Naive knees (n = 6) were used as controls. Monocyte and polarized synovial macrophage subsets were evaluated by flow cytometry. CD64 and CD206 levels on IHC were higher at early timepoints in DMM and sham knees compared to naive knees. iNOS labeling intensity was higher in DMM and sham knees than in naive knees from d3 onwards. CD163 expression was unaltered at all timepoints. Even though macrophage polarization profiles were similar in DMM and sham knees, only in DMM knees the presence of iNOS and CD206 associated with synovial thickness, and CD163 staining inversely correlated with osteophyte presence. At day 14, monocyte subset distribution was different in peripheral blood of DMM mice compared with sham mice. In conclusion, monocyte subsets in blood and synovial macrophage phenotypes vary after joint surgery. High levels of iNOS+, CD163+, and CD206+ cells are found in both destabilized and sham‐operated knees, and coexistence with joint instability may be a requirement to initiate and exacerbate OA progression.Macrophages play an important role in the development and progression of osteoarthritis (OA). The aim of this study was to identify macrophage phenotypes in synovium and monocyte subsets in peripheral blood in C57BL/6 mice by destabilizing the medial meniscus (DMM), and the association of macrophage subsets with OA features. DMM, sham, and non‐operated knees were histologically assessed between 1 and 56 days for macrophage polarization states by immunohistochemistry (IHC), cartilage damage, synovial thickening, and osteophytes ( Non‐classical monocytes exhibit patrolling behavior involving adherence to and migration along vascular endothelium, they may promote angiogenesis and tissue repair processes,In addition to synovial tissue‐resident macrophages, infiltrating monocytes may also participate in OA pathogenesis. Most tissue‐resident macrophages have an embryological origin and self‐renew when necessary.Thus, knowledge of macrophage and monocyte subset kinetics in vivo could provide insights important for therapy. Therefore, the aims of this study were to determine how macrophage phenotypes and monocyte subsets vary with time after destabilization of the medial meniscus and to investigate associations between macrophage phenotypes and OA features.22.12/min (Pharmachemie) and received subcutaneous 0.05 mg/kg Temgesic  analgesic 30 min before the procedures. The medial meniscotibial ligament (MMTL) was transected as described by Glasson et al.The animal experiments were carried out with the approval of the Animal Ethical Committee of the Erasmus University Medical Center, approval no. EMC 3246 (114‐14‐01) and in accordance with the ARRIVE Guidelines for reporting animal research.2.2The knees were fixed in a 120° flexed position and processed for histological analysis, as described in additional detail in the supplementary methods. The knees were embedded in paraffin and sectioned serially at 6 µm. For each staining a minimum of six sections per knee with less than 180 µm intervals from anterior to posterior were collected on hydrophilic glass slides . Sections from all knees were stained with 0.04% thionin in 0.01 M aqueous sodium acetate, pH 4.5 (Sigma‐Aldrich) to evaluate glycosaminoglycans in cartilage, structural cartilage damage, synovial thickness, and the presence of osteophytes. Sections of all knees were immunohistochemically stained in one batch to visualize CD64, inducible nitric oxide synthase (iNOS), CD163, and mannose receptor C type 1/CD206 to identify different macrophage phenotypes.2.3Structural cartilage damage was assessed in four quadrants  of four thionin‐stained sections, and evaluated according to a modified Pritzker scoreOf the sections immunohistochemically stained for presence of CD64, iNOS, CD163, and CD206, six to seven sections per knee of the same anatomical regions were ranked based on the increasing intensity in the entire knee. Meaning that all knees including contralateral knees and naive knees, were ranked from least intensely to most intensely stained evaluated by bright field microscopy. Knees that exhibited the same amount of positivity were assigned the median rank of the number of equally ranked knees. This resulted in a maximum score of 111 for CD64, iNOS, and CD163, and 112 for CD206. These numbers varied due sample loss during harvesting, sectioning, or staining. All scorings and rankings were performed in a blinded manner by two independent researchers.2.4g for 10 min, supernatant was removed and the resulting cell pellet was washed twice and resuspended in FACSFlow buffer (BD Biosciences). For flow cytometric analysis of synovial macrophages, the patella with surrounding synovial tissue was removed from each knee joint and subjected to enzymatic digestion (8 mice per group). Tissue was incubated with 2.4 mg/ml Dispase II (Roche), 2 mg/ml collagenase Type IV (Life Technologies) and 0.2 mg/ml DNase I (Sigma‐Aldrich) in Hanksʼ Buffered Salt Solution (Thermo Fisher Scientific) at 37°C for 1 h. Following digestion, the cell suspension was filtered through a 100 µm cell strainer. Cells were spun at 400 g for 5 min, supernatant was removed and the resulting cell pellet washed and resuspended in FACSFlow buffer. Cells were stained according to Table S2 for cell surface expression of CD11b, F4/80, CD86, and CD206 (All BioLegend) to identify synovial macrophages, and a LIVE/DEAD™ Fixable Dead Cell Stain  for exclusion of dead cells. Cells were stained for 30 min on ice in the dark, washed with FACSFlow and spun at 400 g for 5 min. The supernatant was removed and the resulting cell pellet was washed and resuspended in FACSFlow. Samples were analyzed using a FACSJazz cytometer (BD Biosciences), with 20,000 events recorded per sample. Cellular viability of all digested synovial tissue samples ranged from 69.16 ± 7.59%. Date were analyzed using FlowJo software version 10.0.7 (FlowJo LLC). The applied gating strategies for synovial macrophages and blood monocytes are presented in Figures S2 and S3.To obtain longitudinal data regarding the monocyte subsets in peripheral blood, OA was induced by DMM in a second set of mice and the sham procedure was performed in a third set of mice (11–12 mice per group). Peripheral blood was obtained from the facial vein 1, 7, 14, 28, and 56 days after joint surgery. Blood taken 7 days before surgery was considered as baseline. About 50 µl of whole blood was pre‐incubated with purified rat antimouse CD16/CD32  for 5 min on ice, and stained for cell surface expression of CD45, CD11b, CD115, CD62L, and Ly6C  to identify myeloid cells and specific monocyte subsets. Cells were stained with antibodies for 15 min on ice in the dark, and erythrocytes were lysed following incubation with 2 ml of 1× FACS lysing solution (BD Biosciences) for 10 min. Following centrifugation at 400 2.5Calculations for rank analysis were conducted with MS Excel 2016 (Microsoft) and statistical evaluation was conducted with IBM SPSS 23.0 (IBM). Differences in cartilage damage and synovial thickness between naïve knees and DMM‐knees at each timepoint and sham and DMM‐operated knees were evaluated by Kruskall–Wallis tests followed by Bonferroni post hoc tests. Differences in intensity of the macrophage markers CD64, iNOS, CD163, and CD206 were evaluated between naïve knees and DMM‐operated knees by Kruskall–Wallis tests followed by Bonferroni post hoc.The presence of osteophytes was statistically assessed with Fisherʼs exact test followed by Bonferroni correction. Differences in blood monocyte subsets between DMM and sham mice were evaluated per time‐point by Mann–Whitney‐U tests.ρs) were defined as follows: 0.0–0.19: very weak; 0.20–0.39: weak; 0.40–0.59: moderate; 0.60–0.79: strong; 0.80–1.00: very strong.Correlation analysis was conducted to evaluate associations between the Pritzker and OARSI scores for cartilage damage. Also associations between intensities of macrophage markers  in DMM‐knees or percentages of peripheral blood monocyte subsets and features of OA were evaluated. For the correlations, nonparametric Spearmanʼs rho correlation tests were conducted including bootstrap‐based calculations for the 95% confidence interval (95% CI). Bonferroni correction was applied where needed. Correlation strengths based on the correlation coefficients  for the total cartilage damage within the joint . Since the Pritzker score is more sensitive to mild structural changes, this score was used for further analysis.Structural cartilage damage was evaluated with both the Pritzkerp = 0.08). In addition, cartilage damage was significantly increased in the MTP and the MFC of DMM‐knees compared with sham‐operated at day 56 postsurgery .Associations between IHC staining intensity and OA features were evaluated. iNOS staining in the synovial membrane of DMM knees had a strong positive correlation with synovial thickness Table . CD163 s+F4/80+ synovial macrophages were observed in knees of DMM mice and knees of sham‐operated mice  and tissue repair (CD206+/CD11b+F4/80+) macrophages as well as the ratio between both phenotypes, did not significantly differ between DMM and sham‐operated knees .L. Utomo performed the animal experiments, processed samples, analyzed and interpreted the data, and wrote the manuscript. N. Fahy processed samples, analyzed and interpreted the data, and wrote the manuscript. N. Kops and S.T. van Tiel supported in sample processing. P.J.M. Leenen supported in data analysis and interpretation. J.H. Waarsing supported in statistical analysis. J.A.N. Verhaar supported the interpretation of data. G.J.V.M. van Osch designed the study, guided the animal experiments, interpreted the data, and edited the manuscript. Y.M. Bastiaansen Jenniskens conceived and designed the study, interpreted the data, and edited the manuscript. All authors have revised the manuscript for important intellectual content and have approved the submission of the manuscript.Supplementary Figure S1: Examples of Pritzker cartilage damage grading. Examples of 6 grades of cartilage damage on thionin stained sections of mice knees. Assessment criteria are presented in Supplementary Table S1.Click here for additional data file.Supplementary Figure S2: Gating strategy for synovial macrophages.Click here for additional data file.Supplementary Figure S3: Gating strategy for peripheral blood monocyte subsets.Click here for additional data file.Supplementary Figure S4: Cartilage damage after sham‐surgery or DMM‐surgery. Thionin staining of the tibia plateaus of mice various days after surgery. Scale bar: 50 µm.Click here for additional data file.n=52 DMM‐operated knees).Supplementary Figure S5: Correlations between the Prizker and OARSI scoring methods for structural cartilage damage (Click here for additional data file.Supporting information.Click here for additional data file.Supporting information.Click here for additional data file.


CT colonography enables three-dimensional measurement of colon length. However, previous studies using CT colonography have not examined the association with gender, age, physique, a history of laparotomy and bowel habits, all possible contributory factors to colon length. The aim of this study is to investigate factors associated with colon length.We conducted a post hoc analysis based on data obtained from a previous multi-center trial including 321 patients with positive fecal immunochemical tests who underwent CT colonography. Colon length was measured using a computer-generated center line and was divided at the iliac crest level into the distal and proximal colons. Bowel habits were classified into three groups: A—daily; B—once every 2 or 3 days; and C—less than once in 3 days. Statistical comparison was made using one-way ANOVA with Bonferroni’s correction.p = 0.022). Colon length showed trends associated with age (p = 0.18) and a history of laparotomy (p = 0.14). According to bowel habits, the entire colon measured 147.4 ± 17.9 in group A, 154.7 ± 18.5 in group B and 158.6 ± 18.3 in group C, and significant differences were observed for “A vs. C” (p = 0.002) and “A vs. B” (p = 0.014). In subgroup analysis by colon segment, the proximal colon trended similarly to the entire colon while there were no trends for the distal colon.A total of 295 patients were analyzed. The entire colon length  of individual patients was 150.3 ± 18.5 cm and ranged from 109.7 to 195.9 cm. The female colon was significantly longer than the male colon  patients have a significantly longer colon, and in particular, the proximal colon. Colon length showed trends associated with age and a history of laparotomy.The online version contains supplementary material available at 10.1007/s11604-021-01204-7. Constipation is one of the most common chronic gastrointestinal conditions, which reportedly affects 14–17% of the population , more frn=37) than in controls (n=20), but the difference was not significant probably due to insufficient statistical power of the study.Since the nineteenth century, there have been many studies of the anatomy of the large intestine at autopsy –10. ThesWith the recent emergence of computed tomography (CT) colonography, three-dimensional measurement of colon length is feasible. This means that physicians can easily obtain information on the actual colon length of live patients. So far, several researchers have measured colon length using CT colonography to identify the cause of incomplete colonoscopy , colon lThis study adopted a post hoc design, using data obtained from a previous multi-center trial  including 321 patients with positive fecal immunochemical tests (FIT) who underwent CT colonography , which wPatients were eligible for inclusion into the study if they were 40 years of age or older and were seen at participating institutions to undergo colonoscopy for colorectal cancer examination because of a recent positive FIT result. Patients were excluded for any of the following reasons: serious comorbidity; a history of colon screening tests in the preceding 3 years; known colorectal neoplasms; a history of inflammatory bowel disease, Lynch syndrome, familial polyposis, or colorectal surgery; pregnancy, hyperthyroidism, or iodinated contrast medium allergy. Eligible consecutive patients were prospectively enrolled in the study between December 2011 and September 2012.Prior to enrollment, information on bowel habits was obtained through an interview by nursing staff. Bowel habits were classified into three categories according to the frequency of bowel movements: daily group, every day; intermediate group, once every 2 or 3 days; and constipated group, less than once in 3 days. Patients’ information on age, gender, height, weight, body mass index (BMI) and history of laparotomy were also obtained. Patients status-post gastrointestinal or uterus resection were classified as major, and those without such resections  were classified as minor laparotomies.Preparation started 1 day before CT colonography, and, patients received 380 mL polyethylene glycol solution , 20 mL iodinated oral contrast agent for fecal tagging, and two doses of 20 mg mosapride  the day before CT colonography after breakfast and dinner. On the examination day, patients were placed in the left decubitus position for thin flexible rectal-tube insertion with a balloon. The colon was insufflated using an automated carbon dioxide insufflator prototype  and insufflation pressure was set to 20 mmHg. The total volume of carbon dioxide insufflated was recorded. All CT colonography examinations at all institutions were performed using 16- or 64-row multi-detector CT scanner, with supine and prone positioning. The scanning protocol was as follows: 120 kVp, automatic tube current modulation system or a tube current of 50 mA, and a section thickness ≤ 1.0-mm. Spasmolytic agents and intravenous contrast media were not used during CT colonography .All CT colonography images were analyzed by an experienced radiologist who had over 10 years of abdominal diagnostic radiology experience. As part of image processing, the workstation automatically creates a centerline for 3D fly-through image review. We recorded the distance of the centerline from the anus to the cecal tip. All interpretations were performed using a commercially available workstation . Colon length was measured in two positions: the supine position and the prone position, and the average of the two measurements was defined as the colon length of each subject. The entire colon length was the distance from the anus to the cecal tip, and the colon was divided into two parts . The boundary between the descending colon and sigmoid colon was at the height of the iliac crest.The primary outcome is the mean entire colon length of the two measurements in the supine and prone positions, by age group , gender, body mass index , history of laparotomy  and bowel habits . Secondary outcomes are proximal colon length and distal colon length, using the same factors mentioned above.χ2 test or Fisher exact test if appropriate. The threshold for significance was p < 0.05. All statistical analyses were performed with Intercooled Stata 16.0™ for Windows (Stata Corp. USA).The skewness and kurtosis test was used to test for a normal distribution of colon length. If normal distribution is confirmed, colon length is expressed as mean ± standard deviation (SD) and compared using one-way ANOVA with Bonferroni’s correction for multiple comparisons. Otherwise, colon length is expressed as median [interquartile range] and compared using nonparametric tests. A multivariate linear regression model was applied to analyze factors correlating with colon length. Categorical variables were presented as percentages and numbers and were compared by the p < 0.001; “daily” vs. “constipated”: p < 0.001). Patients with “daily” bowel habits had a trend toward higher weight  and significantly greater height compared to other bowel habit patterns .After excluding patients with poor bowel preparation, insufficient insufflation of the colorectum during CT colonography acquisition, or with a history of bowel resection and advanced cancer (stage T2: proper muscle layer or beyond), 295 patients  were enrolled . The entire colon length (mean ± SD) of individual patients was 150.3 ± 18.5 cm and ranged from 109.7 to 195.9 cm. The entire colon of the “80 years or older” age group had a trend toward being longer, but significant differences were not observed in any comparisons . In contrast, the female colon is significantly longer than the male colon , but not significantly different from the intermediate group (p = 0.877). The colon in the intermediate group was significantly longer than in the daily group (p = 0.014). Examples according to bowel habits are shown in Fig. The length of the entire colon had a normal distribution . The proximal colon in the constipated group was significantly longer than in the daily group (p = 0.001). The proximal colon of patients undergoing major surgery had a trend toward being longer but only comparison between major and minor previous laparotomies approached a statistically significant difference (p = 0.051).In subgroup analysis by segment of colon (shown in Table p = 0.022). The female entire colon in the constipated group was significantly longer than in the daily group (p = 0.026), but there was no significant difference between the constipated group and intermediate group (p = 0.93) and between the intermediate group and daily group (p = 0.25). In contrast, significant differences were not observed in any comparisons in male colon (p = 0.26).In subgroup analysis by gender Table , female p = 0.002) and bowel habits (p = 0.003). Age approached statistical significance (p = 0.053). In analyses of the length of the proximal colon, similar trends were observed, and age was significantly different (p = 0.017). Height was significant in univariate analysis (shown in Supplementary Table 3), but not in multivariate analysis. For distal colon length, only bowel habits were significantly different in univariate analysis (shown in Supplementary Table 3) but not in multivariate analysis.In multivariate linear regression analyses of the length of the entire colon, significant differences were observed for gender (n = 51) utilizing CT colonography reported that patients with functional constipation had a significantly longer colon compared with diarrhea type IBS or control patients [This study using CT colonography shows that females and constipated (less frequent defecation) patients have a significantly longer colon, and that these trends also are shown in analyses limited to the length of the proximal colon. However, colon length is not associated with physique, regardless of gender. These observations are confirmed by two different statistical methods. To our knowledge, this is the first study to show that bowel habits (defecation frequency) clearly correlate with colon length in a cohort study. A previous case–control study  [n = 920) [Notably, the present study has clearly demonstrated that the female colon is longer than the male colon, consistent with two previous relatively large-scale cohort studies; one study applied CT colonography to asymptomatic American patients (n = 505)  and anotn = 920) . Sex horn = 920) . During n = 920) . In addin = 920) . In the n = 650) was significantly longer than in Japanese (n = 650) but the difference was very small [Measurement methods other than CT colonography have individual drawbacks in nature, as mentioned above in the introduction. At present, CT colonography is the most reliable method to measure actual colon length. However, previous studies using CT colonography showed various values for the length of the entire colon, as summarized in Table ry small , which sry small  as well This study has several acknowledged limitations. First, this is a post hoc analysis using data obtained from a previous multi-center trial, and the sample size was not calculated. Second, all patients were Japanese manifesting positive FIT, and the generalizability of these findings may be limited. Third, we did not apply the Rome IV criteria to assess bowel habits but asked about defecation frequency alone. Accordingly, patients with functional constipation may be classified into a non-constipated group. Fourth, colon length was measured by one author (KU). This could result in a lack of objective analysis because colon length was manually estimated in case of failure of the automatic process.In conclusion, this study has clearly demonstrated that bowel habits (defecation frequency) and gender both correlate with the length of the entire colon measured by CT colonography, and in particular, the proximal colon. Proximal colon length might be a new surrogate biomarker to objectively diagnose slow transit constipation.Supplementary file1 (DOCX 25 kb)Below is the link to the electronic supplementary material.


Left atrial volume (LAV) and low voltage areas (LVAs) are acknowledged markers for worse rhythm outcome after ablation of atrial fibrillation (AF). Some studies reported the importance of increased right atrial volume (RAV) as a predictor for arrhythmia recurrences in AF patients.To investigate association between the LAV/RAV ratio and LVAs presence.Patients undergoing first AF ablation were included. LVAs were assessed peri‐procedurally using high‐density 3D maps and defined as <0.5 mV. All patients underwent pre‐procedural cardiovascular magnetic resonance imaging. LAV (biplane) and RAV (monoplane 4‐chamber) were assessed prior to ablation, and the LAV/RAV ratio was calculated.p = .016). The association remained robust in multivariable model after adjustment for persistent AF, CHA2DS2‐VASc score, and heart rate . Using receiver operator curve analysis, LAV > RAV  was significant predictor for LVAs. In multivariable analysis, after adjustment for age, persistent AF, and renal function, RAV≥LAV was threefold higher in males .The study population included 189 patients . There were 149 (79%) patients with LAV > RAV. In univariable analysis LAV > RAV was associated with LVAs (OR 6.803, 95%CI 1.395–26.514, LAV > RAV is useful for the prediction of electro‐anatomical substrate in AF. LAV > RAV was associated with LVAs presence, while male sex remained associated with RAV≥LAV and less LVAs. The role of the LA volume (LAV) and LA function as surrogate parameters for higher AF burden2The study population was described previously.2.1Prior to AF catheter ablation, all patients underwent 1.5 T CMR  for LA anatomy assessment as previously described.2.2Transseptal access and catheter navigation were performed with a steerable sheath . The electro‐anatomical mapping was performed in sinus rhythm as described previously.Multielectrode spiral mapping catheters  were used to generate electro‐anatomical voltage maps of the LA. The cutoff value for LVAs was defined as bipolar signal amplitude <0.5 mV. Ectopic beats were excluded from the voltage map. The number of points obtained was >1000. In case of AF recurrence during electro‐anatomical mapping, only anatomical map was assessed. Then the electro‐anatomical mapping was completed in sinus rhythm after PVI, and if still needed, after further cardioversion.All patients received circumferential ablation lines around the antrum of the ipsilateral pulmonary veins. The ablation catheters (irrigated tip catheter and power of 25–40 W) used in NavX Ensite procedures were TactiCath  and for Carto3 procedures SmartTouch Thermocool . End point of catheter ablation was PV isolation, which was verified with a multipolar circular mapping catheter. Additional linear lesions were added between if LVAs were present in this area. To be considered as relevant the LVAs ought to consist of adjacent low‐amplitude mapping points, bearing certain additional characteristics such as fragmentation and duration. Finally, the relevance of the LVAs was evaluated by experienced operators based on the mapping point qualities as well as induction of extra‐PV macro‐reentry tachycardia, in which case additional linear ablation was performed. Patients with small/negligible LVAs dispersely distributed in LA and not suitable for ablation, who received the PVI only without additional ablation lines, were excluded.2.3t‐test or the Mann–Whitney, and a χ2 test for categorical variables.Data are presented as mean and standard deviation for normally distributed or median  for skewed continuous variables, and as proportions for categorical variables. The differences between continuous values were assessed using an unpaired Model 1 – unadjusted analysis; Model 2 – adjusted for age and sex; and Model 3 – adjusted for persistent AF, heart rate, and CHA2DS2‐VASc score.Logistic regression analysis was used to identify factors associated with LVAs. We performed three analyses using logistic regression of LVAs presence .Receiver operating characteristic curves (ROC) were generated to analyze performance of the LAV/RAV ratio predicting LVAs, with the area under the curve (AUC) being equivalent to the c‐index for determining the predictive value for the parameters. Finally, we compared the c‐indices  of LAV > RAV and LAV using DeLong's method.33.1The study population included 189 patients  undergoing their first AF catheter ablation. Clinical characteristics of the study population are summarized in Table 3.2p = .016). In multivariable analysis, after adjustment for CHA2DS2‐VASc score, persistent AF, and heart rate, LAV > RAV remained significantly associated with LVAs  (Table p = .001)  using DeLong's method, the difference between ROC curves was not significant (p = .353).In univariable analysis logistic regression, LAV > RAV was associated with sixxfold risk of LVAs presence , male sex , and renal function measured as glomerular filtration rate .In univariable analysis, RAV ≥ LAV was associated with younger age  is an acknowledged marker of advanced electro‐anatomical remodeling.The present findings add to our knowledge about the importance of side‐specific atrial remodeling. As previously described, LA remodeling is associated with later stages of AF progression resulting from risk factors like aging, hypertension, left ventricular (LV) diastolic dysfunction and an altered electromechanical activation.In contrast, pathophysiology of RA remodeling seems to be different. In patients without heart failure, volume and pressure overload in the RA is mainly associated with pulmonary resistance, valvular disease, and RV dysfunction.4.3Our findings show a strong association between LVAs and LAV/RAV ratio. Despite previous data reporting a correlation between RAV ≥ LAV and AF recurrences, our results imply that increased RAV is not a suitable parameter for LVAs prediction and therefore not a marker for left atrial myopathy. This is in line with our previous studies that emphasized the importance of LV diastolic dysfunction, electro‐anatomical dysfunction for asymmetric LA remodeling, and ablation outcomes.4.4Several limitations could impact interpretation of our results. First, the study is relatively small and included only 33% women. Therefore, statistical analysis for females is very likely underpowered. Similarly, we cannot exclude that male sex is a possible effect modifier analyzing an impact of sex for RAV ≥ LAV. Of note, the study included only patients of European ancestry from a localized area in Eastern Germany, limiting transferability of the results to other ethnic populations. Furthermore, although LVAs are one of parameters describing atrial myopathy, other parameters such as extrapulmonary substrate and triggers or typical atrial flutter, impairing AF ablation outcome, were not assessed. We did not consider arrhythmia recurrences as an outcome after AF catheter ablation due to several issues: (1) In our opinion LVAs are more robust outcome than arrhythmia recurrences, which occur within weeks/months after catheter ablation, while LVAs are measurable during the procedure; (2) Arrhythmia recurrences depend on many factors such as ablator experience, follow‐up strategy including antiarrhythmic drug prescription, follow‐up frequency, ECG monitoring; (3) In our study, patients did not have a continuous rhythm monitoring. Finally, specific LA fibrosis assessment using late gadolinium enhancement was not conducted in current study and should be addressed in future studies.5LAV/RAV ratio is useful parameter predicting electro‐anatomical substrate in AF. LAV > RAV was associated with sixfold risk for LVAs presence, while male sex was associated with RAV ≥ LAV and less LVAs.Philipp Sommer is in the advisory board for Abbott, Biosense Webster, Medtronic, und Boston Scientific.


To compare drug survival of ixekizumab to other IL‐17 inhibitors (IL‐17i) and TNF inhibitors (TNFi) among patients with psoriasis (PsO) in a real‐world setting. Participants included adult PsO patients enrolled in the Corrona Psoriasis Registry who initiated ixekizumab, TNFi, or other IL‐17i between 16 March 2016 to 10 August 2019 and completed ≥1 follow‐up visit. Multivariable adjusted hazard ratios (HR) were calculated to estimate the risk for drug discontinuation in the ixekizumab group relative to the other drugs. Among the 1604 drug initiations, 552 initiated ixekizumab, 450 initiated TNFi, and 602 initiated other IL‐17i. Mean age was 51 years, 49% were women, and 52% were obese (BMI > 30). Ixekizumab patients had a higher proportion of patients with PASI >12 at drug initiation (24%) than TNFi (15%) and other IL‐17i (19%). Over a median of 11 months of follow‐up, 723/1604 (45%) drug discontinuations occurred. Persistence of ixekizumab, TNFi, and other IL‐17i at 24‐months were 68%, 33%, and 46%, among biologic‐naïve patients (n = 543), and 46%, 23%, and 36%, for biologic‐experienced patients (n = 1061), respectively. Ixekizumab patients had a 64% lower risk of discontinuation vs TNFi  and a 31% lower risk vs other IL‐17i  after adjustment for biologic experience and other covariates. HRs were similar when limited to patients with moderate‐to‐severe PsO  at initiation. In our study of real‐world patients with PsO, initiators of ixekizumab had more prolonged drug survival than both initiators of TNFi and other IL‐17i up to 2 years of follow‐up. In rheumatology, ixekizumab has been approved for active psoriatic arthritis, ankylosing spondylitis, and nonradiographic axial spondyloarthritis (nr‐axSpA).When investigating select categories of adverse events (AEs) , inflammatory bowel disease (IBD) , and serious hypersensitivity events among all patients exposed to ixekizumab in the Corrona PsO Registry, Grace et alCurrently, there are few studies comparing the drug survival for ixekizumab to that of other biologic therapies in real‐world patients with PsO. Two recent claims‐based studies of US patients demonstrated greater drug survival for ixekizumab vs adalimumabThe objective of the current study was to compare drug survival of ixekizumab to that of TNF inhibitors (TNFi) and non‐ixekizumab IL‐17 inhibitors (IL‐17i) among real‐world patients with PsO in the Corrona Psoriasis Registry.22.1This analysis used data from the Corrona Psoriasis Registry, a prospective, multicenter observational disease‐based registry launched in April 2015 in collaboration with the National Psoriasis Foundation, the design of which has been previously described.2.2The study population included 1604 patient drug initiations  that occurred between 22 March 2016  and 10 August 2019 . Initiations were required to occur at or after registry enrollment, initiators had at least one subsequent follow‐up (FU) visit, and an available index visit (defined as the visit coinciding with or within 4 months before initiation) at which baseline characteristics were assessed.2.3The primary outcome was drug survival, defined as persistent use of drug during follow‐up, allowing for a medication gap of ≤60 days. Drug survival time was defined from the date of drug initiation through the date of drug discontinuation. Patients persistent on drug at their last follow‐up visit were censored on the date of their last follow‐up visit.2.4Baseline characteristics included: sociodemographics ; PsO disease characteristics ; disease severity , body surface area (BSA), Investigator Global Assessment (IGA); prior systemic therapy (biologic and nonbiologic); concomitant PsO treatment ; and patient‐reported outcomes (PROs) .2.5Z score of a standard normal distribution and a threshold greater than 0.1 was the criteria used to represent a relevant imbalance between groups. Additionally, thresholds of 0.2, 0.5, and 0.8 are often used to indicate small, medium, and large effect sizes.d) > 0.10. Selection of variables was based upon examination of collinearity between candidate variables , to avoid multicollinearity in Model 2. The additional covariates selected for adjustment in Model 2 were race, education, work status, geographic region, smoking history, history of Crohn's disease, ulcerative colitis, indeterminate IBD, and other gastrointestinal (GI) disorders, history of infections, erythrodermic morphology, inverse/intertriginous morphology, nail morphology, IGA, PASI, concomitant topical therapy, patient‐reported overall itch/pruritis, and patient‐reported health state today (EQ‐VAS).Baseline characteristics were summarized descriptively for the treatment groups . Pairwise standardized differences were used to assess differences in characteristics between the treatment groups. A standardized difference effect size is equivalent to a Sensitivity analyses were conducted for the subset of initiations with moderate‐to‐severe disease activity at baseline . The proportional hazards assumption was evaluated for the models by examining Schoenfeld residuals3There were 1604 initiations among 1412 unique patients that met the inclusion criteria for analysis of drug survival . Duration of PsO was comparable between initiators of ixekizumab and non‐ixekizumab IL‐17i , while duration of disease for initiators of TNFi was shorter . Comorbid psoriatic arthritis was reported by dermatologists for 47% of initiators of ixekizumab, which was slightly lower than that reported for initiators of TNFi (51%), and non‐ixekizumab IL‐17i (54%). Compared with TNFi and non‐ixekizumab IL‐17i initiators, ixekizumab initiators had a higher proportion of patients with PASI >12  and severe IGA   , but not for patient global assessment of PsO . When evaluating WPAI domains, TNFi initiators had a higher mean overall percent of work hours affected by psoriasis (18.9 vs16.1) compared with ixekizumab initiators, although the effect size was small (d = 0.12). Ixekizumab initiators reported lower mean patient‐reported overall fatigue (VAS range 0‐100)  and more ixekizumab initiators (53%) had taken ≥2 previous biologics than patients on TNFi (17%) and non‐ixekizumab IL‐17i (40%).Table There were 723 drug discontinuations among all patient initiations. The median follow‐up time for those persistent at their last Corrona visit was 11 months , and for all initiations, including those resulting in discontinuation, was 8 months . Among biologic‐naïve patients, ixekizumab showed a drug survival trajectory that started diverging versus the non‐ixekizumab IL‐17i after the first 6 months of treatment, at which point ixekizumab began to demonstrate increased persistency out to 24 months Figure , though P < .001), and a 34% lower relative risk of discontinuation in comparison to the non‐ixekizumab IL‐17i group . Hazard ratios were like the observed data after adjustment in multivariable models. The adjusted hazard ratio from Model 2 for the ixekizumab group in comparison to the TNFi group was 0.36 , and for the ixekizumab group in comparison to other non‐ixekizumab IL‐17i group was 0.69   Table  and S2.P < .001), and for the ixekizumab group in comparison to the non‐ixekizumab IL‐17i group was 0.69 .In sensitivity analyses, estimates of drug survival and hazard ratios were similar within the subgroup of patients with moderate‐to‐severe disease activity at baseline Tables  and 4. A4Among patients with PsO in a large North American registry, ixekizumab demonstrated higher drug survival compared with TNFi and non‐ixekizumab IL‐17i therapies. Patterns of drug survival by drug group over 24‐months of follow‐up were similar in both biologic‐naïve and biologic‐experienced patients. Although ixekizumab initiators compared with TNFi and non‐ixekizumab IL‐17 initiators were more likely biologic‐experienced, obese, had a higher prevalence of nail morphology, worked full‐time, and had more severe disease, drug survival differences favorable to ixekizumab initiators remained even after adjusting for potential confounders. These factors, in particular previous biologic experience, often have a negative impact on drug survival. However, in our study, ixekizumab still showed better drug survival.Drug survival of TNFi such as adalimumabBecause line of therapy influences drug survival, analyses were stratified by biologic‐naïve and biologic‐experienced patients. In the current study, 66% (n = 1061) occurred among biologic‐naïve patients, and 34% (n = 543) of initiations occurred among biologic‐experienced patients. Although TNFi are still largely adopted as a first line biologic, among our biologic‐naïve patients, the TNFi group had the lowest drug survival, with 46% and 33% at 12 and 24 months, respectively. As expected, drug survival was worse among biologic‐experienced patients compared with biologic‐naïve patients, yet in both cohorts, ixekizumab had better survival than TNFi and non‐ixekizumab IL‐17i. Our 12‐month drug‐survival rates among biologic‐experienced patients of 65% for ixekizumab vs 34% for TNFi, and 54% for non‐ixekizumab IL‐17i initiators, are comparable to those recently reported for adalimumab The results from the current study, which found ixekizumab initiators experienced longer drug survival compared with TNFi and non‐ixekizumab IL‐17 initiators, are also consistent with studies that have investigated drug survival of ixekizumab in a real‐world setting. A small, retrospective, clinic‐based study conducted between 22 March 2016,  and 25 November 2018, found that 14 of 22 patients (64%) were still taking ixekizumab at the end of the study period and had been taking it for an average of 379 days.Despite the efficacy and safety profile described for the newer generation of biologics in the treatment of psoriatic diseases, Murage et alOur study is not without limitations. The data source is a North American Registry, and the results may not be generalizable to other regions. The data are subject to limitations inherent in all observational studies, such as the lack of randomization to patients for different biologics and the unknown patient factors that may be associated with access to care. Estimation of drug survival between treatments should also be cautiously interpreted when using nonrandomized data. Nevertheless, our study has important strengths. Data for the current study were collected across the United States and Canada from both academic and private practice dermatologists, and these patients are more likely to reflect the typical real‐world patient population than those in clinical trials. The duration and 2‐year follow up of the current study were reasonable and clinically meaningful. We were able to adjust for several potential confounders, including baseline disease severity, clinical outcomes, and treatment patterns, which are not captured in claims databases.5The current study from a large cohort of North American PsO patients demonstrates that over 2 years ixekizumab has a better drug survival compared with TNFi and non‐ixekizumab IL‐17i. The findings were consistent in both biologic‐naïve and biologic‐experienced patients. The current study data offer valuable evidence regarding drug performance and real‐life differences, which may be taken into clinicians' consideration when choosing between biologics.Benjamin Lockshin, Grant/Research Support: AbbVie, Regeneron, Lilly, Franklin, DermTech, Trevi, Dermira, Celgene, Novartis, LEO, Strata; Consultant: AbbVie, DermTech; Speakers Bureau: AbbVie, Lilly, Novartis, Regeneron, Sanofi; Angel Cronin, Employee of Corrona LLC; Ryan W. Harrison, Employee of Corrona LLC; Robert R. McLean, Employee of Corrona LLC; Laura Anatale‐Tardiff, Employee of Corrona LLC; Russel Burge, Employee/Stock, Eli Lilly and Company; Baojin Zhu, Employee/Stock, Eli Lilly and Company; William N. Malatestinic, Employee/Stock, Eli Lilly and Company; Bilal Atiya, Employee/Stock, Eli Lilly and Company; Mwangi J. Murage, Employee/Stock, Eli Lilly and Company; Gaia Gallo, Employee/Stock, Eli Lilly and Company; Bruce Strober, Investigator: AbbVie, Dermavant, Corrona, Dermira; Speaker for AbbVie, Lilly, Janssen, Ortho Dermatologics; Consultant (Honoraria): AbbVie, Almirall, Amgen, Arena, Aristea Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Dermavant, Dermira, Janssen, LEO Pharma, Eli Lilly, Kyowa Hakko Kirin, Meiji Seika Pharma, Novartis, Pfizer, GlaxoSmithKline, UCB, Sun Pharma, Ortho Dermatologics, Regeneron, Sanofi‐Genzyme; Scientific Director (consulting fee): Corrona Psoriasis Registry; Abby Van Voorhees, Advisory Board: Celgene; Consultant: Celgene, DermTech, Lilly, ICOS, Novartis, UCB, WebMD; Grants/Research Support: AbbVie, Celgene, Lilly, ICOS; Other: Merck.TABLE S1 Adjusted model 1 (prespecified covariates): hazard ratios from multivariable Cox proportional hazards regressionTABLE S2 Adjusted model 2 (prespecified covariates plus consideration of characteristics with standardized differences >0.10): hazard ratios from multivariable Cox proportional hazards regressionClick here for additional data file.


Although the burden of influenza is well characterized, the burden of community‐onset non‐influenza respiratory viruses has not been systematically assessed. Understanding the severity and seasonality of non‐influenza viruses, including human coronaviruses, will provide a better understanding of the overall disease burden from respiratory viruses that could better inform resource utilization for hospitals and highlight the value of preventative strategies, including vaccines.From October 2017 to September 2019, a retrospective study was performed in a pre‐defined catchment area to estimate the population‐based incidence of community‐onset respiratory viruses associated with hospitalization. Included patients were ≥18 years old, resided in New York City, were hospitalized for ≥24 hours, and had a respiratory virus detected within 3 calendar‐days of admission. Disease burden was measured by hospital length of stay (LOS), intensive care unit (ICU) admissions, and in‐hospital mortality and compared among those with laboratory‐confirmed influenza versus those with laboratory‐confirmed non‐influenza viruses .During the study period, 4232 eligible patients were identified of whom 50.9% were ≥65 years of age. For each virus, the population‐based incidence was highest for those ≥80 years of age. When compared to those with influenza viruses detected, those with non‐influenza respiratory viruses detected (combined) had higher population‐based incidence, significantly more ICU admissions, and higher in‐house mortality.The burden of non‐influenza respiratory viruses for hospitalized adults is substantial. Prevention and treatment strategies are needed for non‐influenza respiratory viruses, particularly for older adults. Previous approaches have utilized weekly laboratory surveillance and syndromic surveillance associated with discharge data in statistical models to estimate rates of hospitalization and mortality associated with respiratory viruses.22.1From October 2017 to September 2019, a retrospective study was performed to identify hospitalized adults who had respiratory viruses detected from nasopharyngeal swab specimens using a multiplex polymerase chain reaction (mPCR) assay (described below). Study sites are located in Northern Manhattan, are part of the same academically affiliated hospital system, and include three hospitals: a ~750‐bed tertiary care hospital caring for adults, a ~200‐bed community hospital caring for adults, and a ~250‐bed children's hospital.To estimate the population‐based incidence of community‐onset respiratory viruses associated with hospitalization, eligible patients were 18 years of age and older, resided in New York City, as defined by the zip code of their residence, were hospitalized for at least 24 hours, and had a respiratory virus detected within 3 calendar‐days of admission. Patients were identified from the electronic health record (EHR). The Columbia University Irving Medical Center institutional review board approved this study with a waiver of informed consent.2.2As part of the standard of care, patients with ARI symptoms who are being admitted are tested for respiratory viruses to inform appropriate transmission precautions and antiviral therapy for influenza. The study sites use the FilmArray Respiratory Panel  which detects influenza , PIV types 1‐4, RSV, hMPV, AV, rhinovirus/enterovirus (RV/EV), and human coronaviruses .2.3Two one‐year periods, October 2017 to September 2018 (year 1) and October 2018 to September 2019 (year 2), were studied to assess seasonal differences in population‐based incidence and clinical burden for the respiratory viruses detected. To calculate population‐based incidence per 100 000 persons for each virus, the number of adults with a laboratory‐confirmed respiratory virus was divided by the adjusted 2010 US Census population estimate for the catchment area. Population‐based incidence and 95% confidence intervals were calculated overall and for four age strata: 18‐49, 50‐64, 65‐79, and ≥80 years of age.To assess the clinical burden of specific viruses, the following outcomes associated with each virus were determined: the median hospital LOS, the proportion of patients who had an ICU admission, the ICU LOS, and in‐hospital all‐cause mortality. Time spent in the emergency department prior to being admitted to an inpatient unit was included in LOS calculations. If more than one virus was detected in a single specimen, each virus contributed to the respective median LOS, ICU admission and ICU LOS, and in‐hospital mortality, which was determined from recorded death notes in the EHR. Two sample tests of proportions were used to compare outcomes  between each virus and all others . Median hospital LOS and median ICU LOS were compared using the Mann‐Whitney test for each virus vs. all others.The population‐based incidence and clinical burden of influenza viruses  were compared with those of non‐influenza viruses  using the two‐sample test of proportions. RV/EV were excluded from the comparative analyses of the burden of influenza vs. non‐influenza viruses. Patients with co‐detections of influenza and non‐influenza viruses were excluded from these comparative analyses.33.1During the study period, 4232 adults were hospitalized with a laboratory‐confirmed respiratory virus and met the community‐onset case definition. Testing for a respiratory virus occurred on hospital day 1 for 90.7% of patients, on hospital day 2 for 5.0% of patients, and on hospital day 3 for 2.0% of patients, and 2.3% of patients had testing performed in ambulatory settings affiliated with the hospitals.Selected demographic characteristics and the distribution of the zip codes of patients are shown in Table 3.2The proportion of patients who had specific viruses detected is shown in Table Overall, co‐detection of two or more respiratory viruses occurred in 251 patients. In year 1, 116 (5.7%) of 2043 patients had co‐detection and RV/EV was detected in 46 (39.7%) of these 116 co‐detections. In year 2, 135 (6.2%) of 2189 patients had co‐detections and RV/EV was detected in 72 (53.3%) of these 135 co‐detections. Among the 251 total co‐detections, an Influenza virus and a non‐influenza virus were detected in 67 (26.7%).3.3The population‐based incidence for each virus overall and by age strata for year 1 and year 2 is shown in Figure Incidence increased with age for all viruses for both years and those ≥80 years of age consistently had the highest incidence. The highest population‐based incidence in those ≥80 years of age for specific viruses was 660 hospitalizations per 100,000 persons for influenza A H3 in year 1 and 535 hospitalizations per 100 000 persons for the four combined human coronaviruses in year 2. Following RV/EV, the combined CoV types had the highest incidence estimates in both years among patients 18‐49 and 50‐64 years of age.P < .001). Similarly, in year 2, the combined population‐based incidence of influenza viruses was significantly lower than that of these non‐influenza respiratory viruses .In year 1, the combined population‐based incidence of all influenza viruses  for all age strata was significantly lower than the combined population‐based incidence of the non‐influenza respiratory viruses including CoV types, RSV, PIV types, hMPV, and AV  and AV (P = .02) were each associated with a significantly larger proportion of ICU admissions and AV was associated with the longest ICU LOS (P = .03). Of the 225 ICU admissions associated with RV/EV, 19 (8.4%) had another virus co‐detected. Four percent of patients died during hospitalization. RV/EV was associated with 31.8% of deaths, and CoV229E was associated with the highest mortality rate . The median LOS among those who died was 9.7 days  and was longest for AV .The median LOS, the proportion of subjects admitted to an ICU, the ICU LOS, and in‐hospital mortality for each virus are shown in Table P = .002). Compared to patients with influenza, a significantly higher proportion of patients with the non‐influenza respiratory viruses died .Those with RV/EV  and those with influenza/non‐influenza co‐detection (n = 67 patients) were excluded from the analysis comparing the burden of influenza viruses (784 patients) with that of the non‐influenza viruses (1714 patients). Compared to patients with influenza, a significantly higher proportion of patients with the non‐influenza viruses CoV, RSV, PIV, hMPV, and AV were admitted to the ICU  had the highest rates of ICU admission and highest mortality rate. Among all the viruses studied, the combined CoV types had the highest incidence estimates for patients aged 18‐49 and 50‐64 years for both years. We found similar seasonality among the human coronavirus types as has been reported by the Centers for Disease Control and Prevention (CDC) and National Respiratory and Enteric Virus Surveillance System (NREVSS).This study has limitations. It was performed at a university‐affiliated tertiary care referral center in New York City, which limits generalizability. We did not consider the impact of influenza vaccinations on hospitalization rate. Viral detections may not have represented acute infection as mPCR does not distinguish between viable and non‐viable virus. Case detection may have been decreased if not all patients were tested for respiratory viruses, particularly outside influenza season. However, the study period aligns with a prospective surveillance study of RSV in hospitalized adults conducted in the same facilities in which we found that nearly all hospitalized patients meeting ARI criteria during the respiratory viral season, October to April, were tested by treating clinicians.In conclusion, the burden of non‐influenza respiratory viruses is substantial, particularly for older adults who lack durable immunity for respiratory viruses and frequently have comorbid conditions that increase their risk of severe disease. Thus, prevention and treatment strategies for non‐influenza respiratory viruses, including effective vaccines, are needed. Future research should further assess the clinical impact of specific human coronaviruses and the potential impact of specific coronavirus types on the epidemiology and impact of SARS‐CoV‐2.M. P. and L. F. Finelli are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and LS has received research funding from Merck & Co., Inc and served on an Advisory Board for Merck & Co., IncWilliam D. Sieling: Conceptualization ; data curation (lead); formal analysis (lead); investigation (lead); methodology ; software (lead); writing–original draft (lead); writing–review and editing . Connor R. Goldman: Conceptualization (supporting); data curation (supporting); formal analysis (supporting); investigation (supporting); methodology (supporting); project administration (supporting); validation (supporting); writing–original draft (supporting); writing–review and editing (supporting). Matthew Oberhardt: Conceptualization (supporting); data curation ; formal analysis ; writing–review and editing (supporting). Matthew Phillips: Conceptualization (supporting); methodology ; project administration ; writing–review and editing . Lynn Finelli: Conceptualization ; data curation ; formal analysis ; funding acquisition ; investigation ; methodology ; project administration ; writing–review and editing . Lisa Saiman: Conceptualization (lead); data curation (lead); formal analysis (lead); funding acquisition (lead); investigation (lead); methodology (lead); writing–review and editing (lead).https://publons.com/publon/10.1111/irv.12842.The peer review history for this article is available at


To provide the latest evidence for the efficacy and safety of arbidol (umifenovir) in COVID‐19 treatment.A literature systematic search was carried out in PubMed, Cochrane Library, Embase, and medRxiv up to May 2021. The Cochrane risk of bias tool and Newcastle–Ottawa scale were used to assess the quality of included studies. Meta‐analysis was performed using RevMan 5.3.p > .05). However, arbidol was associated with higher adverse events . Compared with lopinavir/ritonavir, arbidol showed better efficacy for primary outcomes (p < .05). Adding arbidol to lopinavir/ritonavir also led to better efficacy in terms of NR‐PCR on Day 7 and PCR‐NCT (p < .05). There was no significant difference between arbidol and chloroquine in primary outcomes (p > .05). No remarkable therapeutic effect was observed between arbidol and other agents (p > .05).Sixteen studies were met the inclusion criteria. No significant difference was observed between arbidol and non‐antiviral treatment groups neither for primary outcomes, including the negative rate of PCR (NR‐PCR) on Day 7 : 0.78–1.14) and Day 14 , and PCR negative conversion time , nor secondary outcomes (The present meta‐analysis showed no significant benefit of using arbidol compared with non‐antiviral treatment or other therapeutic agents against COVID‐19 disease. High‐quality studies are needed to establish the efficacy and safety of arbidol for COVID‐19. The evidence on the antivirus effect of Arbidol against COVID‐19 is controversial. The present meta‐analysis showed no significant benefit of using arbidol compared with non‐antiviral treatment or other therapeutic agents against COVID‐19 disease On the one hand, the efficacy of arbidol was shown in vitro2We have registered the protocol of this systematic review and meta‐analysis with the registry number CRD42020207821 and used the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) checklist.2.1ClinicalTrials.gov, the European Union Clinical Trials Register, and the Chinese Clinical Trial Registry for additional relevant documents. Finally, the reference lists of the included studies and review articles were screened and the search was limited to the articles the abstract or full text of which were in English. Search terms included 2019‐nCoV, SARS‐CoV‐2, COVID‐19, arbidol, and umifenovir. The following terms were used to explore PubMed: ((((((((Coronavirus[Title/Abstract]) OR (Coronavirus[MeSH Terms])) OR (COVID‐19[Title/Abstract])) OR (SARS‐CoV‐2[Title/Abstract])) OR (COVID‐19[MeSH Terms])) OR (SARS‐CoV‐2[MeSH Terms])) OR (2019 novel coronavirus infection[Title/Abstract])) OR (2019‐nCoV infection[Title/Abstract])) AND ((Umifenovir[Title/Abstract]) OR (Arbidol[Title/Abstract])).We conducted a systematic search in the leading bibliographic databases, including PubMed, the Cochrane Library, and Embase for the relevant records up to May 2021. We also searched in medRxiv, Google Scholar, and clinical registry databases, including 2.2Two authors (Behnam Amani and Mahsa Zareei) independently screened the identified records based on inclusion and exclusion criteria. Disagreements between the authors were resolved by discussion among authors. The studies were included based on the following criteria: (1) patients with laboratory‐confirmed positive COVID‐19 test; (2) arbidol as monotherapy or in combination with other therapeutic agents; (3) any therapeutic intervention as a comparison (4); efficacy and safety outcomes of interest. The primary efficacy outcomes were the negative rate of PCR (polymerase chain reaction) and PCR negative conversion time and the secondary efficacy outcomes included the rate of improvement on chest CT, rate of cough alleviation, length of hospital stay, and disease progression. The safety outcome was the incidence of adverse events reported in patients; and (5) clinical trials or observational studies. The exclusion criteria were the studies conducted on animal models, case reports, case series, letters to editors, and editorials.2.3We used the Cochrane collaboration tool to assess the risk of bias of randomized clinical trials.2.4I2 and Chi2 tests. The random‐effects model was used for studies with I2 > 50% or p < .1. Otherwise, we used the fixed‐effect model.We performed a meta‐analysis using RevMan software, version 5.3. The mean difference (MD) with a 95% confidence interval (CI) was used for continuous variables and a risk ratio (RR) with 95% CI for dichotomous variables. The statistical heterogeneity was evaluated using the 33.1Figure 3.23.2.1p = .55) and Day 14 , PCR negative conversion time   and Day 14 , rate of cough alleviation on Day 7  and Day 14 , hospital stay , and disease progression  and PCR negative conversion time  and Day 14 , as well as PCR negative conversion time  and Day 14 , rate of cough alleviation on Day 7  and Day 14 , hospital stay , and disease progression , PCR negative conversion time , rate of improvement on chest CT on Day 7 , and hospital stay (MD: 1.51; 95% CI: −3.94 to 6.97; p = .59; Table Arbidol combined with lopinavir/ritonavir versus exclusive administration of lopinavir/ritonavir was associated with higher negative rate of PCR on Day 7 (RR: 2.06; 95% CI: 1.13–3.76; 3.2.7p = .90; Table p = .65; Table The meta‐analysis result showed no significant difference between exclusive arbidol and interferon/arbidol combination regarding the PCR negative conversion time (MD: −0.99; 95% CI: −16.67 to 14.69; 3.2.8p = .20; Table Several studies3.2.9We conducted a sensitivity analysis by including the case‐series study4This study aimed to provide the latest available evidence on the efficacy and safety of arbidol in the treatment of COVID‐19 disease. The meta‐analysis results showed that arbidol had no clinical efficacy for all primary and secondary outcomes, including the negative rate of PCR, PCR negative conversion time, rate of improvement on chest CT, cough alleviation, hospital stay, and disease progression.Similar to our finding, a meta‐analysis by Huang et al.In another similar meta‐analysis done by Li et al.,Although the present study found no significant treatment benefit for arbidol compared with non‐antiviral interventions, recent findings from two studiesBased on the meta‐analysis results, arabidol showed different efficacies in various outcomes in comparison to other treatments. Arbidol was not more effective than chloroquine in the negative rate of PCR and PCR negative conversion time. Also, chloroquine led to a shorter length of hospital stay than arabidol. However, arbidol showed better efficacy than oseltamivir in terms of the negative rate of PCR, the length of hospital stay, and the mortality rate. Compared with lopinavir/ritonavir, arbidol had better efficacy in the negative rate of PCR and PCR negative conversion time, and also was associated with fewer adverse events, with no significant difference between them for other efficacy outcomes.Our meta‐analysis showed that adding arbidol to lopinavir/ritonavir increased the negative rate of PCR on Day 7 and decreased PCR negative conversion time compared to lopinavir/ritonavir alone. Furthermore, simultaneous prescription of arbidol with interferon has no effect on the PCR negative conversion time in patients. Similar results were also found for interferon as a combination therapy with arbidol. The present meta‐analysis found no benefit for arbidol in combination with traditional Chines medicine. However, more studies are needed to approve this therapeutic alternative. The meta‐analysis of Huang et al.5Despite the efforts to minimize limitations, there were still several limitations to the current study. One of the challenging limitations of our study was the study design. Studies conducted were mostly retrospective and associated with a higher risk of bias. To reduce bias, we applied some strategies recommended by Almeida et al.6The finding of this meta‐analysis revealed that arbidol was not superior to non‐antiviral treatment in patients with COVID‐19. Compared with lopinavir/ritonavir, arbidol showed better efficacy for primary outcomes. No remarkable treatment effect was observed compared with other therapeutic agents. A well‐designed randomized controlled trial with a large sample size is necessary to conclude the efficacy and safety of arbidol against COVID‐19.The authors declare that there are no conflict of interests.Study concept and design: Bahman Amani and Behnam Amani. Literature searching: Bahman Amani and Behnam Amani. Study selection and appraisal: Behnam Amani and Mahsa Zareei. Data extraction: Sara Zareei and Mahsa Zareei. Data analysis and interpretation: Bahman Amani and Behnam Amani. Critical revision of the manuscript: Sara Zareei. All authors reviewed and edited the manuscript and approved the final version of the manuscript.Supplementary information.Click here for additional data file.


Primary mediastinal large B cell lymphoma (PMBCL) is an aggressive large B cell lymphoma originating in the mediastinum, that mainly expresses B cell surface molecules, such as CD19, CD20, CD22, andCD79a. Clinically, they are characterized by rapidly increasing anterior mediastinal masses, which can cause compression of the surrounding tissues. The diagnosis of PMBCL mainly depends on the pathological features, imaging examination and clinical features. Currently, the most commonly used therapeutic regimens are R‐CHOP and R‐EPOCH. Radiotherapy is beneficial in some patients, but it can also lead to long‐term toxicity. The research and development of novel therapies are ongoing, and some studies have achieved encouraging results, including those conducted on chimeric antigen receptor‐modified T (CAR‐T) cell therapy and anti‐PD‐1 drugs. However, randomized controlled trials with larger sample sizes are still needed. Positron emission tomography‐computed tomography (PET‐CT) is mainly used to assess the curative effect after treatment and to guide the subsequent treatment strategy. Management of PMBCL. CR, complete remission; PR, partial remission; PD, progressive disease; SD, stable disease; HDT/ASCR, high‐dose therapy followed by autologous stem cell rescue. Primary mediastinal large B cell lymphoma (PMBCL) is a rare subtype of aggressive B cell lymphoma. It constitutes 2%–3% of all cases of non‐Hodgkin's lymphoma (NHL).The annual incidence of PMBCL is 0.4/million based on more than 400 patients diagnosed between 2000 and 2012, mostly adolescents and young adults (AYAs).Most cases of PMBCL are reported to originate in the anterior superior mediastinum of the thymus region, with bulky masses, 60%–70% of which are larger than 10 cm in diameter. The lungs, pleura and pericardium are often involved. The tumor cells are usually medium to large, with abundant cytoplasm, grayish white and round or oval nuclei. Fibrosis around tumor cells leads to diffuse proliferation, leading to separation and sclerosis.The most common chromosomal abnormalities are +9p, +12q and +Xq. The +9p results in abnormal expansion of JAK2 located on 9p24 and abnormal regulation of the JAK–STAT pathway, overexpression of PDL1 and PDL2, and downregulation downregulation of MHC‐II and CIIA lead to the survival of PMBCL malignant cells in the thymic microenvironment.The characteristic clinical manifestation of PMBCL is a fast‐growing mass in the anterior mediastinum, which leads to local compressed respiratory symptoms, including superior vena cava syndrome, pleural or pericardial effusion. Common symptoms include cough, dyspnea, hoarseness, dysphagia, airway or vascular damage, and B symptoms . Lactate dehydrogenase (LDH) is also elevated. The involvement of distant lymph nodes and bone marrow is rare.The main imaging methods for PMBCL diagnosis are computed tomography (CT), magnetic resonance imaging (MRI) and PET/CT. CT is the first‐line examination method that can detect primary lymph node enlargement and surrounding tissue. On CT, the mass usually shows low‐density features, including varying degrees of bleeding, necrosis or cystic changes.p = 0.0001), and PFS was 99% and 64% (p < 0.0001), respectively.PET/CT can distinguish fibrosis, necrosis and active tumor, and is used for staging, diagnosis, and early response assessment after immunochemotherapy.The diagnosis and staging of PMBCL depends on pathological, imaging and clinical features. The prominent features of PMBCL are a rapidly enlarged anterior mediastinal mass, expression of B‐cell surface molecules by immunohistochemistry, pale cytoplasm and polymorphonuclear cells under light microscopy, and fibrosis around the nucleus. Hardening occurred in half of the cases. Staging was performed according to the Ann Arbor clinical staging system.PMBCL needs to be differentiated from DLBCL, mediastinal gray zone lymphoma (MGZL) and cHL . It is difficult to distinguish based on clinical manifestation alone, and the final diagnosis requires a combination of morphological, immunophenotypic and imaging indicators Table . CD79a, At present, the National Comprehensive Cancer Network (NCCN) guidelines recommend the DA‐EPOCH‐R regimen  with or without RT, and the R‐CHOP regimen  combined with RT and R‐CHOP can bridge the ICE regimen , and can be combined with rituximab or RT.p = 0.046). Consolidative mediastinal radiation was more common after R‐CHOP than after DA‐R‐EPOCH . However, patients treated with DA‐R‐EPOCH were more likely to experience treatment‐related diseases, such as neutropenic fever and acute toxicities  was better than CHOP, and combined radiotherapy could also increase the efficacy. The efficacy of the rituximab combined regimen was significantly improved. The MInT study showed that after combination with rituximab, CR increased from 54% to 80%, 3‐year event‐free survival (EFS) increased from 52% to 78%, and 3‐year OS increased from 78% to 89%. German research shows that PFS and OS in 10 years are 67% and 72%, respectively without combining with rituximab. After combining with rituximab, PFS and OS increased to 95% and 92%, respectively. Some studies have shown that the long‐term OS and/orPFS of first‐line R‐EPOCH is better, but some studies have shown that R‐CHOP‐21 has the same curative effect as R‐EPOCH, and the incidence of grade 3–4 adverse events is lower.PMBCL is a radiosensitive disease, and consolidation mediastinal radiotherapy can improve its curative effect.Disease recurrence usually occurs in the early stage, and recurrence‐refractory patients account for 10%–30% of the total number of cases.The total effective rate of HDT/ASCT was 77.2% . The median follow‐up time was 53.5 months. The 4‐year OS and PFS rates were 70% and 61%, respectively. The 4‐year OS rates of patients with relapse and primary refractory diseases were 73% and 65%, respectively.n = 9), thrombocytopenia (n = 3), and peripheral neuropathy (n = 3).The most promising target of immune checkpoint blockade for PMBCL is PD‐1. The US Food and Drug Administration (FDA) has approved the use of pembrolizumab for patients with RR PMBCL. PD‐1 blockade therapy enhances the immune response mainly by reactivating the existing antitumor T cells in situ, rather than activating de novo antitumor T cells, which is defined as a checkpoint blockade therapy (CBT)‐responsive lymphoma , and its lymphoma environment is enriched in infiltrating immune cells.The potential targets of PMBCL therapy include specific cell surface markers, cell signal transduction pathways, programmed death ligands, etc. At present, several new drugs for PMBCL therapy are undergoing clinical trials, some of which have achieved encouraging results.n = 8) and transformed FL. Among all patients in 1 year, ORR was 82%, CR was 54%, with a median follow‐up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response, and 18 month survival was 52%.Anti‐CD19 CAR‐T cell therapy shows good therapeutic prospects. CD19 is a common target antigen in hematological malignancies, and is commonly found on B cells.The anti‐CD30 antibody drug conjugate brentuximab vedotin (BV) has been approved for the treatment of relapsed or refractory HD and anaplastic large cell lymphoma (ALCL). PMBCL also expresses CD30, but its expression level is low. In a phase II trial, the effective rate was 17% in six cases of PMBCL and three cases of SD. The reaction was not related to the quantitative expression of CD30 on tumor cells.BiTE can simultaneously bind two different antigens. Blinatumomab is a CD19/CD3 BiTE double antibody that is used to treat Philadelphia chromosome‐negative acute B‐lymphoblastic leukemia. Blinatumomab connects CD3 + polyclonal T cells to CD19 + B cells, induces T cell activation, and T cell‐mediated B‐cell lysis. Single drug blinatumomab has been reported to show antilymphoma activity in relapsed or refractory NHL, and PMBCL data needs to be studied further.Ibrutinib, a Bruton tyrosine kinase inhibitor related to the NF‐κB pathway, has also been used in combination with R‐ICE in RR‐DLBCL, including four patients with PMBCL. In four cases of PMBCL patients, ORR was 100%, all showed PR, showing good curative effect, but there were not enough cases in this study.Abnormal activation of the JAK–STAT pathway in PMBCL malignant cells leads to cell proliferation, survival, angiogenesis and transcription of immune target genes. The role of JAK inhibitors in PMBCL has also been studied, and ruxolitinib is ineffective Figure .53The 5‐year survival rate of patients with PMBCL is approximately about 85%. The International prognostic index (IPI), age, LDH, stage, Ki‐67 proliferation index and SUVmax of PET‐CT are significantly correlated with survival rate.In conclusion, PMBCL is a rare subtype of aggressive B‐cell lymphoma, which is more common in adolescents and young adults, mainly women. Treatment should consider maximum efficacy and minimize long‐term toxicity. R‐CHOP + RT and DA‐EPOCH‐R ± RT are effective first‐line choices for PMBCL. Autologous or allogeneic SCT after high‐dose chemotherapy is an effective treatment strategy for relapsed or refractory PMBCL. Following immunochemotherapy, FDG‐PET is used to evaluate the therapeutic effect and decide whether radiotherapy should be used. Some new therapies have shown good prospects, and clinical trials are currently in progress.All authors declare no conflict of interest.


There are few non-invasive monitoring methods that can reliably predict fluid responsiveness (FR) in children. Here, we interrogate the value of doppler ultrasound evaluation of passive leg raising (PLR)-induced changes in stroke volume (SV) and cardiac output (CO) as a predictor of FR in children with mechanical ventilation after congenital cardiac surgery.A total of 40 children with mechanical ventilation following congenital cardiac surgery, who required volume expansion (VE) were included in this study. Hemodynamic parameters such as heart rate (HR), mean arterial pressure (MAP), SV, and central venous pressure (CVP) were monitored before and after PLR and VE. Besides, we assessed changes in SV and CO by bedside ultrasound. Patients showing > 10 % increase in SV in response to VE were considered to be responders (26 patients), while the rest (14 patients) were defined as non-responders.p < 0.001 and r = 0.374, p = 0.017, respectively), and the area under the ROC curve (AUC) of ΔSV-PLR was 0.879 . The best cut-off value for ΔSV-PLR in predicting FR was 13 %, with its sensitivity and specificity were 81.8 and 86.3 %, respectively. ΔCVP, ΔHR, and ΔMAP were weak predictors of FR in the children.Our data demonstrated that ΔSV-PLR and ΔCO- PLR were positively correlated with ΔSV-VE (r = 0.683, Our study demonstrated that SV changes, as evaluated by noninvasive ultrasound combined with PLR, could effectively evaluate FR in children under mechanical ventilation after congenital cardiac surgery. Proper fluid loading is pivotal in maintaining hemodynamic stability in children who undergo congenital cardiac surgery . ClassicPassive leg raising (PLR) is a simple repeatable self-replenishing fluid method done to shift venous blood from the lower limbs toward the intrathoracic compartment , 9. TranHere, we tested whether PLR related changes in SV and CO as monitored by bedside echocardiography could accurately predict FR in children with mechanical ventilation after cardiac surgery.The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Shangrao Fifth People's Hospital (No.2016-12-01). All participants gave written informed consent prior to their enrollment in this study.− 1·h− 1 urine output for at least 1 h), mottled skin, oliguria (less than 0.5 ml·kg− 1·h− 1 diuresis), 1.5-fold increase in arterial blood lactic acid, acute kidney failure, or clinical and laboratory signs of extracellular dehydration [This prospective observational study was carried out at the integrated Intensive Care Unit of the Fifth People’s Hospital of Shangrao City  from December 2016 to July 2017. We enrolled a total of 48 patients who were under mechanical ventilation following cardiac surgery, and whose attending physician conducted a fluid challenge. The execution of the fluid challenge dependent on at least one clinical sign of inadequate tissue perfusion, with no contraindications for infusion. The clinical signs of inadequate tissue perfusion were characterized by acute circulatory failure 2. SV and CO were measured with the equations: SV = VTI × aortic area, and CO = SV × HR. The aortic area was considered to be stable during the trial and was measured only once in the initial measurement. Every VTI measurement was taken based on two or three measurements in one breathing cycle. All of the measurements were conducted by a cardiologist.A 4-5.5fr central venous catheter was inserted into the right internal jugular vein or the right/left subclavian vein to monitor CVP, while a 7 cm 3fr arterial catheter was inserted into the right or left femoral artery to monitor dynamic blood pressure, before operation. MAP was calculated as MAP = /3. The standard transthoracic probe (3SP-D) of GE VIVIVIXE9 Doppler echocardiography was used to measure SV. On the five chambers apical view, the aortic blood flow was recorded using pulsed Doppler, with the sample volume placed on the annulus aorta. A velocity-time integral (VTI) of the aortic blood flow was also measured. The aortic valve area was calculated from the diameter of the aortic orifice, measured at insertion of the aortic cusps, as aortic area = The patients were placed in a supine position, with the upper body parts being 45° higher (Base 1) and four hemodynamic parameters  were measured. Afterwards, the upper parts of the body were lowered to achieve a horizontal position and the lower extremities raised to 45° (Base 2), and then the four hemodynamic parameters were measured again within 30 s to 1 min. The patients were placed back to the initial position  for 10 min and the hemodynamic parameters were remeasured. Besides, the four hemodynamic parameters were again measured immediately following the administration of the bolus of the intravenous fluid challenge using 10 ml/kg of 5 % albumin in 15 min. The patients showing > 10 % increase in SV in response to the VE were considered responders, while the rest were defined as non-responders. All the procedures were conducted while the patients were kept fully sedated, and the parameters such as the use of vasoactive drugs, sedatives and mechanical ventilation remained unchanged.p < 0.05 was considered to be statistically significant. All the statistical analyses were performed with IBM SPSS 23.0 .Continuous variables were presented as the mean ± standard deviation if normally distributed, or as a median (range) if the distribution was not normal. Student’s unpaired t-test or the Mann–Whitney U-test was used to evaluate group differences. To assess the correlation between ΔSV-VE and PLR related ΔSV, ΔMAP, ΔHR, ΔCVP, or ΔCO, linear regression analysis was performed. Linear correlations were tested using the Pearson test and linear regression method. To determine the ability of all the variables to predict fluid responsiveness, receiver operating characteristic (ROC) curves were generated, and the area under the ROC curve was calculated. The ROC curves were compared using the Hanley–McNeil test . Youden’n = 18, 45 %), tetralogy of fallot (TOF) , atrial septal defect (ASD) , or ASD + VSD . There was no significant difference in age, gender, vasoactive drug usage score, ventilator parameters, and indication for ICU stay (p > 0.05). The clinical characteristics for the two groups are shown in Table A total of 48 patients who were under mechanical ventilation with presumed hypovolemia and were considered for VE were included in the study from December 2016 to December 2017. Among these eligible patients, 8 were excluded because of poor transthoracic insonation. Therefore, 40 patients  with mean age of 5.41 ± 3.25 years were included in the study. There were patients with ventricular septum defect (VSD) (p > 0.05) between Base 3 and Base 1. The hemodynamic parameters before and after PLR and VE are listed in Table ΔSV in 26 children (responders) increased by more than 10 % from the base 3 value after VE, while ΔSV in 14 patients (non-responders) increased by less than 10 %. There were no significant shifts in all hemodynamic changes . The highest area under the ROC curve (AUC) for ΔSV-PLR (0.879 ± 0.069) successfully predicted FR in the patients . The correlation between Δ-PLR and ΔSV-VE is shown in Table The ΔSV-PLR and ΔCO- PLR were positively correlated with ΔSV-VE (Pearson’s The optimal ΔSV-PLR threshold for predicting FR was 13 %, and its sensitivity and specificity were 81.8 and 86.3 %, respectively. The positive and negative predictive cut-offs were 85.0 and 82.0 %, respectively. The optimal threshold values and associated sensitivities and specificities are presented in Table Prediction of FR is critical in fluid therapy after cardiac surgery, especially in children. Significant changes in ventricular systolic and diastolic functions after cardiac surgery often lead to difficulties in predicting FR , 16. HerPLR is a simple, noninvasive and repeatable method to change the cardiac preload , 9, 17. In recent years, bedside ultrasonography has been considered as a noninvasive, real-time, convenient, low-cost, and repeatable tool for monitoring hemodynamics , 19–21. Whereas CVP, MAP, and HR were relatively easy to monitor, we did not observe any correlation with ΔSV-VE. Our data showed that ΔCO-PLR could predict FR, with an optimal threshold of 8 %, sensitivity of 81 % and specificity of 71 %. But the correlation between ΔCO-PLR and ΔSV-VE was not comparable to that of the ΔSV-PLR, which may be due to the influence of the HR on CO measurement. Consistent with the previous findings, our study found that ΔSV-PLR can better predict FR compared with the other PLR-Δs .There are some limitations in this study. First, echocardiographic measurement errors may have occurred, even though the same expert obtained all echocardiographic data. Second, because of the different types of congenital heart diseases and the diverse changes in cardiac structure after operation, our results cannot be extrapolated to other types of congenital heart diseases and to children of all ages, because leg elevation in newborns or infants obviously does not have the same volume effect as leg elevation in older children. Third, based on previous studies, we defined a 10 % increase in SV with rapid fluid loading as FR-positive. Whether the 10 % cut off is the appropriate threshold needs further research. Another limitation is that it is also a small sample, non-blinded study, and the results may not be applicable to other centers. Finally, someone is a fluid “responder” does not mean that they need a fluid bolus. If a healthy normally hydrated person is given a fluid bolus, their stroke volume will also increase, however, that does not mean that they need fluid. This is probably why the increases in MAP overall are very modest in our study even in responders. Therefore, further investigations of high-quality are needed to confirm our findings.In conclusion, our study demonstrated that assessment of the SV changes by noninvasive ultrasound combined with PLR could be used to evaluate fluid responsiveness in children under mechanical ventilation after congenital cardiac surgery.


Although alectinib has better CNS penetration than crizotinib, patients treated with alectinib also develop CNS progression. CNS metastases more likely occurs during crizotinib treatment due to less blood‐brain barrier (BBB) penetration capability than alectinib. CNS progression pattern may be different during crizotinib and alecitinib treatment. Understanding the characteristics of CNS progression is important for developing treatment strategies.Most patients treated with anaplastic lymphoma kinase ALK‐positive NSCLCs.We compared the clinical‐radiographic characteristics of CNS metastases among patients undergoing crizotinib and alectinib treatment for ALK‐positive NSCLC patients treated with crizotinib or alectinib at our hospital between July 2011 and May 2020. CNS and systemic tumor progression were evaluated using computed tomography or magnetic resonance imaging. Fifty‐three and 65 patients were treated with crizotinib and alectinib, respectively. Baseline CNS metastasis was observed in 18 and 27 patients in the crizotinib and alectinib groups, respectively. Among the patients in the crizotinib and alectinib groups who developed disease progression, 15/49 (30.6%) and 9/44 (20.5%) had CNS progression, respectively (P = .344). Intra‐CNS progression‐free survival was significantly longer in the alectinib group than in the crizotinib group . The number of CNS metastases sized ≥3 cm, rate of peritumoral brain edema, and the second progression pattern after treatment continuation was not significantly different between the groups.We retrospectively analyzed the radiographic and clinical characteristics of CNS progression in We observed no significant difference in the clinical‐radiographic characteristics of CNS progression between patients undergoing crizotinib and alectinib treatments. Local therapy, including stereotactic radiosurgery, for CNS progression may be suitable and important following alectinib and crizotinib treatment. Its phase III trials have demonstrated that crizotinib yielded significantly longer progression‐free survival (PFS) than cytotoxic chemotherapy.ALK‐positive NSCLC.ALK‐positive patients who were treated with crizotinib.In 2007, Soda et al identified NSCLC with In phase III PLOFILE1014 study, crizotinib achieved a better rate of intracranial disease control compared with cytotoxic chemotherapy; however, there was no significant difference in the time to CNS progression between the two treatments.ALK‐positive NSCLC, whereby alectinib achieved significantly better PFS. Moreover, alectinib showed better efficacy for CNS progression than crizotinib, in the subgroup analysis of the J‐ALEX study.As another ALK‐TKI, alectinib is a second‐generation highly selective and potent drug. Alectinib is not a substrate of p‐glycoprotein and has improved CNS penetration in contrast to crizotinib.Differences in the efficacy of ALK‐TKIs for CNS are considered to be due to differences in the capability to penetrate the BBB.However, despite alectinib treatment, a long‐term follow‐up found cumulative incidence rates of CNS progression at approximately 30% and 10% in patients with and without baseline CNS metastases, respectively.ALK‐positive NSCLC, even if alectinib becomes a standard treatment in first‐line treatment. Local therapy with either stereotactic radiosurgery (SRS) or whole‐brain radiotherapy for isolated CNS progression during EGFR‐ or ALK‐TKI treatment is recommendedEGFR‐ and ALK‐positive NSCLC who developed isolated CNS progression achieved long PFS following local therapy with the maintenance of the same TKI therapy.Therefore, treatment strategies after CNS progression are important in EGFR‐TKIs in EGFR‐positive NSCLC, and resistance mutations such as T790M are known to be one of the causes of LM.Contrarily, leptomeningeal metastasis (LM) has also been reported after first‐generation Furthermore, because CNS metastases cause impairment in the quality of life and performance status, the characteristics of CNS progression are also important.Crizotinib and alectinib have different BBB penetration capabilities; therefore, different CNS progression patterns are expected between patients undergoing the two treatments. Although there are some studies on the incidence of CNS progression in ALK‐TKIs, no study has compared the characteristics of CNS progression between patients undergoing crizotinib and alectinib treatments.The American Society of Radiation Oncology guidelines on Radiotherapeutic and Surgical Management for Newly Diagnosed Brain Metastasis(es) stipulates that the number of CNS metastases (single or multiple), the maximum tumor size (less or more than 3‐4 cm), and expected prognosis are important decision‐making factors for radiosurgery, whole‐brain radiotherapy, surgery, and palliative care for CNS metastases.ALK‐positive NSCLC.Because it may help in determining treatment strategies following CNS progression, this study aimed to investigate the radiographic and clinical characteristics of newly developed or progressed CNS metastases with crizotinib treatment compared to those with alectinib treatment for 22.1ALK‐positive NSCLC treated with crizotinib or alectinib at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research between July 2011 and May 2020. ALK positivity was determined either via immunohistochemistry and/or fluorescence in situ hybridization. Crizotinib was administered at a dose of 250 mg twice daily, while alectinib was administered at 300 mg twice daily. Patients who progressed or newly developed CNS metastases during the treatment period were included in the analysis.This was a retrospective study of patients with advanced 2.2Tumor responses were assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).The number of CNS metastases, the maximum size of CNS metastases, the number of CNS metastases measuring ≥3 cm in size, presence/absence of peritumoral brain edema, and presence/absence of LM were assessed as radiographic characteristics. Meanwhile, presence/absence of CNS symptoms, presence/absence of extra‐CNS progression, intra‐CNS PFS, local therapy for CNS progression, the number of patients who continued treatment after CNS progression, time to treatment failure(TTF) from CNS progression, and the site of progression after treatment continuation were assessed as clinical characteristics.CNS symptoms were defined as headache, paralysis, nausea, and seizure in this study. We defined CNS progression as intracranial disease progression based on the RECIST 1.1. Intra‐CNS PFS was calculated from the start date of ALK‐TKIs until CNS progression. TTF from CNS progression was defined as the time from the first CNS progression to ALK‐TKIs discontinuation beyond the first CNS progression in patients who underwent local therapy after CNS progression and continued ALK‐TKIs beyond.2.3U test. Meanwhile, Fisher's exact test or Pearson's chi‐square test compared the other patient characteristics as appropriate. Intra‐CNS PFS and time to treatment failure were evaluated using the Kaplan‐Meier method and compared between groups using the log‐rank test. All statistical analyses were performed using EZR  for statistical computing.P value of <0.05 was considered statistically significant.Between‐group comparisons of age and the size of brain metastases were conducted using the Mann‐Whitney 33.1ALK‐positive NSCLC received crizotinib alone (n = 33 patients) or alectinib alone (n = 45 patients). Of them, 20 patients were treated with both crizotinib and alectinib. The patient inclusion flowchart is shown in Figure In total, 98 patients with P = .344). None of the patients progressed to CNS metastases in either group. Overall, 11/44 (25.0%) and 4/44 (9.1%) patients without prior ALK‐TKIs in the crizotinib and alectinib groups, respectively, developed CNS progression (P = .087). There were 5/18 (27.8%) and 6/27 (22.2%) patients with baseline metastases who developed CNS progression in the crizotinib and alectinib groups, respectively (P = .732). Meanwhile, 10/35 (28.6%) and 3/38 (7.9%) patients who had no baseline metastases developed CNS progression (P = .031).CNS metastases at baseline were observed in 18 and 27 patients in the crizotinib and alectinib groups, respectively. Among the 53 patients in the crizotinib group, 40 patients had received prior chemotherapy, 44 patients had not received prior ALK‐TKIs, 6 patients had received prior alectinib, 2 patients had received prior other ALK‐TKIs, and 1 patient had received 2 or more prior ALK‐TKIs. Among the 65 patients in the alectinib group, 25 patients had received prior chemotherapy, 44 patients had not received prior ALK‐TKIs, 18 patients had received prior crizotinib, and 3 patients received 2 or more ALK‐TKIs. Disease progression was observed in 49 and 44 patients in the crizotinib and alectinib groups, respectively. Of them, 15/49 (30.6%) patients in the crizotinib group and 9/44 (20.5%) patients in the alectinib group developed CNS progression (3.2P = .682). No CNS metastases sized ≥3 cm in size were observed in both groups. Peritumoral brain edema was observed in 3/15 (20.0%) and 4/9 (44.4%) patients in the crizotinib and alectinib groups, respectively (P = .356). LM was observed in 1/15 (6.7%) and 2/9 (22.2%) patients in the crizotinib and alectinib groups, respectively (P = .533).The radiographic characteristics of CNS metastases were evaluated in 24 patients with CNS progression. With respect to modality, CNS metastases were assessed via CT in 23 patients (95.8%) and via MRI in 1 patient (4.2%). The radiographic characteristics classified by groups are shown in Table 3.3P = 1.000). The intra‐CNS PFS was significantly longer in the alectinib group than that in the crizotinib group . Overall, 3/15 (20.0%) and 4/9 (44.4%) patients in the crizotinib and alectinib groups underwent radiosurgery for CNS metastases, respectively. In addition, there were 4/15 (26.7%) patients who continued crizotinib and 4/9 (44.4%) patients who continued alectinib treatment after CNS progression (P = .412).The patients' clinical characteristics are shown in Table P = .652).The treatment time course is shown in Figure P = .257).Similarly, we did not observe a significant difference in the second progression pattern after the continuation of crizotinib and alectinib. Extra‐CNS progression after CNS progression was observed in four patients who continued crizotinib, and it was observed in one patient who continued alectinib  patients in the crizotinib group and 4/9 (44.4%) patients in the alectinib group underwent radiosurgery following CNS progression.In this study, there was no significant difference in the radiographic and clinical characteristics of CNS progression between patients undergoing crizotinib and alectinib treatments. Similar trends in patients with isolated CNS progression were observed in both treatment groups. Continuation of the drug beyond CNS progression may lead to long second PFS. This indicates that radiation therapy, including SRS for CNS metastases, may be as important as treatment strategies for CNS metastases during alectinib as CNS metastases during crizotinib.ALK‐positive NSCLC is relatively rare, and data on CNS progression after ALK‐TKIs are also limited. Thus, it is difficult to evaluate the characteristics of CNS progression in a large‐scale study. Despite these limitations, our study included a detailed description of the characteristics of CNS progression and, therefore, may be useful for establishing the optimal treatment strategy for ALK‐positive NSCLCs.This study has some limitations owing to its single‐institutional retrospective design and small sample size. The treatment varied among the patients, and therefore, we could not detect statistically significant differences owing to the small sample size. However, There was no significant difference in the radiographic and clinical characteristics of CNS progression between patients undergoing crizotinib and alectinib treatments. Local therapy, including SRS for CNS progression, may be suitable and important, following both alectinib or crizotinib treatment.Makoto Nishio reports honoraria from Ono Pharmaceutical, Bristol‐Myers Squibb, Pfizer, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, Boehringer‐Ingelheim, MSD, and Novartis and research funding from Novartis, Daiichi Sankyo, Taiho Pharmaceutical, Bristol‐Myers Squibb, Boehringer‐Ingelheim, Ono Pharmaceutical, Eli Lilly, Chugai Pharmaceutical, AstraZeneca, Merck Sernon, MSD, and Pfizer. Noriko Yanagitani reports an employment/leadership position/advisory role in Chugai Pharmaceutical. Ken Uchibori reports an employment/leadership position/advisory role in Daiichi Sankyo. All other authors have stated that they have no conflicts of interest.Hiroaki Sakamoto: Conceptualization; data curation; formal analysis; investigation; methodology; resources; visualization; writing‐original draft. Ryo Manabe: Data curation; resources. Ryosuke Tsugitomi: Data curation; resources. Shinsuke Ogusu: Data curation; resources. Hiroshi Yoshida: Data curation; resources. Takehiro Tozuka: Data curation; resources. Yoshiaki Amino: Data curation; resources. Ryo Ariyasu: Data curation; resources. Ken Uchibori: Data curation; resources. Satoru Kitazono: Data curation; resources. Noriko Yanagitani: Conceptualization; data curation; methodology; resources; writing‐review & editing. Sadatomo Tasaka: Writing‐review & editing. Makoto Nishio: Conceptualization; methodology; project administration; supervision; writing‐review & editing.This study was approved by the Ethics Committee of the Cancer Institute Hospital of the Japanese Foundation for Cancer Research  and was conducted according to the Declaration of Helsinki's guidelines. The need for informed consent was waived owing to the retrospective nature of the study.