An integrated approach reveals regulatory controls on bacterial translation elongation.

Ribosomes elongate at a nonuniform rate during translation. Theoretical models and experiments disagree on the in vivo determinants of elongation rate and the mechanism by which elongation rate affects protein levels. To resolve this conflict, we measured transcriptome-wide ribosome occupancy under multiple conditions and used it to formulate a whole-cell model of translation in E. coli. Our model predicts that elongation rates at most codons during nutrient-rich growth are not limited by the intracellular concentrations of aminoacyl-tRNAs. However, elongation pausing during starvation for single amino acids is highly sensitive to the kinetics of tRNA aminoacylation. We further show that translation abortion upon pausing accounts for the observed ribosome occupancy along mRNAs during starvation. Abortion reduces global protein synthesis, but it enhances the translation of a subset of mRNAs. These results suggest a regulatory role for aminoacylation and abortion during stress, and our study provides an experimentally constrained framework for modeling translation.

Translational Control through Differential Ribosome Pausing during Amino Acid Limitation in Mammalian Cells.

Limitation for amino acids is thought to regulate translation in mammalian cells primarily by signaling through the kinases mTORC1 and GCN2. We find that a selective loss of arginine tRNA charging during limitation for arginine regulates translation through ribosome pausing at two of six arginine codons. Surprisingly, limitation for leucine, an essential and abundant amino acid in protein, results in little or no ribosome pausing. Chemical and genetic perturbation of mTORC1 and GCN2 signaling revealed that their robust response to leucine limitation prevents ribosome pausing, while an insufficient response to arginine limitation leads to loss of tRNA charging and ribosome pausing. Ribosome pausing decreases protein production and triggers premature ribosome termination without reducing mRNA levels. Together, our results suggest that amino acids that are not optimally sensed by the mTORC1 and GCN2 pathways still regulate translation through an evolutionarily conserved mechanism based on codon-specific ribosome pausing.

Coordinated missplicing of TMEM14C and ABCB7 causes ring sideroblast formation in SF3B1-mutant myelodysplastic syndrome.

SF3B1 splicing factor mutations are near-universally found in myelodysplastic syndromes (MDS) with ring sideroblasts (RS), a clonal hematopoietic disorder characterized by abnormal erythroid cells with iron-loaded mitochondria. Despite this remarkably strong genotype-to-phenotype correlation, the mechanism by which mutant SF3B1 dysregulates iron metabolism to cause RS remains unclear due to an absence of physiological models of RS formation. Here, we report an induced pluripotent stem cell model of SF3B1-mutant MDS that for the first time recapitulates robust RS formation during in vitro erythroid differentiation. Mutant SF3B1 induces missplicing of ∼100 genes throughout erythroid differentiation, including proposed RS driver genes TMEM14C, PPOX, and ABCB7. All 3 missplicing events reduce protein expression, notably occurring via 5' UTR alteration, and reduced translation efficiency for TMEM14C. Functional rescue of TMEM14C and ABCB7, but not the non-rate-limiting enzyme PPOX, markedly decreased RS, and their combined rescue nearly abolished RS formation. Our study demonstrates that coordinated missplicing of mitochondrial transporters TMEM14C and ABCB7 by mutant SF3B1 sequesters iron in mitochondria, causing RS formation.

Serum hepcidin levels in chronic liver disease: a systematic review and meta-analysis.

OBJECTIVES: Dysregulation of hepcidin-iron axis is presumed to account for abnormal iron status in patients with chronic liver disease (CLD). Our aim is to determine the effect of specific etiologies of CLD and of cirrhosis on serum hepcidin levels. METHODS: PubMed, Embase, Web of Science were searched for studies comparing serum hepcidin levels in patients with CLD to that in controls using enzyme-linked immunosorbent assay. The study was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Guidelines. Statistical analysis was carried out with STATA using random effects model to calculate the mean difference (MD) between two groups. RESULTS: Hepcidin levels were significantly lower in subjects with hepatitis C virus (16 studies) [MD -1.6 (95 % CI: -2.66 to -0.54), p<0.01] and alcoholic liver disease (3 studies) [MD -0.84 (95 % CI: -1.6 to -0.07), p=0.03] than controls. Serum hepcidin was significantly higher in subjects with non-alcoholic fatty liver disease (12 studies) [MD 0.62 (95 % CI: 0.21 to 1.03), p<0.01], but did not differ in subjects with hepatitis B and controls (eight studies) [MD -0.65 (95 % CI: -1.47 to 0.16), p=0.12]. Hepcidin levels were significantly lower in patients with cirrhosis of any etiology (four studies) [MD -1.02 (CI: -1.59 to -0.45), p<0.01] vs. controls (CI: confidence interval). CONCLUSIONS: Serum hepcidin levels are altered in common forms of CLD albeit not in a consistent direction. Additional study is needed to determine how changes in hepcidin levels are related to dysregulation of iron metabolism in CLD.

The amino acid sensor GCN2 suppresses terminal oligopyrimidine (TOP) mRNA translation via La-related protein 1 (LARP1).

La-related protein 1 (LARP1) has been identified as a key translational inhibitor of terminal oligopyrimidine (TOP) mRNAs downstream of the nutrient sensing protein kinase complex, mTORC1. LARP1 exerts this inhibitory effect on TOP mRNA translation by binding to the mRNA cap and the adjacent 5'TOP motif, resulting in the displacement of the cap-binding protein eIF4E from TOP mRNAs. However, the involvement of additional signaling pathway in regulating LARP1-mediated inhibition of TOP mRNA translation is largely unexplored. In the present study, we identify a second nutrient sensing kinase GCN2 that converges on LARP1 to control TOP mRNA translation. Using chromatin-immunoprecipitation followed by massive parallel sequencing (ChIP-seq) analysis of activating transcription factor 4 (ATF4), an effector of GCN2 in nutrient stress conditions, in WT and GCN2 KO mouse embryonic fibroblasts, we determined that LARP1 is a GCN2-dependent transcriptional target of ATF4. Moreover, we identified GCN1, a GCN2 activator, participates in a complex with LARP1 on stalled ribosomes, suggesting a role for GCN1 in LARP1-mediated translation inhibition in response to ribosome stalling. Therefore, our data suggest that the GCN2 pathway controls LARP1 activity via two mechanisms: ATF4-dependent transcriptional induction of LARP1 mRNA and GCN1-mediated recruitment of LARP1 to stalled ribosomes.

Metabolic excretion associated with nutrient-growth dysregulation promotes the rapid evolution of an overt metabolic defect.

In eukaryotes, conserved mechanisms ensure that cell growth is coordinated with nutrient availability. Overactive growth during nutrient limitation ("nutrient-growth dysregulation") can lead to rapid cell death. Here, we demonstrate that cells can adapt to nutrient-growth dysregulation by evolving major metabolic defects. Specifically, when yeast lysine-auxotrophic mutant lys- encountered lysine limitation, an evolutionarily novel stress, cells suffered nutrient-growth dysregulation. A subpopulation repeatedly evolved to lose the ability to synthesize organosulfurs (lys-orgS-). Organosulfurs, mainly reduced glutathione (GSH) and GSH conjugates, were released by lys- cells during lysine limitation when growth was dysregulated, but not during glucose limitation when growth was regulated. Limiting organosulfurs conferred a frequency-dependent fitness advantage to lys-orgS- by eliciting a proper slow growth program, including autophagy. Thus, nutrient-growth dysregulation is associated with rapid organosulfur release, which enables the selection of organosulfur auxotrophy to better tune cell growth to the metabolic environment. We speculate that evolutionarily novel stresses can trigger atypical release of certain metabolites, setting the stage for the evolution of new ecological interactions.

Effectiveness and Safety of EUS Rendezvous After Failed Biliary Cannulation With ERCP: A Systematic Review and Proportion Meta-analysis.

BACKGROUND: Endoscopic ultrasound-guided rendezvous (EUS-RV) endoscopic retrograde cholangiopancreatography (ERCP) is an alternative to interventional radiology-guided rendezvous ERCP in patients who failed biliary cannulation with conventional ERCP. However, there is significant variation in reported rates of success and adverse events associated with EUS-RV-assisted ERCP. We performed a systematic review and a proportion meta-analysis to reliably assess the effectiveness and safety of the EUS-RV-assisted ERCP. MATERIALS AND METHODS: We conducted a comprehensive search of multiple electronic databases and conference proceedings (from inception through August 2020) to identify studies reporting EUS-RV-assisted ERCP in patients who failed biliary cannulation with conventional ERCP techniques. Using the random-effects model described by DerSimonian and Laird, we calculated the pooled rates of technical success, clinical success, and adverse events of EUS-RV-assisted ERCP. RESULTS: Twelve studies reporting a total of 342 patients were included in the meta-analysis. The pooled rate of technical success (12 studies reporting a total of 342 patients) was 86.1% [95% confidence interval (CI): 78.4-91.3]. The pooled rate of clinical success (4 studies reporting a total of 94 patients) was 80.8% (95% CI: 64.1-90.8). The pooled rate of overall adverse events (12 studies; 42 events in 342 patients) was 14% (95% CI: 10.5-18.4). Low to moderate heterogeneity was noted in the analyses. CONCLUSIONS: EUS-RV-assisted ERCP appears to be effective and safe in patients who failed biliary cannulation with conventional ERCP. Given the risk of adverse events, it should be performed in centers with expertise in therapeutic endoscopic ultrasound.

Vaccine effectiveness against COVID-19 breakthrough infections in patients with cancer (UKCCEP): a population-based test-negative case-control study.

BACKGROUND: People with cancer are at increased risk of hospitalisation and death following infection with SARS-CoV-2. Therefore, we aimed to conduct one of the first evaluations of vaccine effectiveness against breakthrough SARS-CoV-2 infections in patients with cancer at a population level. METHODS: In this population-based test-negative case-control study of the UK Coronavirus Cancer Evaluation Project (UKCCEP), we extracted data from the UKCCEP registry on all SARS-CoV-2 PCR test results (from the Second Generation Surveillance System), vaccination records (from the National Immunisation Management Service), patient demographics, and cancer records from England, UK, from Dec 8, 2020, to Oct 15, 2021. Adults (aged ≥18 years) with cancer in the UKCCEP registry were identified via Public Health England's Rapid Cancer Registration Dataset between Jan 1, 2018, and April 30, 2021, and comprised the cancer cohort. We constructed a control population cohort from adults with PCR tests in the UKCCEP registry who were not contained within the Rapid Cancer Registration Dataset. The coprimary endpoints were overall vaccine effectiveness against breakthrough infections after the second dose (positive PCR COVID-19 test) and vaccine effectiveness against breakthrough infections at 3-6 months after the second dose in the cancer cohort and control population. FINDINGS: The cancer cohort comprised 377 194 individuals, of whom 42 882 had breakthrough SARS-CoV-2 infections. The control population consisted of 28 010 955 individuals, of whom 5 748 708 had SARS-CoV-2 breakthrough infections. Overall vaccine effectiveness was 69·8% (95% CI 69·8-69·9) in the control population and 65·5% (65·1-65·9) in the cancer cohort. Vaccine effectiveness at 3-6 months was lower in the cancer cohort (47·0%, 46·3-47·6) than in the control population (61·4%, 61·4-61·5). INTERPRETATION: COVID-19 vaccination is effective for individuals with cancer, conferring varying levels of protection against breakthrough infections. However, vaccine effectiveness is lower in patients with cancer than in the general population. COVID-19 vaccination for patients with cancer should be used in conjunction with non-pharmacological strategies and community-based antiviral treatment programmes to reduce the risk that COVID-19 poses to patients with cancer. FUNDING: University of Oxford, University of Southampton, University of Birmingham, Department of Health and Social Care, and Blood Cancer UK.

Inverted translational control of eukaryotic gene expression by ribosome collisions.

The canonical model of eukaryotic translation posits that efficient translation initiation increases protein expression and mRNA stability. Contrary to this model, we find that increasing initiation rate can decrease both protein expression and stability of certain mRNAs in the budding yeast Saccharomyces cerevisiae. These mRNAs encode a stretch of polybasic residues that cause ribosome stalling. Our computational modeling predicts that the observed decrease in gene expression at high initiation rates occurs when ribosome collisions at stalls stimulate abortive termination of the leading ribosome or cause endonucleolytic mRNA cleavage. Consistent with this prediction, the collision-associated quality-control factors Asc1 and Hel2 (orthologs of human RACK1 and ZNF598, respectively) decrease gene expression from stall-containing mRNAs only at high initiation rates. Remarkably, hundreds of S. cerevisiae mRNAs that contain ribosome stall sequences also exhibit lower translation efficiency. We propose that inefficient translation initiation allows these stall-containing endogenous mRNAs to escape collision-stimulated reduction in gene expression.

Biliary Sphincterotomy Alone versus Biliary Stent with or without Biliary Sphincterotomy for the Management of Post-Cholecystectomy Bile Leak: A Systematic Review and Meta-Analysis.

BACKGROUND: Endoscopic therapy with endoscopic retrograde cholangiopancreatography is considered the first-line treatment in the management of post-cholecystectomy bile leak (PCBL). Currently, there is no consensus on the most effective endoscopic intervention for PCBL. Hence, we performed a systematic review and meta-analysis to compare the effectiveness and safety of the two interventional groups (biliary sphincterotomy [BS] alone vs. biliary stent ± BS) in management of PCBL. METHODS: We conducted a comprehensive search of multiple electronic databases and conference proceedings (from inception through January 2021). The primary outcome was to compare the pooled rate of clinical success between the 2 groups. The secondary outcome was to estimate the pooled rate of adverse events. RESULTS: The pooled rate of clinical success with BS alone (5 studies, 299 patients) was 88% (95% confidence interval (CI): 84-92%, I2: 0%) and for biliary stent ± BS (5 studies, 864 patients) was 97% (CI: 93-100%, I2: 79%). The rate of clinical success in biliary stent ± BS group was significantly higher than BS alone group (OR: 3.91 95% CI: 2.29-6.69, p < 0.001, I2: 13%). The rate of adverse events was numerically lower in biliary stent ± BS group compared to BS alone (3 studies; OR: 0.65 95% CI: 0.41-1.03, p = 0.07) without statistical significance. Low heterogeneity was noted in the analysis. CONCLUSIONS: Biliary stent ± BS is more effective in endoscopic management of PCBL compared to BS alone. This may be related to inter-endoscopist variation in completeness of sphincterotomy and post-sphincterotomy edema, which can influence the preferential trans-papillary flow of bile.

Ursodeoxycholic Acid Decreases Incidence of Primary Biliary Cholangitis and Biliary Complications After Liver Transplantation: A Meta-Analysis.

After liver transplantation (LT), the role of ursodeoxycholic acid (UDCA) is not well characterized. We examine the effect of UDCA after LT in the prophylaxis of biliary complications (BCs) in all-comers for LT and the prevention of recurrent primary biliary cholangitis (rPBC) in patients transplanted for PBC. Two authors searched PubMed/MEDLINE and Embase from January 1990 through December 2018 to identify all studies that evaluate the effectiveness of UDCA prophylaxis after LT for BCs in all LT recipients and rPBC after LT in patients transplanted for PBC. Odds ratios (ORs) were calculated for endpoints of the BC study. Pooled recurrence rates were calculated for rPBC. The study was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. A total of 15 studies were included, comprising 530 patients in the analysis for BCs and 1727 patients in the analysis for rPBC. UDCA was associated with decreased odds of BCs (OR, 0.70; 95% confidence interval [CI], 0.52-0.93; P = 0.01) and biliary stones and sludge (OR, 0.49; 95% CI, 0.24-0.77; P = 0.004). Prophylactic use of UDCA did not affect the odds of biliary stricture. For patients transplanted for PBC, the rate of rPBC was lower with the prophylactic use of UDCA (IR 16.7%; 95% CI, 0.114%-22.0%; I2 = 36.1%) compared with not using prophylactic UDCA (IR 23.1%; 95% CI, 16.9%-29.3%; I2 = 86.7%). UDCA after LT reduces the odds of BC and bile stones and sludge in all-comer LT recipients and reduces or delays the incidence of rPBC in patients transplanted for PBC. UDCA use after LT could be considered in all LT recipients to reduce the odds of BC and may be particularly beneficial for patients transplanted for PBC by reducing the incidence of rPBC.

Comprehensive profiling of translation initiation in influenza virus infected cells.

Translation can initiate at alternate, non-canonical start codons in response to stressful stimuli in mammalian cells. Recent studies suggest that viral infection and anti-viral responses alter sites of translation initiation, and in some cases, lead to production of novel immune epitopes. Here we systematically investigate the extent and impact of alternate translation initiation in cells infected with influenza virus. We perform evolutionary analyses that suggest selection against non-canonical initiation at CUG codons in influenza virus lineages that have adapted to mammalian hosts. We then use ribosome profiling with the initiation inhibitor lactimidomycin to experimentally delineate translation initiation sites in a human lung epithelial cell line infected with influenza virus. We identify several candidate sites of alternate initiation in influenza mRNAs, all of which occur at AUG codons that are downstream of canonical initiation codons. One of these candidate downstream start sites truncates 14 amino acids from the N-terminus of the N1 neuraminidase protein, resulting in loss of its cytoplasmic tail and a portion of the transmembrane domain. This truncated neuraminidase protein is expressed on the cell surface during influenza virus infection, is enzymatically active, and is conserved in most N1 viral lineages. We do not detect globally higher levels of alternate translation initiation on host transcripts upon influenza infection or during the anti-viral response, but the subset of host transcripts induced by the anti-viral response is enriched for alternate initiation sites. Together, our results systematically map the landscape of translation initiation during influenza virus infection, and shed light on the evolutionary forces shaping this landscape.

Randomized controlled trial comparing the Franseen needle with the Fork-tip needle for EUS-guided fine-needle biopsy.

BACKGROUND AND AIMS: EUS-guided FNA primarily provides cytologic samples. EUS-guided fine-needle biopsy (FNB) with needles that provide histologic specimens may enhance diagnostic yield and facilitate accessory tissue staining. Several different needle designs are currently available and design superiority is unknown. We designed a randomized controlled trial to compare 2 commonly used EUS-FNB needles in their ability to provide histologic tissue samples (primary endpoint) and to reach an accurate diagnosis (secondary endpoint). METHODS: A total of 150 lesions from 134 patients (November 2018 to June 2019) were randomized 1:1 between biopsy with a Franseen needle and a Fork-tip needle. The groups were compared regarding the quality of the tissue samples and diagnostic accuracy. RESULTS: Of 150 lesions, 75 were pancreatic and 75 were other solid lesions in and around the GI tract. There was no statistically significant difference between the Franseen needle and the Fork-tip needle in the yield of adequate histologic samples, 71 of 75 (94.7%) versus 72 of 75 (96%), (P = 1.00), an absolute difference of -1.3% (95% confidence interval [CI], -8.1% to 5.4%). The 2 groups were similar in the diagnostic accuracy of histologic analysis, 64 of 75 (85.3%) versus 68 of 75 (90.7%) (P = .45), absolute difference -5.4% (95% CI, -15.7% to 5%); and in the diagnostic accuracy of combined cytologic and histologic analysis, 65 of 75 (86.7%) versus 69 of 75 (92%) (P = .43), absolute difference -5.3% (95% CI, -15.2% to 4.5%). CONCLUSIONS: There was no significant difference in the performance of the Franseen needle versus the Fork-tip needle. Both needles achieved a high yield of histologic tissue samples and high diagnostic accuracy. (Clinical trial registration number: NCT03672032.).

Outcomes of Radiofrequency Ablation versus Endoscopic Surveillance for Barrett's Esophagus with Low-Grade Dysplasia: A Systematic Review and Meta-Analysis.

BACKGROUND: Endoscopic therapy using radiofrequency ablation (RFA) is a recommended treatment for Barrett's esophagus with high-grade dysplasia (BE-HGD) without a visible lesion which is managed by resection. However, currently, there is no consensus on the management of BE with low-grade dysplasia (BE-LGD) - RFA versus endoscopic surveillance. Hence, we performed a systematic review and meta-analysis of these comparative studies to compare the risk of progression to HGD or esophageal adenocarcinoma (EAC) among patients with BE-LGD treated with RFA versus endoscopic surveillance. METHODS: The primary outcome was to compare the risk of progression to HGD or EAC among patients with BE-LGD treated with RFA versus endoscopic surveillance. RESULTS: Four comparative studies reporting a total of 543 patients with BE-LGD were included in the meta-analysis (234 in RFA and 309 in endoscopic surveillance). The progression of BE-LGD to either HGD or EAC was significantly lower in patients treated with RFA compared to endoscopic surveillance (OR: 0.17, 95% confidence interval [CI]: 0.04-0.65, p = 0.01). The progression to HGD alone was significantly lower in patients treated with RFA versus endoscopic surveillance (OR: 0.23, 95% CI: 0.08-0.61, p = 0.003). The progression to EAC alone was numerically lower in RFA than endoscopic surveillance without statistical significance (OR: 0.44, 95% CI: 0.17-1.16, p = 0.09). Moderate heterogeneity was noted in the analysis. CONCLUSIONS: Based on our meta-analysis, there was a significant reduction in the risk of progression to HGD or EAC among patients with BE-LGD treated with RFA compared with those undergoing endoscopic surveillance. Endoscopic eradication therapy with RFA should be the preferred management approach for BE-LGD.

A Novel Score to Predict Esophageal Varices in Patients with Compensated Advanced Chronic Liver Disease.

BACKGROUND AND AIMS: Several criteria have been described to noninvasively predict the presence of high-risk esophageal varices in patients with compensated advanced chronic liver disease (cACLD). However, a recent study showed that treatment with ß blockers could increase decompensation-free survival in patients with clinically significant portal hypertension, thereby making it important to predict the presence of any esophageal varices. We aimed to develop a simple scoring system to predict any esophageal varices. METHODS: We retrospectively reviewed patients who had vibration-controlled transient elastography (VCTE) at Cook County Hospital, Chicago, USA. Patients with cACLD and liver stiffness measurement (LSM) ≥ 10 kPa with esophagogastroduodenoscopy performed within one year of VCTE were analyzed. We generated a novel score to predict esophageal varices, using the beta coefficient of predictive variables. The score was validated in an external cohort at the University of Iowa Hospital, USA. RESULTS: There were 372 patients in the development cohort and 200 patients in the validation cohort. LSM, platelet count, and albumin were identified as predictors of esophageal varices and were included for generating the Cook County score as "platelet count * - 0.0155872 + VCTE score * 0.0387052 + albumin * - 0.8549209." The area under receiver operating curve for our score was 0.86 for any varices and 0.85 for high risk varices and avoided more endoscopies than the expanded Baveno VI criteria while maintaining a very low miss rate (negative predictive value > 99%). CONCLUSION: We propose a new, highly accurate, and easy-to-use scoring system to predict the presence of not only high-risk but any esophageal varices in patients with cACLD.

Multimedia based education on bowel preparation improves adenoma detection rate: Systematic review & meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Colorectal cancer (CRC) is the third most common cause of cancer worldwide. Studies have shown a strong association between screening colonoscopy and a reduced risk of death from colorectal cancers. The incidence of poor bowel preparation has been reported in up to 25% cases. We conducted a systematic review and comprehensive meta-analysis to evaluate the effect of patient education using multimedia platforms on adenoma detection rate and adequacy of bowel preparation. METHODS: Multiple databases were searched through May 2020 for studies that reported the efficacy of multimedia education (smartphone app and online audio-visual aids) in improving quality of bowel preparation and its effect on adenoma detection rate (ADR). Meta-analysis was performed to determine whether multimedia based patient education (MM) helps improve ADR and bowel preparation quality as compared to controls (CT). RESULTS: We included 13 randomized controlled trials with a total of 3754 patients. Eight studies reported outcomes on ADR and 12 reported on adequacy of bowel preparation. Overall ADR was higher in patients receiving multimedia based education as compared to CT (risk ratio (RR) 1.25, confidence interval (CI) 1.01-1.56, P = 0.04). A higher proportion of patients receiving multimedia based education achieved adequate bowel preparation (RR 1.2, CI 1.1-1.3, P = 0.001). In patients with mean age over 50 years, ADR was better in MM cohort as compared to controls (RR 1.3, CI 1.1-1.6, P = 0.001). CONCLUSION: Pre-colonoscopy patient education using multimedia based platforms seems to improve ADR and the adequacy of bowel preparation.

Sentinel node mapping using indocyanine green and near-infrared fluorescence imaging technology for endometrial cancer: A prospective study using a surgical algorithm in Indian patients.

BACKGROUND: Indocyanine green (ICG) fluorescence with high-definition, three-dimensional imaging systems is emerging as the latest strategy to reduce trauma and improve surgical outcomes during oncosurgery. MATERIALS AND METHODS: This is a prospective study involving 100 patients with carcinoma endometrium who underwent robotic-assisted Type 1 pan-hysterectomy, with ICG-directed sentinel lymph node (SLN) biopsy from November 2017 to December 2019. The aim was to assess the feasibility and diagnostic accuracy of SLN algorithm and to evaluate the location and distribution of SLN in pelvic, para-aortic and unusual areas and the role of frozen section. RESULTS: The overall SLN detection rate was 98%. Bilateral detection was possible in 92% of the cases. Right side was detected in 98% of the cases and left side was visualised in 92% of the cases. Complete node dissection was done where SLN mapping failed. The most common location for SLN in our series was obturator on the right hemipelvis and internal iliac on the left hemipelvis. SLN in the para-aortic area was detected in 14% of cases. In six cases, SLN was found in atypical locations, that is pre-sacral area. Eight patients had SLN positivity for metastasis and underwent complete retroperitoneal lymphadenectomy. Comparison of final histopathological report with frozen section reports showed no false negatives. CONCLUSIONS: SLN mapping holds a great promise as a modern staging strategy for endometrial cancer. In our experience, cervical injection was an optimal method of mapping the pelvis. ICG showed a high overall detection rate, and bilateral mapping appears to be a feasible alternative to the more traditional methods of SLN mapping in patients with endometrial cancer. The ICG fluorescence imaging system is simple and safe and may become a standard in oncosurgery in view of its staging and anatomical imaging capabilities. This approach can reduce the morbidity, operative times and costs associated with complete lymphadenectomy while maintaining prognostic and predictive information.

Predictive Factors and Time to Development of Hepatic Decompensation in Patients with Non-alcoholic Fatty Liver Disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of cirrhosis in the USA. OBJECTIVES: We aimed to determine the time to develop hepatic events in patients with NAFLD and develop a simple model to identify patients at risk for hepatic decompensation. DESIGN: Retrospective cohort study. PATIENTS: Seven hundred patients with NAFLD met inclusion criteria for the study. Patients were divided into model construction (n = 450) and validation (n = 250) cohorts. MAIN MEASURES: Demographic, clinical, and laboratory variables were gathered at the time of diagnosis of NAFLD. Kaplan-Meier analysis determined the time to development of hepatic events from initial diagnosis. A time-to-event prediction model was established in the model construction cohort using the multivariate Cox proportional hazards model and was then internally validated. KEY RESULTS: Forty-nine (7%) patients developed hepatic events at a mean duration of 6.2 ± 4.2 years from initial diagnosis. Kaplan-Meier probability of developing a hepatic event at 5-, 10-, and 12-year intervals was 4.8%, 10.6%, and 11.3%, respectively. Age, presence of diabetes, and platelet count were identified as significant variables to predict hepatic events. NAFLD decompensation risk score was developed as "age × 0.06335 + presence of diabetes (yes = 1, no = 0) × 0.92221 - platelet count × 0.01522" to predict the probability of hepatic decompensation. Risk score model had an area under the curve of 0.89 (95% CI = 0.92, 0.86) and it performed well in both the validation (0.91, 0.87-0.94) and the overall cohort (0.89, 0.87-0.91). CONCLUSIONS: A significant proportion of patients with NAFLD developed hepatic decompensation. We have provided a simple, objective model to help identify "at-risk" patients.

ERCP with overtube-assisted enteroscopy in patients with Roux-en-Y gastric bypass anatomy: a systematic review and meta-analysis.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) in patients with Roux-en-Y gastric bypass (RYGB) anatomy is challenging. Overtube-assisted enteroscopy (OAE) is usually needed to perform ERCP in these patients. There is significant variation in the reported rates of success and adverse events across published studies. We performed a systematic review and meta-analysis to reliably estimate the pooled rates of success and adverse events. METHODS: We performed a systematic search of multiple electronic databases through February 2020 to identify studies reporting outcomes of OAE-ERCP in post-RYGB patients. The pooled rates of enteroscopy success, technical success, and adverse events were estimated for OAE-ERCP. The pooled rates of success and adverse events were also estimated for ERCP using double-balloon enteroscopes (DBE) alone. RESULTS: 10 studies reporting a total of 398 procedures were included in the meta-analysis. The pooled rates of enteroscopy and technical success of OAE-ERCP were 75.3 % (95 % confidence interval [CI] 64.5 - 83.6) and 64.8 % (95 %CI 53.1 - 74.9) respectively. The pooled rate of adverse events was 8.0 % (95 %CI 5.2 - 12.2). The pooled rates of enteroscopy and technical success of DBE-ERCP (four studies) were 83.5 % (95 %CI 68.3 - 92.2) and 72.5 % (95 %CI 52.3 - 86.4), respectively. The pooled rate of adverse events with DBE-ERCP was 9.0 % (95 %CI 5.4 - 14.5). Substantial heterogeneity was noted. CONCLUSIONS: OAE-ERCP appears to be effective and safe in post-RYGB patients. Among the currently available techniques, OAE-ERCP is the least invasive approach in this challenging group of patients. Future studies comparing the effectiveness and safety of alternative novel techniques, such as endosonography-directed transgastric ERCP, with OAE-ERCP are needed.

Serrated polyp detection rate and advanced adenoma detection rate from a US multicenter cohort.

BACKGROUND: Interval colorectal cancers may be associated with a low serrated polyp detection rate (SDR) and advanced adenoma detection rate (AADR). We aimed to determine the SDR and AADR for endoscopists in a United States multicenter cohort. METHODS: We included average-risk screening colonoscopies from five medical centers in the United States. Endoscopists with data on at least 100 average-risk screening colonoscopies were included. We calculated median SDR and AADR for endoscopists with adequate adenoma detection rates (ADRs) > 25 %. We analyzed the relationship between ADR and SDR, and between ADR and AADR using nonparametric Spearman correlation coefficients, scatter plots, and linear regression. RESULTS: We included 3513 screening colonoscopies performed by 26 gastroenterologists. The mean age of patients was 56.8 years (SD 7.4) and 1585 (45 %) were male. All but one endoscopist had an ADR above 25 %. There was a significant positive but modest correlation between ADR and SDR (rho = 0.67, P < 0.01), and between ADR and AADR (rho = 0.56, P < 0.01). For endoscopists with an adequate ADR, median (interquartile range) ADR was 43 % (32.0 % - 48.6 %), median SDR was 8.4 % (7.3 % - 11.4 %), and median AADR was 9.3 % (6.4 % - 12.6 %). CONCLUSION: A significant percentage of endoscopists have either a low SDR or low AADR despite an adequate ADR, justifying the need for separate SDR and AADR benchmarks. Based on our multicenter cohort, endoscopists with adequate ADRs had a median SDR and median AADR of about 8 % and 9 %, respectively.