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Background Diabetes mellitus and high platelet reactivity (HPR) on clopidogrel are both associated with increased risk of ischemic events after percutaneous coronary intervention, but whether the HPR-associated risk of adverse ischemic events differs by diabetes mellitus status is unknown. Methods and Results ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) was a prospective, multicenter registry of patients treated with coronary drug-eluting stents. HPR was defined as P2Y12 reaction units >208 by the VerifyNow point-of-care assay. Cox multivariable analysis was used to assess whether HPR-associated risk of major adverse cardiac events (MACE; cardiac death, myocardial infarction, or stent thrombosis) varied for patients with insulin-treated diabetes mellitus (ITDM), non-ITDM, and no diabetes mellitus. Diabetes mellitus and HPR were included in an interaction analysis. Of 8582 patients enrolled, 2429 (28.3%) had diabetes mellitus, of whom 998 (41.1%) had ITDM. Mean P2Y12 reaction units were higher in patients with diabetes mellitus versus without diabetes mellitus, and HPR was more frequent in patients with diabetes mellitus. HPR was associated with consistently increased 2-year rates of MACE in patients with and without diabetes mellitus ( P interaction =0.36). A significant interaction was present between HPR and non-insulin-treated diabetes mellitus versus ITDM for 2-year MACE (adjusted hazard ratio [HR] for non-ITDM, 2.28 [95% CI, 1.39-3.73] versus adjusted HR for ITDM, 1.02 [95% CI, 0.70-1.50]; P interaction =0.01). Conclusions HPR was more common in patients with diabetes mellitus and was associated with an increased risk of MACE in both patients with and without diabetes mellitus. In patients with diabetes mellitus, a more pronounced effect of HPR on MACE was present in lower-risk non-ITDM patients than in higher-risk patients with ITDM. Registration URL: https://clinicaltrials.gov/ct2/show/NCT00638794; Unique identifier: NCT00638794. ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents).

Objective: T-cell receptor (TCR) repertoire diversity is getting increasing attention as a predictive biomarker in cancer patients. However, the characteristics of the TCR together with its predictive significance for high grade serous ovarian cancer (HGSOC) patients receiving poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance therapy remain unknown., Methods: Twenty-seven patients with HGSOC were analyzed including 22 patients receiving PARPi maintenance therapy and 5 untreated patients as control. Peripheral blood samples were collected for TCR sequencing at baseline as well as one month and three months after the exposure to PARPi. To determine whether TCR diversity was related to PARPi efficacy, we compared the TCR repertoire between patients who had received PARPi and those who had not., Results: For patients receiving PARPi treatment or not, we evaluated changes in clone abundance during PARPi maintenance and the similarity of the TCR repertoire before and after the treatment. The results revealed that patients receiving PARPi had TCR repertoires that were more stable than those of untreated cases. We next correlated TCR diversity with the efficacy of PARPi in the treatment group. The rising trend of TCR diversity after three months with PARPi treatment was associated with a longer PFS (21.7 vs 7.4 months, hazard ratio = 0.19, p < 0.001) and a better response to PARPi (91.7% vs 25.0%, p = 0.004). Furthermore, we discovered that the primary characteristic with predictive value for the effectiveness of PARPi is the considerable reduction of the high-frequency T cell clones., Conclusion: We suggested that the circulating TCR diversity could be a potential predictive biomarker for PARPi maintenance therapy in HGSOC., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: Anterior cruciate ligament reconstruction (ACLR) is the most common surgery for anterior cruciate ligament (ACL) injuries, and the relationships between patients' return to sports (RTS) readiness and different physical functions are inconclusive among patients with ACLR. This study aimed to investigate the correlations of strength, proprioception, and tactile sensation to the RTS readiness among patients with ACLR. Methods: Forty-two participants who received ACLR for at least 6 months were enrolled in this study. Their strength, proprioception, and tactile sensation were tested, and their RTS readiness was measured with the Knee Santy Athletic Return to Sports (K-STARTS) test, which consists of a psychological scale [Anterior Cruciate Ligament Return to Sports after Injury scale (ACL-RSI)] and seven functional tests. Partial correlations were used to determine their correlations while controlling for covariates (age, height, weight, and postoperative duration), and factor analysis and multivariable linear regressions were used to determine the degrees of correlation. Results: Knee extension strength was moderately correlated with K-STARTS total, ACL-RSI, and functional scores. Knee flexion strength, knee flexion and extension proprioception, and tactile sensation at the fifth metatarsal were moderately correlated with K-STARTS total and functional scores. Strength has higher levels of correlation with functional scores than proprioception. Conclusion: Rehabilitation to promote muscle strength, proprioception and tactile sensation should be performed among patients with ACLR, muscle strength has the highest priority, followed by proprioception, with tactile sensation making the least contribution., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ma, Lu, Zhou, Sun, Chen, Dai, Wang, Ding, Fong and Song.)

Objective: Overactive bladder (OAB) is a disease that seriously affects patients' quality of life and mental health. To address this issue, more and more researchers are examining the relationship between OAB treatment and urinary microecology. In this study, we sought to determine whether differences in treatment efficacy were related to microbiome diversity and composition as well as the abundance of specific genera. Machine learning algorithms were used to construct predictive models for urine microbiota-based treatment of OAB., Methods: Urine samples were obtained from 64 adult female OAB patients for 16S rRNA gene sequencing. Patients' overactive bladder symptom scores (OABSS) were collected before and after mirabegron treatment and patients were divided into effective and ineffective groups. The relationship between the relative abundance of certain genera and OABSS were analyzed. Three machine learning algorithms, including random forest (RF), supporting vector machine (SVM) and eXtreme gradient boosting (XGBoost) were utilized to predict the therapeutic effect of mirabegron based on the relative abundance of certain genera in OAB patients' urine microbiome., Results: The species composition of the two groups differed. For one, the relative abundance of Lactobacillus was significantly higher in the effective group than in the ineffective group. In addition, the relative abundance of Gardnerella and Prevotella in the effective group was significantly lower than in the ineffective group. Alpha-diversity and beta-diversity differed significantly between the two groups. LEfSe analysis revealed that Lactobacillus abundance increased while Prevotella and Gardnerella abundance decreased in the effective group. The Lactobacillus abundance ROC curve had high predictive accuracy. The OABSS after treatment was negatively correlated with the abundance of Lactobacillus , whereas the relationship between OABSS and Prevotella and Gardnerella showed the opposite trend. In addition, RF, SVM and XGBoost models demonstrated high predictive ability to assess the effect of mirabegron in OAB patients in the test cohort., Conclusions: The results of this study indicate that urinary microbiota might influence the efficacy of mirabegron, and that Lactobacillus might be a potential marker for evaluating the therapeutic efficacy of mirabegron in OAB patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Qiu, Li, Sun, Xie, Huang, Yu, Wang, Xue, Zhu, Feng, Zhao and Wu.)

Background: Cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) are critical for immune suppression by restricting immune cell infiltration in the tumor stromal zones from penetrating tumor islands and changing their function status, particularly for CD8 + T cells. However, assessing and quantifying the impact of CAFs on immune cells and investigating how this impact is related to clinical outcomes, especially the efficacy of immunotherapy, remain unclear., Materials and Methods: The TME was characterized using immunohistochemical (IHC) analysis using a large-scale sample size of gene expression profiles. The CD8 + T cell/CAF ratio (CFR) association with survival was investigated in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) lung cancer cohorts. The correlation between CFR and immunotherapeutic efficacy was computed in five independent cohorts. The correlation between CFR and objective response rates (ORRs) following pembrolizumab monotherapy was investigated in 20 solid tumor types. To facilitate clinical translation, the IHC-detected CD8/α-SMA ratio was applied as an immunotherapeutic predictive biomarker in a real-world lung cancer cohort., Results: Compared with normal tissue, CAFs were enriched in cancer tissue, and the amount of CAFs was overwhelmingly higher than that in other immune cells. CAFs are positively correlated with the extent of immune infiltration. A higher CFR was strongly associated with improved survival in lung cancer, melanoma, and urothelial cancer immunotherapy cohorts. Within most cohorts, there was no clear evidence for an association between CFR and programmed death-ligand 1 (PD-L1) or tumor mutational burden (TMB). Compared with TMB and PD-L1, a higher correlation coefficient was observed between CFR and the ORR following pembrolizumab monotherapy in 20 solid tumor types (Spearman's r = 0.69 vs. 0.44 and 0.21). In a real-world cohort, patients with a high CFR detected by IHC benefited considerably from immunotherapy as compared with those with a low CFR (hazard ratio, 0.37; 95% confidence interval, 0.19-0.75; p < 0.001)., Conclusions: CFR is a newly found and simple parameter that can be used for identifying patients unlikely to benefit from immunotherapy. Future studies are needed to confirm this finding., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zheng, Jiang, Xiao, Zeng, Peng, Bai, Chen, Li, Zhang, Zheng, Miao, Wang, Wu, Xu, Xu, Li, Li, Gao, Zheng, Li, Wang, Zhou, Xia, Yang, Li, Cui, Zhang, Chen, Lin and Lin.)

Aims: The impact of mitral valve geometry on outcomes after MitraClip treatment in secondary mitral regurgitation (MR) has not been examined. We therefore sought to evaluate the association between mitral valve geometry and outcomes of patients with heart failure (HF) and secondary MR treated with guideline-directed medical therapy (GDMT) and MitraClip., Methods and Results: Mitral valve geometry was assessed from the baseline echocardiograms in 614 patients from the COAPT trial. The primary endpoint for the present study was the composite of all-cause mortality or HF hospitalization (HFH) within 2 years. Effect of treatment arm (MitraClip plus maximally tolerated GDMT vs. GDMT alone) on outcomes according to baseline variables was assessed. Among 29 baseline mitral valve echocardiographic parameters, increasing anteroposterior mitral annular diameter was the only independent predictor of the composite endpoint of all-cause mortality or HFH [adjusted hazard ratio (aHR) per cm 1.49; P = 0.04]. The effective regurgitant orifice area (EROA) was independently associated with all-cause mortality alone (aHR per cm2 2.97; P = 0.04) but not with HFH, whereas increasing anteroposterior mitral annular diameter was independently associated with HFH alone (aHR per cm 1.85; P = 0.005) but not all-cause mortality. Other mitral valve morphologic parameters were unrelated to outcomes. MitraClip reduced HFH and mortality independent of anteroposterior mitral annular diameter and EROA (Pinteraction = 0.77 and 0.27, respectively)., Conclusion: In patients with HF and severe secondary MR, a large anteroposterior mitral annular diameter and greater EROA were the strongest echocardiographic predictors of HFH and death in patients treated with GDMT alone and with the MitraClip., Competing Interests: Conflict of interest: The present study was funded by Abbott Vascular. The Department of Cardiology of Leiden University Medical Centre has received unrestricted research grants from Abbott, Bayer, Biotronik, Boston Scientific, Edwards Lifesciences, GE Healthcare, and Medtronic. F.N. and S.M.P. received a research grant support from Abbott Vascular. N.A.M. received speaker fees from Abbott Vascular. V.D. received speaker fees from Abbott Vascular, Medtronic, Edwards Lifesciences, MSD, Novartis and GE Healthcare. F.M.A. and N.J.W. are Director and Associate Director of an academic echocardiography core lab (MedStar Health Research Institute) with Institutional contracts with Abbott, Boston Scientific, Edwards Lifesciences, Neovasc, Ancora, Mitralign, MVRx, Innovheart, Polares Medical, Medtronic, Biotronik, Livanova. J.A.L. receives research grant support from AstraZeneca and consulting income from Abbott and Edwards. W.T.A. receives research grant support and consulting income from Abbott. M.J.M. has non-financial relationships with Edwards Lifesciences (co-PI of the PARTNER 3 Trial), Abbott (Co-PI of the COAPT Trial), and Medtronic (study chairman of the APOLLO Trial). G.W.S. has received speaker or other honoraria from Cook, Terumo, QOOL Therapeutics and Orchestra Biomed; has served as a consultant to Valfix, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals, Vectorious, Reva, Matrizyme, Cardiomech; and has equity/options from Ancora, Qool Therapeutics, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, MedFocus family of funds, Valfix. J.J.B. has received speaker fees from Abbott and Edwards Lifesciences. The remaining authors have no conflicts of interest to disclose., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Although it is known that changes in bacterial components of the urinary microbiome are associated with overactive bladder (OAB), the specific role of viruses is still insufficiently investigated. The aim of the present study is to evaluate the role of urinary viruses in woman with OAB, and analyze the potential relationship between viruses, bacteria and disease. Catheterized urine samples were collected from 55 women with OAB and 18 control individuals. OAB patients fulfilling the following criteria were considered eligible for this study: female, 18 years of age or older; presented with classic OAB symptoms defined by the International Continence Society; and OAB Symptom Score (OABSS) total score ≥ 3 points and question 3 (urgency) score ≥ 2 points. Based on results of metagenomic next-generation sequencing (mNGS), all participants were divided into virus-infected and virus-uninfected groups for analysis. The results of mNGS showed that the diversity of the OAB group was lower than that of the control group when focused on bacterial sequences, which was consistent with our previous study. According to the questionnaire filled out by the patients, OABSS and 8-item OAB questionnaire, female OAB patients who had viruses detected in their urine had more severe symptoms. In parallel, John Cunningham virus (mainly subtype 7 and subtype 2) was the most frequently detected virus in urine. Correlation analysis indicated that risk factors for virus infection in OAB patients include age, habit of holding urine and pelvic surgery history. Given our preliminary data, viral infection can aggravate OAB severity and affect the composition of bacterial. Further research is required to explain how viral infections can aggravate OAB patient symptoms and cause bacterial changes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sun, Li, Zhou, Wu, Gao, Wu, Qiu, Zhou, Song, Zhao and Wu.)

Population aging has increased the demand for elderly care worldwide. The home-based elderly care system plays an important role in meeting this demand in developing countries. The quality of home-based elderly care is associated with the job satisfaction of caregivers in home-based elderly care programs, which has rarely been studied. This paper explores the factors that affect the job satisfaction of these elderly caregivers, including personal characteristics, working conditions, employment status, training, caregiver-client relationships, welfare, work experience, and burnout. It utilizes data from the Shanghai Domestic-work Professionalization Survey (SDPS), which was conducted among four types of in-home caregivers ( n = 1000) in Shanghai over the period from May to September 2021. This paper selected a sample of elderly caregivers ( n = 285) to examine their job satisfaction. The results show that gender, age, marital status, how they earned the job, relation with clients, social insurance, and work experience are significantly associated with the job satisfaction of in-home elderly caregivers, and their job satisfaction is negatively associated with their burnout levels. However, training and working conditions have no significant effect on the job satisfaction of in-home elderly caregivers, which is different from previous studies on formal care workers, such as nurses, in the institutional care system.

Purpose: Microvascular invasion (MVI) impairs long-term prognosis of patients with hepatocellular carcinoma (HCC). We aimed to develop a novel nomogram to predict MVI and patients' prognosis based on radiomic features of contrast-enhanced CT (CECT)., Patients and Methods: HCC patients who underwent curative resection were enrolled. The radiomic features were extracted from the region of tumor, and the optimal MVI-related radiomic features were selected and applied to construct radiomic signature (Rad-score). The prediction models were created according to the logistic regression and evaluated. Biomarkers were analyzed via q-PCR from randomly selected HCC patients. Correlations between biomarkers and radiomic signature were analyzed., Results: A total of 421 HCC patients were enrolled. A total of 1962 radiomic features were extracted from the region of tumor, and the 11 optimal MVI-related radiomic features showed a favor predictive ability with area under the curves (AUCs) of 0.796 and 0.810 in training and validation cohorts, respectively. Aspartate aminotransferase (AST), tumor number, alpha-fetoprotein (AFP) level, and radiomics signature were independent risk factors of MVI. The four factors were integrated into the novel nomogram, named as CRM, with AUCs of 0.767 in training cohort and 0.793 in validation cohort for predicting MVI, best among radiomics signature alone and clinical model. The nomogram was well-calibrated with favorable clinical value demonstrated by decision curve analysis and can divide patients into high- or low-risk subgroups of recurrence and mortality. In addition, gene BCAT1, DTGCU2, DOCK3 were analyzed via q-PCR and serum AFP were identified as having significant association with radiomics signature., Conclusion: The novel nomogram demonstrated good performance in preoperatively predicting the probability of MVI, which might guide clinical decision., Competing Interests: The authors have no conflicts of interest for this work., (© 2022 Xu et al.)

Objective: To develop and validate a radiomic nomogram for individualized prediction of hepatocellular carcinoma (HCC) in HBV cirrhosis patients based on baseline magnetic resonance imaging examinations and clinical data., Methods: 364 patients with HBV cirrhosis from five hospitals were assigned to the training, internal validation, external validation-1 or external validation-2 cohort. All patients underwent baseline magnetic resonance image (MRI) scans and clinical follow-up within three-year time. Clinical risk factors and MRI-based features were extracted and analyzed. The radiomic signatures were built using the radiomics-score (Rad-score) that calculated for each patient as a linear weighted combination of selected MRI-based features. Prognostic performances of the clinical and radiomic nomograms were evaluated with Cox modeling in the training and validation cohorts., Results: Eighteen features were selected for inclusion in the Rad-score prognostic model. The radiomic signature from multi-sequence MRI yielded a concordance index (C-index) of 0.710, 0.681, 0.632 and 0.658 in the training, internal validation, external validation-1, external validation-2 cohorts, respectively. Sex and Child-Turcotte-Pugh (CTP) class were the most prognostic clinical risk factors in univariate Cox proportional hazards analyses. The radiomic combined nomogram that integrated the radiomic signature with the clinical factors yielded a C-index of 0.746, 0.710, and 0.641 in the training, internal validation, and external validation-1 cohorts, respectively, which was an improvement over either the clinical nomogram or radiomic signature alone., Conclusion: We developed an MRI-based radiomic combined nomogram with good discrimination ability for the individualized prediction of HCC in HBV cirrhosis patients within three-year time., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wei, Gong, He, Liu, Liu, Yang, Zhou, Liang, Zhan, Xia, Duan, Lin, Han, Li, Qin, Pickhardt and Deng.)

Despite increasing evidence that dysbiosis of urinary microbiota is closely correlated with bladder cancer, the influence of the urinary microbiota on immune evasion and tumor growth in bladder cancer is unknown. This study investigated whether the urinary microbiota influences intratumoral infiltration of FoxP3+ regulatory T cells, expression of Ki-67 and clinical prognosis in non-muscle-invasive bladder cancer. Forty male patients, including 12 and 28 with or without recurrence, respectively, were retrospectively enrolled. Midstream urine samples were preoperatively collected. Urinary microbiota composition was analyzed by 16s rDNA sequencing. Alpha and beta diversities were measured. LEfSe analysis was employed to identify specific bacteria associated with recurrence. Intratumoral infiltration of FoxP3+ regulatory T cells and Ki-67 expression were evaluated by immunohistochemistry. Patients with recurrence had higher α-diversity compared to those without (Shannon Index, P = 0.0007, Simpson Index, P = 0.0004). Distinct beta diversity was observed between recurrence and non-recurrence groups (weighted Unifrac P = 0.02; unweighted Unifrac P = 0.001). LEfSe analysis showed that the recurrence group displayed marked enrichment of Pseudomonas, Staphylococcus, Corynebacterium, and Acinetobacter genera. Patients with higher alpha diversity had elevated Ki-67 expression than those with lower alpha diversity (P = 0.0194), although microbial diversity was unassociated with infiltration of FoxP3+ regulatory T cells (P = 0.1653). Patients with lower urinary microbial diversity had prolonged recurrence-free survival compared to those with higher diversity. Perturbation of urinary microbiota may induce immune evasion and tumor growth, eventually contributing to unfavorable outcomes. Additional study is warranted to confirm a causal role of urinary microbiota in modulating antitumor immune response and survival in bladder cancer., (© 2021. The Author(s) under exclusive licence to Japan Human Cell Society.)

The aim of this study was to explore the effects of miR-939 and miR-376A on the pathogenesis of ulcerative colitis (UC) by using a decoy strategy to regulate the expression of nuclear transcription factor kappa B (NF-κB) and nuclear factor of activated T cells (NFAT). Such strategies represent a potential novel treatment for UC. Quantitative polymerase chain reaction (qPCR) analysis was used to detect the differences between the expression of miR-939, miR-376a, NF-κB, NFAT in the tissue samples from the resting and active stages of UC and healthy controls, and analyzed the correlation. The electrophoretic mobility shift assay was used to validate the ability of miRNAs to bind to NF-κB and NFAT. The expression of components of the intestinal barrier in UC and changes in apoptosis-related factors were examined by western blotting, qPCR, and immunofluorescence. After a dextran sulfate sodium (DSS)-induced mouse model of UC was established, the morphological changes in the colonic tissues of mice, the changes in serum inflammatory factors, and the changes in urine protein or urine leukocytes, liver enzymes, and prothrombin time were measured to examine intestinal permeability. The expression of miR-939 and miR-376a in human UC tissue was significantly lower than that in the normal control tissue, and was negatively correlated with the expression of NF-κB and NFAT. miR-939 and miR-376a decoy strategies resulted in a beneficial increase in the expression of claudins, occludins, and ZO-1 protein and inhibited apoptosis in intestinal epithelial cells. The disease activity index of the UC model group was significantly higher than that of the normal control group. The expression of inflammatory factors in the decoy group was higher than that in the UC model group. Therefore, from the experimental results, it can be concluded that using miR-939 and miR-376a to trap NF-κB and NFAT inhibits the activation of transcription factors NF-κB and NFAT, which in turn inhibits the expression of inflammatory factors and results in partial recovery of the intestinal barrier in UC. The decoy strategy inhibited apoptosis in the target cells and had a therapeutic effect in the mice model of UC. This study provides new ideas for the development of future clinical therapies for UC.

Acute cardiac injury is prevalent in critical COVID-19 and associated with increased mortality. Its etiology remains debated, as initially presumed causes - myocarditis and cardiac necrosis - have proved uncommon. To elucidate the pathophysiology of COVID-19-associated cardiac injury, we conducted a prospective study of the first 69 consecutive COVID-19 decedents at CUIMC in New York City. Of 6 acute cardiac histopathologic features, presence of microthrombi was the most commonly detected among our cohort. We tested associations of cardiac microthrombi with biomarkers of inflammation, cardiac injury, and fibrinolysis and with in-hospital antiplatelet therapy, therapeutic anticoagulation, and corticosteroid treatment, while adjusting for multiple clinical factors, including COVID-19 therapies. Higher peak erythrocyte sedimentation rate and C-reactive protein were independently associated with increased odds of microthrombi, supporting an immunothrombotic etiology. Using single-nuclei RNA-sequencing analysis on 3 patients with and 4 patients without cardiac microthrombi, we discovered an enrichment of prothrombotic/antifibrinolytic, extracellular matrix remodeling, and immune-potentiating signaling among cardiac fibroblasts in microthrombi-positive, relative to microthrombi-negative, COVID-19 hearts. Non-COVID-19, nonfailing hearts were used as reference controls. Our study identifies a specific transcriptomic signature in cardiac fibroblasts as a salient feature of microthrombi-positive COVID-19 hearts. Our findings warrant further mechanistic study as cardiac fibroblasts may represent a potential therapeutic target for COVID-19-associated cardiac microthrombi.

Background: Compared with everolimus-eluting metallic stents, the Absorb bioresorbable scaffold (BRS) results in increased rates of myocardial infarction (MI) and scaffold thrombosis (ST) during its three-year bioresorption phase. It is unknown whether prolonged dual antiplatelet therapy (DAPT) duration might decrease the risk of ischaemic events., Aims: We sought to evaluate the impact of DAPT duration on ischaemic and bleeding outcomes following BRS implantation., Methods: We conducted an individual patient data pooled analysis from four ABSORB randomised trials and one prospective ABSORB registry. Study endpoints were MI, ST, bleeding, and death up to three-year follow-up. Propensity score-adjusted Cox regression analysis was used to account for baseline differences related to DAPT duration., Results: The five ABSORB studies included 2,973 patients. DAPT use was 91.7%, 53.2%, and 48.0% at 1, 2, and 3 years, respectively. DAPT use within the first year after BRS implantation was associated with markedly lower risks of MI (adjusted hazard ratio [aHR] 0.17, 95% CI: 0.10-0.32; p<0.0001) and ST (aHR 0.08, 95% CI: 0.03-0.19; p<0.0001). Conversely, DAPT use between 1 and 3 years did not significantly affect the risk of MI (aHR 1.04, 95% CI: 0.70-1.55; p=0.84) or ST (aHR 0.86, 95% CI: 0.42-1.75; p=0.67). DAPT did not have major effects upon bleeding or death in either period., Conclusions: DAPT use during the first year after BRS implantation was strongly associated with lower risks of ST and MI. However, a benefit of ongoing DAPT use between 1 and 3 years after BRS implantation was not apparent.

Objectives: The aim of this study was to determine the prognostic impact of right ventricular (RV)-pulmonary arterial (PA) coupling in patients with heart failure (HF) with severe secondary mitral regurgitation (SMR) enrolled in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial., Background: RV contractile function and PA pressures influence outcomes in patients with SMR, but the impact of RV-PA coupling in patients randomized to transcatheter edge-to-edge repair (TEER) vs guideline-directed medical therapy (GDMT) is unknown., Methods: RV-PA coupling was assessed by the ratio of RV free wall longitudinal strain derived from speckle-tracking echocardiography and noninvasively measured RV systolic pressure. Advanced RV-PA uncoupling was defined as RV free wall longitudinal strain/RV systolic pressure ≤0.5%/mm Hg. The primary endpoint was a composite of all-cause mortality or HF hospitalization at 24-month follow-up., Results: A total of 372 patients underwent speckle-tracking echocardiography, and 70.2% had advanced RV-PA uncoupling. By multivariable analysis, advanced RV-PA uncoupling was strongly associated with an increased risk for the primary 24-month endpoint of death or HF hospitalization (HR: 1.87; 95% CI: 1.31-2.66; P = 0.0005). A similar association was present for all-cause mortality alone (HR: 2.57; 95% CI: 1.54-4.29; P = 0.0003). The impact of RV-PA uncoupling was consistent in patients randomized to TEER and GDMT alone. Compared with GDMT alone, the addition of TEER improved 2-year outcomes in patients with (48.0% vs 74.8%; HR: 0.51; 95% CI: 0.37-0.71) and those without (28.8% vs 47.8%; HR: 0.51; 95% CI: 0.27-0.97) advanced RV-PA uncoupling (P interaction  = 0.98)., Conclusions: In the COAPT trial, advanced RV dysfunction assessed by RV-PA uncoupling was a powerful predictor of 2-year adverse outcomes in patients with HF and SMR. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial]; NCT01626079)., Competing Interests: Funding Support and Author Disclosures This work was supported by Abbott. Dr Grayburn has received research grants from Abbott Vascular, Boston Scientific, Edwards Lifesciences, Cardiovalve, W.L. Gore, Medtronic, and NeoChord; and consulting fees from Abbott Vascular, Edwards Lifesciences, W.L. Gore, and 4C Medical. Drs Asch and Weissman have core laboratory contracts with Abbott, Neovasc, Ancora, Medtronic, Boston Scientific, Edwards Lifesciences, Biotronik, and LivaNova, for which they receive no direct compensation. Dr Stone has received speaker or other honoraria from Cook, Terumo, Qool Therapeutics, and Orchestra Biomed; served as a consultant to Valfix, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals, Vectorious, Reva, Matrizyme, and CardioMech; and has equity and options from Ancora, Cagent, Applied Therapeutics, the Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, the MedFocus family of funds, and Valfix. Dr Hahn has received speaker fees from Boston Scientific, Baylis Medical, Edwards Lifesciences, and Medtronic; institutional consulting contracts for which she receives no direct compensation with Abbott Structural, Edwards Lifesciences, Gore & Associates, Medtronic, and Philips Healthcare; received nonfinancial support from 3mensio; holds equity with Navigate; and is the chief scientific officer for the echocardiography core laboratory at the Cardiovascular Research Foundation for multiple industry-sponsored trials, for which she receives no direct industry compensation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Radiotherapy is known to influence immune function, including T cell receptor (TCR) repertoire. We evaluated the TCR repertoire before and after stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer (NSCLC) and explored correlations between TCR indexes and distant failure after SBRT. TCR repertoires were analyzed in peripheral blood mononuclear cells (PBMCs) collected before and after SBRT from 19 patients. TCR combinational diversity in V and J genes was assessed with multiplex PCR of genomic DNA from PBMCs and tested for associations with clinical response. All patients received definitive SBRT to a biologically effective dose of >=100 Gy. The number of unique TCR clones was decreased after SBRT versus before, but clonality and the Shannon Entropy did not change. Four patients (21%) developed distant metastases after SBRT (median 7 months); those patients had lower Shannon Entropy in post-SBRT samples than patients without metastasis. Patients with a low change in Shannon Entropy from before to after SBRT [(post-SBRT Shannon Entropy minus baseline Shannon)/(baseline Shannon) * 100] had poorer metastasis-free survival than those with high change in Shannon Entropy (P<0.001). Frequencies in V/J gene fragment expression in the TCR β chain were also different for patients with or without metastases (two V fragments in baseline samples and 2 J and 9 V fragments in post-treatment samples). This comprehensive analysis of immune status before and after SBRT showed that quantitative assessments of TCRs can help evaluate prognosis in early-stage NSCLC., Competing Interests: PaL and ZZ were employed by Geneplus-Beijing Institute. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wu, Zhu, Rudqvist, Welsh, Lee, Liao, Xu, Jiang, Zhu, Pan, Li, Zhou, He, Yin and Feng.)

Background: Left ventricular (LV) global longitudinal strain (GLS) is a sensitive marker of LV function and may help identify patients with heart failure (HF) and secondary mitral regurgitation who would have a better prognosis and are more likely to benefit from edge-to-edge transcatheter mitral valve repair with the MitraClip. The aim of this study was to assess the prognostic utility of baseline LV GLS during 2-year follow-up of patients with HF with secondary mitral regurgitation enrolled in the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation trial., Methods: Patients with symptomatic HF with moderate to severe or severe secondary mitral regurgitation who remained symptomatic despite maximally tolerated guideline-directed medical therapy (GDMT) were randomized to transcatheter mitral valve repair plus GDMT or GDMT alone. Speckle-tracking-derived LV GLS from baseline echocardiograms was obtained in 565 patients and categorized in tertiles. Death and HF hospitalization at 2-year follow-up were the principal outcomes of interest., Results: Patients with better baseline LV GLS had higher blood pressure, greater LV ejection fraction and stroke volume, lower levels of B-type natriuretic peptide, and smaller LV size. No significant difference in outcomes at 2-year follow-up were noted according to LV GLS. However, the rate of death or HF hospitalization between 10 and 24 months was lower in patients with better LV GLS (P = .03), with no differences before 10 months. There was no interaction between GLS tertile and treatment group with respect to 2-year clinical outcomes., Conclusions: Baseline LV GLS did not predict death or HF hospitalization throughout 2-year follow-up, but it did predict outcomes after 10 months. The benefit of transcatheter mitral valve repair over GDMT alone was consistent in all subgroups irrespective of baseline LV GLS., (Copyright © 2021 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to evaluate various stent expansion indexes to determine the best predictor of clinical outcomes., Background: Numerous intravascular ultrasound (IVUS) studies have shown minimum stent area (MSA) to be the most powerful predictor of future events., Methods: ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) was a prospective, multicenter registry of 8,582 patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents. Native coronary artery lesions treated with IVUS-guided PCI with final analyzable IVUS were included. Ten stent expansion indexes (MSA, MSA/vessel area at MSA site, conventional stent expansion [MSA/average of proximal and distal reference luminal area], minimum stent expansion using Huo-Kassab or linear model accounting for vessel tapering, stent asymmetry [minimum/maximum stent diameter within the entire stent], stent eccentricity [smallest minimum/maximum stent diameter at a single slice within the stent], IVUS-XPL [Impact of intravascular Ultrasound Guidance on Outcomes of Xience Prime Stents in Long Lesions] criteria, ULTIMATE [Intravascular Ultrasound Guided Drug Eluting Stents Implantation in "All-Comers" Coronary Lesions] criteria, and ILUMIEN IV criteria) were evaluated for their associations with lesion-specific 2-year clinically driven target lesion revascularization (TLR) or definite stent thrombosis., Results: Overall, 2,140 lesions in 1,831 patients were included; final MSA measured 6.2 ± 2.4 mm 2 . Among the 10 stent expansion indexes, only MSA/vessel area at the MSA site was independently associated with 2-year clinically driven TLR or definite stent thrombosis (hazard ratio: 0.77; 95% confidence interval: 0.59-0.99; P = 0.04) after adjusting for morphologic and procedural parameters., Conclusions: In this IVUS-guided PCI cohort with excellent final MSA overall, stent/vessel area at the MSA site, an index of relative stent expansion, was superior to absolute MSA and other expansion indexes in predicting 2-year clinically driven TLR or definite stent thrombosis., Competing Interests: Funding Support and Author Disclosures The ADAPT-DES study was sponsored by the Cardiovascular Research Foundation, with funding provided by Boston Scientific, Abbott Vascular, Medtronic, Cordis, Biosensors, The Medicines Company, Daiichi-Sankyo, Eli Lilly, Volcano, and Accumetrics. Dr Matsumura is a consultant for Terumo. Dr. Metzger has received symposium honoraria from Abbott Vascular and Boston Scientific. Dr Rinaldi is an advisory board member for Abbott, Boston Scientific, Cordis, and 4C Medical; has taught courses for Abbott and Edwards Lifesciences; is a consultant for Abbott, Boston Scientific, Edwards Lifesciences, and Cordis; and has received research and grant support from Boston Scientific. Dr Duffy is a consultant and speaker for Philips Medical/Volcano. Dr Weisz has received consulting fees from Filterlex, Intratech, and Magenta; holds stock options in Filterlex, Intratech, Magenta, Medivizer, Trisol, and Vectorious; and has received honoraria from Cardiovascular Systems. Dr Stuckey is an advisory board member for Boston Scientific; and has received speaker honoraria from Boston Scientific and Eli Lilly/Daiichi-Sankyo. Dr Ali has received institutional research grants to Columbia University from Abbott, Cardiovascular Systems; is a consultant for Amgen, AstraZeneca, and Boston Scientific; and holds equity in Shockwave Medical. Dr. Mintz has received honoraria from Boston Scientific, Philips, Terumo, and Medtronic. Dr Stone has received speaker or other honoraria from Cook, Terumo, Qool Therapeutics, and Orchestra Biomed; is a consultant to Valfix, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals, Vectorious, Reva, Matrizyme, CardioMech; and holds equity or options in Ancora, Qool Therapeutics, Cagent, Applied Therapeutics, the Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, the MedFocus family of funds, and Valfix. Dr Maehara has received grant support from and is a consultant for Abbott Vascular and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Gynecologic malignancies, mainly including ovarian cancer, cervical cancer and endometrial cancer, are leading causes of death among women worldwide with high incidence and mortality rate. Recently, adoptive T cell therapy (ACT) using engineered T cells redirected by genes which encode for tumor-specific T cell receptors (TCRs) or chimeric antigen receptors (CARs) has demonstrated a delightful potency in B cell lymphoma treatment. Researches impelling ACT to be applied in treating solid tumors like gynecologic tumors are ongoing. This review summarizes the preclinical research and clinical application of engineered T cells therapy for gynecologic cancer in order to arouse new thoughts for remedies of this disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Xu, Jiang, Wang, Wang, Li, Lai, Zhou, Zhu, Xiang, Wang, Zhu, Yu, Huang, Zheng and Wu.)

Background: The association between Clostridioides difficile colonization and C. difficile infection (CDI) is unknown in solid-organ transplant (SOT) patients. We examined C. difficile colonization and healthcare-associated exposures as risk factors for development of CDI in SOT patients., Methods: The retrospective study cohort included all consecutive SOT patients with at least 1 screening test between May 2017 and April 2018. CDI was defined as the presence of diarrhea (without laxatives), a positive C. difficile clinical test, and the use of C. difficile-directed antimicrobial therapy as ordered by managing clinicians. In addition to demographic variables, exposures to antimicrobials, immunosuppressants, and gastric acid suppressants were evaluated from the time of first screening test to the time of CDI, death, or final discharge., Results: Of the 348 SOT patients included in our study, 33 (9.5%) were colonized with toxigenic C. difficile. In total, 11 patients (3.2%) developed CDI. Only C. difficile colonization (odds ratio [OR], 13.52; 95% CI, 3.46-52.83; P = .0002), age (OR, 1.09; CI, 1.02-1.17; P = .0135), and hospital days (OR, 1.05; 95% CI, 1.02-1.08; P = .0017) were independently associated with CDI., Conclusions: Although CDI was more frequent in C. difficile colonized SOT patients, the overall incidence of CDI was low in this cohort.

Codon usage bias is a fundamental feature of all genomes and plays an important role in determining gene expression levels. The codon usage was thought to influence gene expression mainly due to its impact on translation. Recently, however, codon usage was shown to affect transcription of fungal and mammalian genes, indicating the existence of a gene regulatory phenomenon with unknown mechanism. In Neurospora , codon usage biases strongly correlate with mRNA levels genome-wide, and here we show that the correlation between codon usage and RNA levels is maintained in the nucleus. In addition, codon optimality is tightly correlated with both total and nuclear RNA levels, suggesting that codon usage broadly influences mRNA levels through transcription in a translation-independent manner. A large-scale RNA sequencing-based genetic screen in Neurospora identified 18 candidate factors that when deleted decreased the genome-wide correlation between codon usage and RNA levels and reduced the codon usage effect on gene expression. Most of these factors, such as the H3K36 methyltransferase, are chromatin regulators or transcription factors. Together, our results suggest that the transcriptional effect of codon usage is mediated by multiple transcriptional regulatory mechanisms., Competing Interests: The authors declare no competing interest.

Brain metastasis (BM) is a common malignant event in lung cancer. Here, we recruited 33 lung cancer patients with brain oligo-metastasis to explore the genomic features and tumor immune microenvironment (TIME) of the lung and BM independently. For genomic profiling, targeted sequencing was performed. We found that high-frequent ZFHX3 occurred in the lung (40%) and brain tumor (28%), which might relate to brain metastasis event; the vast majority of patients had lesions-shared mutations in primary tumor and BM, confirming the common clonal events; and EGFR was the most frequently clonal gene in both lung and BM, indicating its driver capability. To characterize TIME status, we also sequenced the T cell receptor (TCR) repertoires and performed immunohistochemistry (IHC) on CD8+ tumor-infiltrating lymphocytes (TILs) and PD-L1 expression in 28 patients who had paired samples. Through the comparison, the TCR clonality of BM was higher than lung tumor, indicating the distinct pattern of the stronger oligoclonal T cell expansion in BM; the primary tumor had a higher TMB than oligo-BM (13.9 vs 8.7 mutations, p = 0.019); CD8 + TILs of BM were significantly lower than lung tumor (10% vs 30%, p = 0.015), revealing the lower level of cytotoxic T cell infiltration; BM showed statistically equivalent level of PD-L1 compared with lung tumor (p = 0.722). We further investigated the potential biomarkers associated with overall survival (OS) after brain surgery. We found that higher TCR clonality was related to prolonged OS in EGFR-treated patients (HR 0.175, p < 0.001) but the worse outcomes in non-EGFR-treated (HR 2.623, p = 0.034). More CD8+ TILs were an independently positive indicator for OS, in EGFR-treated (HR 0.160, p = 0.001) and non-EGFR-treated patients (HR 0.308, p = 0.009). These findings provide a meaningful molecular and clinical understanding of lung carcinoma and brain oligo-metastasis.

Graph Convolution Network (GCN) has been successfully used for 3D human pose estimation in videos. However, it is often built on the fixed human-joint affinity, according to human skeleton. This may reduce adaptation capacity of GCN to tackle complex spatio-temporal pose variations in videos. To alleviate this problem, we propose a novel Dynamical Graph Network (DG-Net), which can dynamically identify human-joint affinity, and estimate 3D pose by adaptively learning spatial/temporal joint relations from videos. Different from traditional graph convolution, we introduce Dynamical Spatial/Temporal Graph convolution (DSG/DTG) to discover spatial/temporal human-joint affinity for each video exemplar, depending on spatial distance/temporal movement similarity between human joints in this video. Hence, they can effectively understand which joints are spatially closer and/or have consistent motion, for reducing depth ambiguity and/or motion uncertainty when lifting 2D pose to 3D pose. We conduct extensive experiments on three popular benchmarks, e.g., Human3.6M, HumanEva-I, and MPI-INF-3DHP, where DG-Net outperforms a number of recent SOTA approaches with fewer input frames and model size.

The aim of the present study was to explore the value of T 1 mapping on gadolinium-ethoxybenzyl diethylenetriamine pentaacetic (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) for grading hepatocellular carcinoma (HCC) and predicting its recurrence rate. A retrospective study was performed that included 75 patients (66 men and 9 women; mean age, 52.89 years; age range, 23-79 years) with HCC who had undergone Gd-EOB-DTPA-enhanced MRI with T 1 mapping before surgery. The T 1 relaxation time of the 81 lesions and non-tumorous liver parenchyma in 75 patients with HCC were measured before Gd-EOB-DTPA was injected and then at 5, 10 and 20 min after administration, respectively. T 1[lesion (L)-hepatic parenchyma (H)]/H (%) was calculated as the increment rate of the T 1 value in the lesions relative to the non-tumorous liver parenchyma. One-way analysis of variance and Spearman's correlation analysis was used to compare the differences and relationship of T 1 mapping values among the three grades of HCC. A total of 81 lesions were divided into well-differentiated HCC (grades I; n=21), moderately differentiated HCC (grades II; n=40) and poorly differentiated HCC (grades III; n=20) according to the histopathology. The T 1(L-H)/H (%) value among grades I, II and III HCC on pre-contrast results and on post-contrast results at the 5-, 10- and 20-min hepatobiliary phase (HBP) were significantly different (P<0.05), and T 1(L-H)/H (%) was correlated with the histological grade of HCC at each time point (r=0.637, r=0.554, r=0.499 and r=0.560, respectively, P<0.001). A total of 41 recurrence cases [grade I (n=5), grade II (n=23) and grade III (n=13)] were verified by imaging (CT, MRI or ultrasound) or reoperation. Patients with grade III and grade II HCC had higher recurrence rates compared with that in patients with grade I HCC (P<0.05; median recurrence times were 258 days, 605 days and undefined, respectively). According to the optimal cut-off point for the T 1(L-H)/H (%) of the three grades of HCC, patients with HCC in the low T 1(L-H)/H (%) value group (≤155.15%) had lower cumulative recurrence rates compared with that in the medium (T 1(L-H)/H (%) >155.15% and T1 (L-H)/H (%) ≤241.20%) and high (T 1(L-H)/H (%) >241.20%) value groups at the 20-min HBP (P<0.05; median recurrence times were undefined, 530 days and 447 days, respectively). These results indicate that the parameters of T 1 mapping would be beneficial for predicting the grading and recurrence of HCC.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely malignant tumor in humans. Thus, understanding the tumorigenesis of PDAC appears to help develop efficient therapy. Here, we show that activated TGFβ receptor signaling induces apoptosis of pancreatic carcinoma cells in vitro and in vivo, suggesting that activation of TGFβ receptor signaling may prevent development of PDAC.

Objectives: Spontaneous rupture of hepatocarcinoma (HCC) is a fatal complication of advanced HCC and is associated with poor prognosis. However, there is no consensus on the best approach to treat hemoperitoneum due to ruptured HCC. In this paper, we evaluate and discuss the outcomes of different treatment methods employed at our center for ruptured HCC., Methods: We reviewed the medical records of 132 patients diagnosed with ruptured HCC at our hospital from January 2003 to December 2012 and evaluated and compared the outcomes of five treatment methods for ruptured HCC: conservative treatment, surgical hemostasis, transarterial embolization (TAE), and one- and two-stage resections., Results: There was no significant difference in the median survival time between the conservative treatment and surgical hemostasis groups. Patients in the TAE alone group had a better prognosis than those in the conservative treatment and surgical hemostasis groups. The survival time of the tumor resection group was obviously better than that of the conservative treatment, surgical hemostasis, and TAE alone groups, but no significant difference was observed between the one-stage and two-stage resection groups., Conclusions: One-stage hepatectomy is a better option for patients with preserved liver function, whereas TAE is a better option for those with poorly preserved liver function.