A Diagnostic Test Meta-Analysis Evaluating Imaging-Based and Blood Biomarker-Based Assessment Tools for Fibrosis After Liver Transplantation.

Early detection of liver graft fibrosis is crucial for risk stratification to identify patients for liver biopsy and timely treatment. However, diagnostic accuracy of noninvasive tests (NITs) remains unclear. Thus, this study sought to evaluate diagnostic accuracy of NITs in assessing liver allograft fibrosis and compare the differences in specificities and sensitivities among NITs. Medline and Embase databases were searched to include articles on diagnostic tests in liver transplantation (LT) patients with fibrosis. A meta-analysis on diagnostic test accuracy was conducted in a random-effects model. Sensitivities and specificities among the diagnostic tests were compared, and threshold values were calculated where applicable. A total of 25 articles were included. Vibration-controlled transient elastography (VCTE) met the minimum diagnostic accuracy requirements, yielding sensitivity, specificity, and diagnostic odds ratios of 0.9 (CI, 0.8-1.0), 0.9 (CI, 0.8-1.0), and 379.6 (CI, 45.8-1728.7), respectively. In the threshold assessment, the optimal cutoff was 9.30 kPa with a sensitivity, specificity, and area under the curve of 0.7 (CI, 0.5-0.9), 0.9 (CI, 0.8-0.9), and 0.9 (CI, 0.8-0.9), respectively. For significant fibrosis, acoustic radiation force impulse (ARFI) was superior to FibroTest (LabCorp [Burlington, NC]) and magnetic resonance elastography (MRE) in sensitivity. VCTE was superior to FibroTest in specificity. For advanced fibrosis, ARFI was superior to the Fibrosis-4 Index (FIB-4) in sensitivity. VCTE was superior to the AST to Platelet Ratio Index (APRI), MRE, and FIB-4 in specificity. In cirrhosis, VCTE was superior to APRI in specificity (P = 0.004) with comparable sensitivity. This study demonstrates the potential of VCTE and ARFI as diagnostic tools for fibrosis in LT recipients compared with blood-based NITs, which were shown to be less optimal.

Temporal Changes in Extracellular Vesicle Hemostatic Protein Composition Predict Favourable Left Ventricular Remodeling after Acute Myocardial Infarction.

The subset of plasma extracellular vesicles (EVs) that coprecipitate with low-density lipoprotein (LDL-EVs) carry coagulation and fibrinolysis pathway proteins as cargo. We investigated the association between LDL-EV hemostatic/fibrinolysis protein ratios and post-acute myocardial infarction (post-AMI) left ventricular (LV) remodeling which precedes heart failure. Protein concentrations of von Willebrand factor (VWF), SerpinC1 and plasminogen were determined in LDL-EVs extracted from plasma samples obtained at baseline (within 72 h post-AMI), 1 month and 6 months post-AMI from 198 patients. Patients were categorized as exhibiting adverse (n = 98) or reverse (n = 100) LV remodeling based on changes in LV end-systolic volume (increased or decreased ≥15) over a 6-month period. Multiple level longitudinal data analysis with structural equation (ML-SEM) model was used to assess predictive value for LV remodeling independent of baseline differences. At baseline, protein levels of VWF, SerpinC1 and plasminogen in LDL-EVs did not differ between patients with adverse versus reverse LV remodeling. At 1 month post-AMI, protein levels of VWF and SerpinC1 decreased whilst plasminogen increased in patients with adverse LV remodeling. In contrast, VWF and plasminogen decreased whilst SerpinC1 remained unchanged in patients with reverse LV remodeling. Overall, compared with patients with adverse LV remodeling, higher levels of SerpinC1 and VWF but lower levels of plasminogen resulted in higher ratios of VWF:Plasminogen and SerpinC1:Plasminogen at both 1 month and 6 months post-AMI in patients with reverse LV remodeling. More importantly, ratios VWF:Plasminogen (AUC = 0.674) and SerpinC1:Plasminogen (AUC = 0.712) displayed markedly better prognostic power than NT-proBNP (AUC = 0.384), troponin-I (AUC = 0.467) or troponin-T (AUC = 0.389) (p < 0.001) to predict reverse LV remodeling post-AMI. Temporal changes in the ratios of coagulation to fibrinolysis pathway proteins in LDL-EVs outperform current standard plasma biomarkers in predicting post-AMI reverse LV remodeling. Our findings may provide clinical cues to uncover the cellular mechanisms underpinning post-AMI reverse LV remodeling.

A meta-analysis on the incidence of donor-related depression after liver transplant.

Living donor liver transplantation (LDLT) is increasing, yet gaps exist in the understanding of psychological wellbeing of donors after liver transplant. This meta-analysis seeks to evaluate the incidence and risk factors for donor-related depression after liver transplantation. A search was conducted on Medline and Embase database. Articles assessing incidence of depression in LDLT donors were included. Incidence was pooled after Freeman-Turkey double-arcsine transformation. For risk factors, dichotomous variables were analyzed with generalized linear model, while a conventional meta regression with logit transformation was conducted for continuous variables. Of 1069 abstracts, 40 articles underwent full-text review. Seventeen articles were included. The pooled incidence of depression among 1888 LT donors was 7.66% (CI: 4.47-12.80%). Depression rates were significantly higher in Asian compared to Western studies (RR: 1.73, CI: 1.19-2.52, P = 0.0039). Female gender (P < 0.001), Caucasian ethnicity (P = 0.047), employment status (P < 0.001) and lower education levels (P = 0.044) were significantly associated with depression. Donor relationship with recipients was not a significant risk factor. LDLT remains a core aspect of the treatment of end-stage liver disease. However, the high depression rates after LT suggest that there remains room for improvement in the care of donors' mental health post-transplant.

A 10-year review on older patients undergoing colorectal cancer surgery: surgeon-led geriatric service and good quality surgery are drivers of good outcomes.

BACKGROUND: Older age and frailty are associated with worse postoperative outcomes and prolonged length of stay (LOS). In this study, we aimed to analyze the long-term outcomes after the implementation of our geriatric surgical service (GSS). METHODS: This was a single-center retrospective study from July 2010 to December 2021 on patients aged ≥75 years or patients aged ≥65 years with frailty. Our GSS includes multidisciplinary assessment and optimization by specialized nurses, physiotherapists, anesthetists, dietitians, and geriatricians. Cumulative sum (CUSUM) analysis was used to assess the performance of our GSS. Our primary outcome was defined as the presence of 30-day mortality, prolonged LOS ≥ 14 days, and/or >10% decrease in the modified Barthel Index at 6 weeks, which depicts the failure of GSS. A downsloping CUSUM curve implies consecutive cases of success. RESULTS: There were 233 patients with a mean age of 79.0 ± 4.9 years; of these, 73 patients (31.3%) were frail. The overall 30-day mortality (1.7%), Clavien-Dindo ≥ grade IIIA complications (12.0%), and LOS (median, 7.0 days) were low. The CUSUM analysis showed 3 phases with overall sustained improvement in outcomes. Transient inconsistency in the second phase (during midimplementation of GSS) may be due to the early adoption of laparoscopic surgery (44.6% vs 24.1%; adjusted P =.031) and expansion of service to include patients with higher perioperative risks (weighted Charlson Comorbidity Index score ≥4: 64.9% vs 38.0%; adjusted P =.002) in the second period compared with the first period. The outcomes subsequently improved in the third phase after overcoming the learning curve. CONCLUSION: Our GSS showed sustained performance over the past decade. Good quality surgery and surgeon-led geriatric service are paramount for good postoperative outcomes.

Is underwater endoscopic mucosal resection of colon polyps superior to conventional techniques? A network analysis of endoscopic mucosal resection and submucosal dissection.

Background and study aims Evidence from recent trials comparing conventional endoscopic mucosal resection (EMR) to underwater EMR (UEMR) have matured. However, studies comparing UEMR to endoscopic submucosal dissection (ESD) are lacking. Hence, we sought to conduct a comprehensive network meta-analysis to compare the efficacy of UEMR, ESD, and EMR. Methods Embase and Medline databases were searched from inception to December 2020 for articles comparing UEMR with EMR and ESD. Outcomes of interest included rates of en bloc and complete polyp resection, risk of perforation and bleeding, and local recurrence. A network meta-analysis comparing all three approaches was conducted. In addition, a conventional comparative meta-analysis comparing UEMR to EMR was performed. Analysis was stratified according to polyp sizes (< 10 mm, ≥ 10 mm, and ≥ 20 mm). Results Twenty-two articles were included in this study. For polyps ≥ 10 mm, UEMR was inferior to ESD in achieving en bloc resection ( P  = 0.02). However, UEMR had shorter operating time for polyps ≥ 10 mm ( P  < 0.001), and ≥20 mm ( P  = 0.019) with reduced perforation risk for polyps ≥ 10 mm ( P  = 0.05) compared to ESD. In addition, en bloc resection rates were similar between UEMR and EMR, although UEMR had reduced recurrence for polyps ≥ 10 mm ( P  = 0.013) and ≥ 20 mm ( P  = 0.014). UEMR also had shorter mean operating than EMR for polyps ≥ 10 mm ( P  < 0.001) and ≥ 20 mm ( P  < 0.001). Risk of bleeding and perforation with UEMR and EMR were similar for polyp of all sizes. Conclusions UEMR has demonstrated technical and oncological outcomes comparable to ESD and EMR, along with a desirable safety profile. UEMR appears to be a safe and effective alternative to conventional methods for resection of polyps ≥ 10 mm.

Plasma tissue factor coagulation activity in post-acute myocardial infarction patients.

Introduction: Coagulation is involved in fibroproliferative responses following acute myocardial infarction (AMI). Left ventricular (LV) remodeling following AMI is closely associated with progression to heart failure. This study aims to assess the association between plasma tissue factor activity and LV remodeling in post-AMI patients. Methods: We studied 228 patients with AMI and 57 healthy subjects. Patients with AMI were categorized into two age- and sex-matched groups: patients with adverse LV remodeling or reverse LV remodeling, defined by an increase or decrease, respectively, in LV end systolic volume by ≥15% over 6 months. TF activity was measured in plasma collected at baseline (within 72 hours of revascularization), 1 month and 6 months post-AMI. Multiple level longitudinal data analysis with structural equation (ML-SEM) model was used to assess the impact of various clinical variables on TF activity in post-AMI. Results: Plasma TF activity in post-AMI patients at baseline (29.05 ± 10.75 pM) was similar to that in healthy subjects but fell at 1 month (21.78 ± 8.23, p<0.001) with partial recovery by 6 months (25.84 ± 8.80, p<0.001) after AMI. Plasma TF activity at 6 month post-AMI was better restored in patients with reverse LV remodeling than those with adverse LV remodeling (27.35 ± 7.14 vs 24.34 ± 9.99; p=0.009) independent of gender, age and relevant cardiovascular risk factors. Conclusions: Plasma TF activity decreased after AMI but was better restored at 6 months in patients with reverse LV remodeling. The clinical significance of changes in post-AMI plasma TF activity needs further investigation.

Extracellular vesicles in cardiovascular disease.

Cardiovascular disease remains the leading cause of morbidity and mortality globally. Extracellular vesicles (EVs), a group of heterogeneous nanosized cell-derived vesicles, have attracted great interest as liquid biopsy material for biomarker discovery in a variety of diseases including cardiovascular disease. Because EVs inherit bioactive components from parent cells and are able to transfer their contents to recipient cells, EVs hold great promise as potential cell-free therapeutics and drug delivery systems. However, the development of EV-based diagnostics, therapeutics or drug delivery systems has been challenging due to the heterogenicity of EVs in biogenesis, size and cellular origin, the lack of standardized isolation and purification methods as well as the low production yield. In this review, we will provide an overview of the recent advances in EV-based biomarker discovery, highlight the potential usefulness of EVs and EV mimetics for therapeutic treatment and drug delivery in cardiovascular disease. In view of the fast development in this field, we will also discuss the challenges of current methodologies for isolation, purification and fabrication of EVs and potential alternatives.

Endoscopic submucosal dissection versus endoscopic mucosal resection for rectal carcinoid tumor. A meta-analysis and meta-regression with single-arm analysis.

OBJECTIVE: As there has been so far no consensus on the best endoscopic resection technique, a meta-analysis was conducted to compare the efficacy and safety of endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) for treating rectal carcinoid tumors. METHODS: MEDLINE and EMBASE databases were searched for articles on the treatment of rectal carcinoid tumors using ESD vs EMR published up to October 2020 for outcomes including en bloc and complete resection, margin involvement, procedure time, requirement for additional surgery, bleeding, perforation and recurrence. Risk ratio and weighted mean differences were used for a DerSimonian and Laird random effects pairwise meta-analysis. Single-arm meta-analyses of proportions and random effects meta-regression analysis were also conducted. RESULTS: Twenty-two studies involving 1360 rectal carcinoid tumors were included, in which 655 and 705 rectal carcinoid tumors were resected with ESD and EMR, respectively. The resection efficacy of ESD was comparable to that of EMR for tumors <10 mm. However, there were a significantly higher complete resection rate, and lower rates of vertical margin involvement and requirement for additional surgery using ESD than using EMR for tumors ≤20 mm. ESD had a longer procedure time and an increased likelihood of bleeding than EMR. CONCLUSIONS: ESD is more effective in providing a curative treatment for rectal carcinoid tumors ≤20 mm in size as ESD can achieve a higher complete resection rate with lower vertical margin involvement than EMR. While they are suitable for treating rectal carcinoid tumors <10 mm as both techniques provide similar efficacy.

Endoscopic submucosal dissection vs endoscopic mucosal resection for colorectal polyps: A meta-analysis and meta-regression with single arm analysis.

BACKGROUND: Endoscopic submucosal dissection (ESD) has shown to be effective in management of colorectal neoplasm in the Asian countries, while its implementation in Western countries where endoscopic mucosal resection (EMR) is preferred is still debatable. AIM: To compare the surgical, histological, and oncological outcomes between ESD and EMR in the treatment of colorectal polyps, with subgroup analysis comparing the efficacy of ESD and EMR between Japan and the rest of the world. METHODS: Embase and Medline databases were searched from inception to October 2020 in accordance with PRISMA guidelines for studies comparing en bloc, complete resection, margin involvement, resection time, need for additional surgery, complications, and recurrence rate of ESD with EMR. RESULTS: Of 281344 colorectal polyps from 21 studies were included. When compared to EMR, the pooled analysis revealed ESD was associated with higher en bloc and complete resection rate, and lower lateral margin involvement and recurrence. ESD led to increased procedural time, need for additional surgery, and perforation risk. No significant difference in bleeding risk was found between the two groups. Meta-regression analysis suggested only right colonic polyps correlated with an increased perforation risk in ESD. Confounders including polyp size and invasion depth did not significantly influence the en bloc and complete resection rate, bleeding risk and recurrence. In subgroup analysis, Japan performed better than the rest of the world in both ESD and EMR with perforation risk of 4% and 0.0002%, respectively, as compared to perforation risk of 8% and 1%, respectively, in reports coming from rest of the world. CONCLUSION: ESD resulted in better resection outcomes and lower recurrence compared to EMR. With appropriate training, ESD is preferred over EMR as the first-line therapy for resection of colorectal polyps, without restricting to lesions greater than 20 mm and those with high suspicion of submucosal invasion.

Tissue factor cytoplasmic domain exacerbates post-infarct left ventricular remodeling via orchestrating cardiac inflammation and angiogenesis.

The coagulation protein tissue factor (TF) regulates inflammation and angiogenesis via its cytoplasmic domain in infection, cancer and diabetes. While TF is highly abundant in the heart and is implicated in cardiac pathology, the contribution of its cytoplasmic domain to post-infarct myocardial injury and adverse left ventricular (LV) remodeling remains unknown. Methods: Myocardial infarction was induced in wild-type mice or mice lacking the TF cytoplasmic domain (TF∆CT) by occlusion of the left anterior descending coronary artery. Heart function was monitored with echocardiography. Heart tissue was collected at different time-points for histological, molecular and flow cytometry analysis. Results: Compared with wild-type mice, TF∆CT had a higher survival rate during a 28-day follow-up after myocardial infarction. Among surviving mice, TF∆CT mice had better cardiac function and less LV remodeling than wild-type mice. The overall improvement of post-infarct cardiac performance in TF∆CT mice, as revealed by speckle-tracking strain analysis, was attributed to reduced myocardial deformation in the peri-infarct region. Histological analysis demonstrated that TF∆CT hearts had in the infarct area greater proliferation of myofibroblasts and better scar formation. Compared with wild-type hearts, infarcted TF∆CT hearts showed less infiltration of proinflammatory cells with concomitant lower expression of protease-activated receptor-1 (PAR1) - Rac1 axis. In particular, infarcted TF∆CT hearts displayed markedly lower ratios of inflammatory M1 macrophages and reparative M2 macrophages (M1/M2). In vitro experiment with primary macrophages demonstrated that deletion of the TF cytoplasmic domain inhibited macrophage polarization toward the M1 phenotype. Furthermore, infarcted TF∆CT hearts presented markedly higher peri-infarct vessel density associated with enhanced endothelial cell proliferation and higher expression of PAR2 and PAR2-associated pro-angiogenic pathway factors. Finally, the overall cardioprotective effects observed in TF∆CT mice could be abolished by subcutaneously infusing a cocktail of PAR1-activating peptide and PAR2-inhibiting peptide via osmotic minipumps. Conclusions: Our findings demonstrate that the TF cytoplasmic domain exacerbates post-infarct cardiac injury and adverse LV remodeling via differential regulation of inflammation and angiogenesis. Targeted inhibition of the TF cytoplasmic domain-mediated intracellular signaling may ameliorate post-infarct LV remodeling without perturbing coagulation.

Recovery of spiked troponin I in four routine assays.

INTRODUCTION: This study aimed to examine the recovery of spiked human cardiac troponin I (cTnI) results measured by four routine assays, and investigate possible interference from microclots. MATERIALS AND METHODS: 457 consecutive samples with cTnI concentration below limit of quantitation (12 ng/L), declared by the Vitros TnI ES assay (reference assay), were measured on Beckman Coulter Accu TnI+3, Siemens TnI-Ultra and Roche TnI STAT assays. These samples were enriched with native full-length cTnI to a concentration of 100 ng/L and retested. A post-spiking result that exceeded the critical difference at a predefined probability of 0.0005 of the target concentration (the median post-spiking result for each individual assay) was considered as outlier. To determine whether microclots were a significant cause of critically discrepant outlier results, a separate 50 samples were centrifuged twice between two post-spiking measurements using the Vitros TnI ES assay. RESULTS: The median recovery of the enriched cTnI was highest with the Roche assay (271 ng/L) and lowest with the Vitros assay (29 ng/L). The Vitros assay had the highest percentage of results that exceeded the critical difference (49%), followed by the Siemens (38%), Roche (18%) and Beckman Coulter (7%) assays. None of the 50 additional samples produced a critically lower cTnI result after re-centrifugation. CONCLUSIONS: Our findings underscored the variability of cTnI assays in measuring native cTnI. The lack of cTnI results that became significantly lower after re-centrifugation suggested that microclots are unlikely to be a major cause of the outlier results.