High serum copper as a risk factor of all-cause and cause-specific mortality among US adults, NHANES 2011-2014.

Background: Several studies have shown that serum copper levels are related to coronary heart disease, diabetes, and cancer. However, the association of serum copper levels with all-cause, cause-specific [including cardiovascular disease (CVD) and cancer] mortality remains unclear. Objectives: This study aimed to prospectively examine the association of copper exposure with all-cause, CVD, and cancer mortality among US adults. Methods: The data for this analysis was obtained from the National Health and Nutrition Examination Survey (NHANES) between 2011 and 2014. Mortality from all-causes, CVD, and cancer mortality was linked to US National Death Index mortality data. Cox regression models were used to estimate the association between serum copper levels and all-cause, CVD, and cancer mortality. Results: A total of 2,863 adults were included in the main study. During the mean follow-up time of 81.2 months, 236 deaths were documented, including 68 deaths from cardiovascular disease and 57 deaths from cancer. The weighted mean overall serum copper levels was 117.2 ug/L. After adjusting for all of the covariates, compared with participants with low (1st tertile, <103 µg/L)/medium (2st tertile, 103-124 µg/L) serum copper levels, participants with high serum copper levels (3rd tertile, ≥124 µg/L) had a 1.75-fold (95% CI, 1.05-2.92)/1.78-fold (1.19,2.69) increase in all-cause mortality, a 2.35-fold (95% CI, 1.04-5.31)/3.84-fold (2.09,7.05) increase in CVD mortality and a 0.97-fold (95% CI, 0.28-3.29)/0.86-fold (0.34,2.13) increase in cancer mortality. In addition, there was a linear dose-response association between serum copper concentration with all-cause and CVD mortality (P for nonlinear > 0.05). Conclusions: This prospective study found that serum copper concentrations were linearly associated with all-cause and CVD mortality in US adults. High serum copper levels is a risk factor for all-cause and CVD mortality.

Expression and prognosis analysis of integrin subunit α3 (ITGA3) in papillary thyroid cancer.

Integrin subunit α3 (ITGA3) is a member of the integrin family and interacts with extracellular matrix proteins. However, there have been few reports regarding the role of ITGA3 in papillary thyroid cancer. The expression levels of ITGA3 were firstly analyzed by bioinformatics tools and in vitro experiments, followed by evaluating its prognostic significance in papillary thyroid cancer patients using Kaplan-Meier, receiver operating characteristic, and Cox regression analyses. Then, cBioportal and GSCA databases were applied to evaluate genetic alterations of ITGA3. Functional enrichment analysis was conducted and the upstream miRNAs of ITGA3 were determined. The results showed that the ITGA3 mRNA and protein levels were higher in the papillary thyroid cancer group than those in the normal group (all P < 0.05). Moreover, ITGA3 performed well in distinguishing the recurrence-free survival (RFS) status and served as an independent prognostic factor of papillary thyroid cancer patients (P < 0.01). Besides, significant relations between ITGA3 and genetic alterations were observed (FDR <0.01). Functional enrichment analysis indicated ECM-receptor interaction and cell adhesion molecules were the shared regulatory pathways. Moreover, ITGA3 might be the target gene of hsa-miR-3129, hsa-miR-181d, hsa-miR-181b, hsa-miR-199a, and hsa-miR-199b. Of note, the ITGA3 mRNA level was reduced after has-miR-199b-3p/5p was overexpressed. In conclusion, ITGA3 could be a reliable biomarker and have potential value in predicting the RFS status of papillary thyroid cancer patients.

LncRNA MALAT1-targeting antisense oligonucleotide ameliorates the AngII-induced vascular smooth muscle cell proliferation and migration via Nrf2/GPX4 antioxidant pathway.

ABSTRACT: The high level of oxidative stress induced by angiotensin II (AngII) is the main pathophysiological process that promotes the proliferation and migration of vascular smooth muscle cells (VSMCs) and induces vascular remodeling. LncRNA Metastasis-related lung adenocarcinoma transcript 1 (MALAT1) has been determined to play an important role in the modulation of oxidative stress and the development of cardiovascular diseases. Nevertheless, the function and underlying mechanism of MALAT1 in restenosis induced by hypertensive angioplasty remain unclear. AngII increased the expression of MALAT1 in VSMCs. We found that anti-sense oligonucleotide lncRNA MALAT1 (ASO-MALAT1) could inhibit AngII induced reactive oxygen species (ROS) production and VSMCs proliferation and migration by inducing the expression of glutathione peroxidase 4 (GPX4), which can be reversed by siRNA-GPX4. And GPX4 overexpression can inhibit the proliferation and migration of VSMCs induced by AngII. In addition, we found that the process by which MALAT1 knockdown induces GPX4 expression involves nuclear factor erythrocyte 2 related factor 2 (Nrf2). Overexpression of Nrf2 can increase the expression of GPX4, and down-regulation of GPX4 by ML385 (Nrf2 inhibitor) blocked the protective effect of ASO-MALAT1 on AngII-induced proliferation and migration of VSMCs. Ferrostatin-1 (Fer-1, ip 5mg/kg per day for 2 weeks), a GPX4 agonist, significantly inhibited neointimal formation in spontaneously hypertensive rat (SHR) by the inhibition of oxidative stress. In conclusion, these data imply that ASO-MALAT1 suppresses the AngII-induced oxidative stress, proliferation and migration of VSMCs by activating Nrf2/GPX4 antioxidant signaling. GPX4 may be a potential target for the therapeutic intervention of hypertensive vascular restenosis.

The Long non-coding RNA MALAT1 functions as a competing endogenous RNA to regulate vascular remodeling by sponging miR-145-5p/HK2 in hypertension.

Long non-coding RNAs (LncRNAs) have been found to play a regulatory role in the pathophysiology of vascular remodeling-associated illnesses through the lncRNA-microRNA (miRNA) regulation axis. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is thought to be involved in proliferation, migration, apoptosis, and calcification of vascular smooth muscle cells (VSMCs). The purpose of this study was to investigate the regulatory role of MALAT1 on vascular remodeling in hypertension. Our data indicate that the expression of MALAT1 is significantly upregulated in hypertensive aortic smooth muscle. Knockdown of MALAT1 inhibited the proliferation, migration, and phenotypic transition of VSMCs induced by Ang II. Bioinformatics analysis was used to predict the complementary binding of miR-145-5p to the 3'-untranslated region of MALAT1. Besides, the expressions of MALAT1 and miR-145-5p were negatively correlated, while luciferase reporter assays and RNA immunoprecipitation assay validated the interaction between miR-145-5p and MALAT1. The proliferation, migration and phenotypic transformation of VSMCs induced by overexpression of MALAT1 were reversed in the presence of miR-145-5p. Furthermore, we verified that miR-145-5p could directly target and bind to hexokinase 2 (HK2) mRNA, and that HK2 expression was negatively correlated with miR-145-5p in VSMCs. Knockdown of HK2 significantly inhibited the effects of overexpression of MALAT1 on Ang II-induced VSMCs proliferation, migration and phenotypic transformation. Taken together, the MALAT1/miR-145-5p/HK2 axis may play a critical regulatory role in the vascular remodeling of VSMCs in hypertension.

Predictive Value of Post-Percutaneous Coronary Intervention Quantitative Flow Ratio for Vessel-Oriented Composite Endpoint.

At present, there is a lack of indicators, which can accurately predict the post-percutaneous coronary intervention (post-PCI) vessel-oriented composite endpoint (VOCE). Recent studies showed that the post-PCI quantitative flow ratio (QFR) can predict post-PCI VOCE. PubMed, Embase, and Cochrane were searched from inception to March 27, 2022, and the cohort studies about that the post-PCI QFR predicts post-PCI VOCE were screened. Meta-analysis was performed, including 6 studies involving 4518 target vessels. The results of the studies included in this meta-analysis all showed that low post-PCI QFR was an independent risk factor for post-PCI VOCE after adjusting for other factors, HR (95% CI) ranging from 2.718 (1.347-5.486) to 6.53 (2.70-15.8). Our meta-analysis showed that the risk of post-PCI VOCE was significantly higher in the lower post-PCI QFR group than in the higher post-PCI QFR group (HR: 4.14, 95% CI: 3.00-5.70, P < 0.001, I2 = 27.9%). Post-PCI QFR has a good predictive value for post-PCI VOCE. Trial Registration. This trial is registered with CRD42022322001.

Prevalence of Chronic Kidney Disease Among US Adults With Hypertension, 1999 to 2018.

BACKGROUND: Hypertension is a major cause of end-stage renal disease. Assessing temporal trends in the prevalence of chronic kidney disease (CKD) in hypertension could provide information for public health policies and plans. METHODS: From the National Health and Nutrition Examination Survey from 1999 to 2018, a probability sample of adults aged ≥20 years was collected. The primary outcomes were classified according to the estimated glomerular filtration rate and urinary albumin. Trend tests were performed to assess age-standardized prevalence trends of CKD, albuminuria, and macroalbuminuria in US adults with hypertension. RESULTS: A total of 23 120 US adults with hypertension were included in this study. The prevalence of any CKD, albuminuria, or macroalbuminuria in hypertension remained relatively stable. However, the age-standardized prevalence of stage 1 CKD in hypertension increased from 4.9% in 2003 to 2006 to 7.0% in 2015 to 2018 (P=0.0077 for trend). The age-standardized prevalence of stage 3b CKD in hypertension decreased from 2.9% in 2011 to 2014 to 2.1% in 2015 to 2018 (P=0.0350 for trend). A similar trend was observed for the age-standardized prevalence of stages 3 to 5 CKD in hypertension, which declined from 10.9% in 2011 to 2014 to 8.9% in 2015 to 2018 (P=0.0160 for trend). CONCLUSIONS: Among US adults with hypertension, the prevalence of any CKD, albuminuria, and macroalbuminuria remained relatively stable from 1999 to 2018, whereas the hypertensive population showed an increasing trend in stage 1 CKD from 2003 to 2006 to 2015 to 2018 and a decreasing trend in the prevalence of stages 3 to 5 and 3b CKD from 2011 to 2014 to 2015 to 2018.

TRIM16 promotes aerobic glycolysis and pancreatic cancer metastasis by modulating the NIK-SIX1 axis in a ligase-independent manner.

Enhanced aerobic glycolysis contributes to the metastasis of pancreatic cancer metastasis, but the mechanism underlying the abnormal activation of glycolysis has not been fully elucidated. The E3 ligase tripartite motif 16 (TRIM16) is involved in the progression of many cancers. However, the role of and molecular mechanism by which TRIM16 acts in pancreatic cancer are unclear. In this study, we report that TRIM16 was significantly upregulated in pancreatic cancer tissues, and high expression of TRIM16 was associated with poor prognosis in patients with pancreatic cancer. Multivariate analyses showed that TRIM16 was an independent predictor of poor outcomes among patients with pancreatic cancer. In addition, in vitro and in vivo evidence showed that TRIM16 promoted pancreatic cancer cell metastasis by enhancing glycolysis. Furthermore, we revealed that TRIM16 controlled glycolysis and pancreatic cancer cell's metastasis by regulating sine oculis homeobox 1 (SIX1), an important transcription factor that promotes glycolysis. TRIM16 upregulated SIX1 by inhibiting its ubiquitination and degradation, which was mediated by NF-κB-inducing kinase (NIK), an upstream regulator of SIX1. Hence, NIK inhibitor can suppress SIX1 expression, glycolysis and metastasis in TRIM16-overexpressing pancreatic cancer cells. Mechanistic investigations demonstrated that TRIM16 competed with NIK's E3 ligase, TNF receptor-associated factor 3 (TRAF3), at the ISIIAQA sequence motif of NIK, and then stabilized NIK protein. Our study identified the TRIM16-NIK-SIX1 axis as a critical regulatory pathway in aerobic glycolysis and pancreatic cancer metastasis, indicating that this axis can be an excellent therapeutic target for curing pancreatic cancer.

Bivalirudin plus a high-dose infusion versus heparin monotherapy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a randomised trial.

BACKGROUND: Previous randomised trials of bivalirudin versus heparin in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) have reported conflicting results, in part because of treatment with different pharmacological regimens. We designed a large-scale trial examining bivalirudin with a post-PCI high-dose infusion compared with heparin alone, the regimens that previous studies have shown to have the best balance of safety and efficacy. METHODS: BRIGHT-4 was an investigator-initiated, open-label, randomised controlled trial conducted at 87 clinical centres in 63 cities in China. Patients with STEMI undergoing primary PCI with radial artery access within 48 h of symptom onset who had not received previous fibrinolytic therapy, anticoagulants, or glycoprotein IIb/IIIa inhibitors were randomly assigned (1:1) to receive bivalirudin with a post-PCI high-dose infusion for 2-4 h or unfractionated heparin monotherapy. There was no masking. Glycoprotein IIb/IIIa inhibitor use was reserved for procedural thrombotic complications in both groups. The primary endpoint was a composite of all-cause mortality or Bleeding Academic Research Consortium (BARC) types 3-5 bleeding at 30 days. This trial is registered with ClinicalTrials.gov (NCT03822975), and is ongoing. FINDINGS: Between Feb 14, 2019, and April 7, 2022, a total of 6016 patients with STEMI undergoing primary PCI were randomly assigned to receive either bivalirudin plus a high-dose infusion after PCI (n=3009) or unfractionated heparin monotherapy (n=3007). Radial artery access was used in 5593 (93·1%) of 6008 patients. Compared with heparin monotherapy, bivalirudin reduced the 30-day rate of the primary endpoint (132 events [4·39%] in the heparin group vs 92 events [3·06%] in the bivalirudin group; difference, 1·33%, 95% CI 0·38-2·29%; hazard ratio [HR] 0·69, 95% CI 0·53-0·91; p=0·0070). All-cause mortality within 30 days occurred in 118 (3·92%) heparin-assigned patients and in 89 (2·96%) bivalirudin-assigned patients (HR 0·75; 95% CI 0·57-0·99; p=0·0420), and BARC types 3-5 bleeding occurred in 24 (0·80%) heparin-assigned patients and five (0·17%) bivalirudin-assigned patients (HR 0·21; 95% CI 0·08-0·54; p=0·0014). There were no significant differences in the 30-day rates of reinfarction, stroke, or ischaemia-driven target vessel revascularisation between the groups. Within 30 days, stent thrombosis occurred in 11 (0·37%) of bivalirudin-assigned patients and 33 (1·10%) of heparin-assigned patients (p=0·0015). INTERPRETATION: In patients with STEMI undergoing primary PCI predominantly with radial artery access, anticoagulation with bivalirudin plus a post-PCI high-dose infusion for 2-4 h significantly reduced the 30-day composite rate of all-cause mortality or BARC types 3-5 major bleeding compared with heparin monotherapy. FUNDING: Chinese Society of Cardiology Foundation (CSCF2019A01), and a research grant from Jiangsu Hengrui Pharmaceuticals.

Safety and Effectiveness of Coronary Angiography or Intervention through the Distal Radial Access: A Meta-Analysis.

OBJECTIVES: Searching the literature for coronary angiography (CAG) or intervention through distal radial access (DRA) and performing a meta-analysis. BACKGROUND: Coronary angiography (CAG) or intervention through distal radial access (DRA) may have a similar success rate, low radial artery occlusion rate, low radial artery spasm rate, and low rate of puncture site hematoma for patients with coronary heart disease. Therefore, the randomized controlled trials (RCTs) were searched, and the data were pooled for meta-analysis to evaluate the effectiveness and safety of DRA. METHODS: RCTs comparing the CAG or intervention through DRA vs. transradial access (TRA) published between January 1, 2017, and May 4, 2021, were searched in the PubMed, Embase, and Cochrane databases. The endpoints included the rate of access success and the number of radial artery occlusions, radial artery spasms, and puncture site hematomas. The data were extracted, and a random-effects model was used for analysis. RESULTS: Among 204 studies, 6 RCTs (with 2825 participants) met the inclusion criteria. Compared to TRA, the access success rate in DRA (p=0.1) and the lower rate of puncture site hematoma were not significantly different (p=0.646), while the radial artery occlusion rate (p < 0.001) and radial artery spasm rate (p=0.029) were significantly lower. CONCLUSION: In summary, DRA has a similar access success rate and incidence of hematoma at the puncture site, but a lower incidence of RAO and spasm compared to TRA. These findings demonstrated that DRA is a safe and effective access for CAG or intervention.

Vaccinia-related kinase 2 drives pancreatic cancer progression by protecting Plk1 from Chfr-mediated degradation.

As a key cell cycle regulator, polo-like kinase 1 (Plk1) has been recognized as a crucial factor involved in the progression of pancreatic cancer (PC). However, its regulatory mechanism is poorly understood. Here, we present evidence that Plk1 is a novel substrate of vaccinia-related kinase 2 (VRK2), a serine-threonine kinase that is highly expressed and predicts poor prognosis in PC. VRK2 phosphorylates Plk1 at threonine 210 and protects it from ubiquitin-dependent proteasomal degradation. We showed that mechanistically complement factor H-related protein (CFHR), as a major E3 ligase, promotes Plk1 degradation by ubiquitinating it at lysine 209. Phosphorylation of Plk1 at threonine 210 by VRK2 interferes with the interaction of Chfr with Plk1 and antagonizes Plk1 ubiquitination, thereby stabilizing the Plk1 protein. Taken together, our data reveal a mechanism of Plk1 overexpression in PC and provide evidence for targeting VRK2 as a potential therapeutic strategy.

RING-finger protein 6 enhances c-Myc-mediated Warburg effect by promoting MAD1 degradation to facilitate pancreatic cancer metastasis.

Aerobic glycolysis (the Warburg effect) promotes tumor metastasis; hence, drugs targeting its regulators are being developed. c-Myc, a critical transcription factor that regulates the Warburg effect, is involved in the tumorigenesis of many cancers, including pancreatic cancer (PC). However, the upstream regulating mechanisms of c-Myc in PC are unclear. Herein, we reported that E3 ubiquitin ligase RING-finger protein 6 (RNF6) was upregulated in PC tissues, and an elevated RNF6 level was closely associated with metastasis and poor prognosis in patients with PC. In functional experiments, RNF6 over-expression accelerated the metastatic ability of PC cells, whereas RNF6 knockdown impaired PC cell motility and invasiveness along with metastasis in an orthotopic mouse model. Furthermore, we found that RNF6 promoted PC cell metastasis by enhancing c-Myc-mediated aerobic glycolysis. Mechanistically, RNF6 increased the expression level of c-Myc by catalyzing the ubiquitination of Max-dimerization protein-1 (MAD1), a cellular antagonist of c-Myc. Lastly, RNF6 promoted the degradation of MAD1 via the ubiquitin-proteasome pathway, and this reduction in the MAD1 levels enabled c-Myc to promote the Warburg effect in PC. Our results demonstrate that RNF6 may be a novel biomarker in PC carcinogenesis, thereby indicating that targeting the RNF6/MAD1/c-Myc axis is a potential strategy for PC therapy.

Electrocardiogram-Based R Wave Pulse Wave Index for Assessment of Carotid Atherosclerosis.

BACKGROUND Carotid atherosclerosis (CA) is a common disease in middle-aged and elderly people, which is closely related to cardiovascular and cerebrovascular disease. In this study, we investigated the benefits of the electrocardiogram (ECG)-based R wave pulse wave index (ERWVI) for the diagnosis of CA. MATERIAL AND METHODS According to CA examinations by color Doppler ultrasound, patients were assigned to positive and negative groups. The ECG R wave-Pulse wave transit time (ERWPTT) was obtained by synchronously collecting ECG signals (R wave in ECG) and the time variations in maximum finger pulse oxygen (DOP) on the ECG monitor. RESULTS ERPWI was positively correlated with sex, age, BMI, diastolic/systolic blood pressure, fasting blood glucose, uric acid, cholesterol and triglyceride levels, LDL-cholesterol, non-alcoholic fatty liver disease (NAFLD), creatinine, and homocysteine, and was negatively correlated with HDL-cholesterol (P<0.05). With the increase of ERPWI, the incidence of CA significantly increased to various degrees among the subgroups (P<0.05). The binary logistic regression model showed that ERPWI was an independent risk factor for atherosclerosis. The ROC curve showed that when ERPWI was above 0.505, the incidence of CA increased significantly. CONCLUSIONS There is a close relationship between ERPWI and CA. ERPWI is an independent risk factor for CA. ERPWI ≥0.505 can be used as a diagnostic threshold for CA and a reference index for the diagnosis of CA.

Ameliorative effects of protodioscin on experimental diabetic nephropathy.

BACKGROUND: Diabetic nephropathy is one of the most common and serious complications of diabetes mellitus. HYPOTHESIS/PURPOSE: The present study aimed to investigate the effects of protodioscin on renal damage in high-fat diet-fed and streptozotocin-induced diabetic rats. METHODS: After 4 weeks of feeding a high-fat diet, male Sprague-Dawley rats were injected 35 mg/kg streptozotocin intraperitoneally. The diabetic rats were divided into 4 groups, and treated orally with carboxymethylcellulose sodium, metformin, or protodioscin (20 or 40 mg/kg). After 12 weeks of treatment, blood, urine, and renal tissue were collected for biochemical and histological examination. RESULTS: Protodioscin significantly reduced the levels of blood glucose, serum creatinine, and blood urea nitrogen, and also the excretion of urinary protein and albumin in diabetic rats. Histological examinations showed that protodioscin ameliorated the diabetes-induced glomerular and tubular pathological changes. Furthermore, protodioscin significantly reduced the renal concentrations of total cholesterol, triglycerides, free fatty acids, phospholipids, and TNF-α. CONCLUSION: These results indicate that protodioscin has ameliorative effects on diabetic nephropathy.

Learning curve for performing choledochotomy bile duct exploration with primary closure after laparoscopic cholecystectomy.

BACKGROUND: Primary closure after laparoscopic cholecystectomy (LC) and laparoscopic common bile duct exploration (LCBDE) is a safe and effective approach for treating cholecystolithiasis with choledocholithiasis. The aim of this study was to evaluate the learning curve of performing primary closure after LC+LCBDE. METHODS: We retrospectively identified all patients who underwent primary closure after LC+LCBDE performed by a single surgeon from January 2009 to April 2015 in our institution, and analyzed preoperative, intraoperative, and postoperative data using the cumulative sum (CUSUM) analysis to evaluate the learning curve for this procedure. RESULTS: Overall, there were 390 patients. The total postoperative complications rate was 7.2%, including bile leakage in 9 (2.3%) patients and retained common bile duct stone in 3 (0.8%) patients. The CUSUM operating time (OT) learning curve was best modeled by the equation: CUSUMOT = 312.209 × procedure0.599 × e(-0.011×procedure) + 122.608 (R2 = 0.96). The learning curve was composed of two phases, phase 1 (the initial 54 patients) and phase 2 (the remaining 336 patients). A significant decrease in the OT (116.8 ± 22.4 vs. 93.8 ± 17.8 min; p < 0.001) and complication rate (16.7 vs. 5.7%; p < 0.01) including the rate of bile leakage (7.4 vs. 1.5%; p < 0.01) and retained stone (3.7 vs. 0.3%; p < 0.01) was observed between the two phases. In addition, 20 patients had conversion to open surgery. Impacted stones were independently associated with conversion, as indicated by a multivariable analysis. CONCLUSION: The data suggest that the learning curve of this procedure was achieved in approximately 54 cases. An impacted stone was the only risk factor that affected the conversion rate.

Laparoscopic Transcystic Common Bile Duct Exploration: T-Shaped Incision of Cystic Duct with FREDDY Laser Lithotripsy.

OBJECTIVES: Optimal laparoscopic techniques for management of gallstones concomitant with common bile duct (CBD) stones remain under debate. The aim of this study was to evaluate a novel approach to managing gallstones concomitant with large or impacted CBD stones through a modified laparoscopic transcystic CBD exploration (LTCBDE) with frequency-doubled double-pulse neodymium:YAG (FREDDY) laser lithotripsy. MATERIALS AND METHODS: This retrospective review includes 32 consecutive patients with gallstones concomitant with large or impacted CBD stones who were offered LTCBDE with FREDDY laser lithotripsy between June 2012 and December 2014. Demographic, perioperative, and follow-up data were collected and analyzed retrospectively. RESULTS: CBD stone clearance was achieved for all patients. There were 13 males and 19 females, among whom there were three patients with a history of abdominal surgery. The diameter of the CBD ranged from 10 to 20 (mean 15.1) mm, and the number of CBD stones ranged from 1 to 5. CBD stones ranged in diameter from 9 to 18 (mean 11.7) mm and 9 patients had stones that were impacted in the CBD. The mean operative time was 123 ± 18 minutes with a range of 72 to 155 minutes. The mean length of postoperative hospital stay was 5.3 (range 4-7) days. All patients recovered normally without morbidity or mortality. CONCLUSIONS: The modified LTCBDE with a T-shaped incision of the cystic duct and FREDDY laser lithotripsy is a safe and effective means of managing gallstones concomitant with large or impacted CBD stones.