tumours were excluded, as these factors may have led to increased PGE-MUM levelsThis prospective observational study aimed to longitudinally investigate whether PGE-MUM values changed with changes in endoscopic scores of patients with UC. The primary endpoint was whether the PGE-MUM value increased or decreased significantly as the endoscopic score increased or decreased during the two measurements over time. The secondary endpoint was whether the PGE-MUM value increased or decreased significantly with the exacerbation or achievement of MH. To evaluate these endpoints, we compared PGE-MUM and CRP values among three cohorts Fig. .Figure 5In Cohort 1, changes in the Mayo endoscopic subscore (MES) at 100 intervals were used for the classification of the three subgroups: increase, no change, and decrease. Changes in PGE-MUM and CRP values were then evaluated for each subgroup. In Cohort 2, an MES of 0 or 1 was suggestive of endoscopic remission. Changes in PGE-MUM and CRP values were evaluated after categorizing MES values into four subgroups: MES 0 or 1 to 2 or 3 (remission phase to active phase); no change in MES 0 or 1 (stable remission phase); MES 2 or 3 to 0 or 1 (active phase to remission phase); and no change in MES 2 or 3 (stable active phase). In Cohort 3, the sum of MES (S-MES), an endoscopic score that reflects the mucosal state of the entire colon, was used for the classification of the three subgroups: S-MES increase, no change, and decrease. Changes in PGE-MUM and CRP values were then evaluated for each subgroup.44. Clinical remission was defined as CAI ≤ 4, and a clinical response represented a decrease of ≥ 4 points relative to the baseline. Values of serum CRP were also used for disease assessment, and were measured on the same day as CS.Disease intensity was evaluated using the clinical activity index (CAI) according to Rachmilewitz31. The MES was employed to assess UC mucosal status and was defined as follows: 0, normal or inactive; 1, mild friability with erythema and decreased vascular pattern; 2, moderate disease with marked erythema, absence of vascular patterns, friability, and erosions; and 3, severe disease with spontaneous haemorrhage and ulceration45. MH was defined as MES of 0 or 1. Endoscopic scores were first evaluated by the physician who performed the colonoscopy, and then by five expert gastroenterologists . Any differences between these experts were resolved by consensus. To assess the entire mucosal state, S-MES was calculated by totalling the MES values of the five segments of the colon 43.CS was performed after bowel preparation was completed using a polyethylene glycol-based electrolyte solution, as previously reported in the literatureSpot urinary samples (≥ 0.8 mL) for the measurement of PGE-MUM were collected on the morning CS was performed. Samples were frozen at − 20 °C and delivered to the SRL Hachioji Laboratory , and the values were obtained with a ɤ-counter (Hitachi) using a bicyclic PGE-MUM radioimmunoassay (RIA) kit . Biomarker levels corrected for urinary creatinine were used to avoid the effect of urine concentration.SPSS version 24.0  and EZR  software were used for all statistical analyses of the data collected. The Wilcoxon signed-rank test was used to assess for significant changes in PGE-MUM and CRP values, and the Spearman’s rank correlation coefficient was used to assess the association between differences in the S-MES, PGE-MUM, and CRP changes in the precedent and the subsequent CS. A P-value of < 0.05 was considered significant.