Over-the-scope clip as first-line treatment of peptic ulcer bleeding: a multicenter randomized controlled trial (TOP Study).

BACKGROUND: First-line over-the-scope (OTS) clip treatment has shown higher efficacy than standard endoscopic therapy in acute nonvariceal upper gastrointestinal bleeding (NVUGIB) from different causes. We compared OTS clips with through-the-scope (TTS) clips as first-line mechanical treatment in the specific setting of peptic ulcer bleeding. METHODS: We conducted an international, multicenter randomized controlled trial on consecutive patients with suspected NVUGIB. Patients with Forrest Ia-IIb gastroduodenal peptic ulcer were randomized 1:1 to OTS clip or TTS clip treatment. The primary outcome was the rate of 30-day rebleeding after successful initial hemostasis. Secondary outcomes included the rates of successful initial hemostasis and overall clinical success, defined as the composite of successful initial hemostasis and no evidence of 30-day rebleeding. RESULTS: 251 patients were screened and 112 patients were randomized to OTS (n = 61) or TTS (n = 51) clip treatment. The 30-day rebleeding rates were 1.6% (1/61) and 3.9% (2/51) in patients treated with OTS clips and TTS clips, respectively (Kaplan-Meier log-rank, P = 0.46). Successful initial hemostasis rates were 98.4% (60/61) in the OTS clip group and 78.4% (40/51) in the TTS clip group (P = 0.001). Overall clinical success rates were 96.7% (59/61) with OTS clips and 74.5% (38/51) with TTS clips (P = 0.001). CONCLUSIONS: Low rates of 30-day rebleeding were observed after first-line endoscopic treatment of acute peptic ulcer bleeding with either OTS or TTS clips. However, OTS clips showed higher efficacy than TTS clips in achieving successful initial hemostasis and overall clinical success.

Multiparametric Orthogonal Characterization of Extracellular Vesicles by Liquid Chromatography Combined with In-Line Light Scattering and Fluorescence Detection.

Extracellular vesicles (EVs) are membrane-enclosed biological nanoparticles with potential as diagnostic markers and carriers for therapeutics. Characterization of EVs poses severe challenges due to their complex structure and composition, requiring the combination of orthogonal analytical techniques. Here, we demonstrate how liquid chromatography combined with multi-angle light scattering (MALS) and fluorescence detection in one single apparatus can provide multiparametric characterization of EV samples, including concentration of particles, average diameter of the particles, protein amount to particle number ratio, presence of EV surface markers and lipids, EV shape, and sample purity. The method requires a small amount of sample of approximately 107 EVs, limited handling of the sample and data analysis time in the order of minutes; it is fully automatable and can be applied to both crude and purified samples.

High-Yield Separation of Extracellular Vesicles Using Programmable Zwitterionic Coacervates.

Programmable coacervates based on zwitterionic polymers are designed as dynamic materials for ion exchange bioseparation. These coacervates are proposed as promising materials for the purification of soft nanoparticles such as liposomes and extracellular vesicles (EVs). It is shown that the stimulus-responsiveness of the coacervates and the recruitment of desired molecules can be independently programmed by polymer design. Moreover, the polymeric coacervates can recruit and release intact liposomes, human EVs, and nanoalgosomes in high yields and separate vesicles from different types of impurities, including proteins and nucleic acids. This approach combines the speed and simplicity of precipitation methods and the programmability of chromatography with the gentleness of aqueous two-phase separation, thereby guaranteeing product stability. This material represents a promising alternative for providing a low-shear, gentle, and selective purification method for EVs.

Repeated endoscopic ultrasound-guided fine-needle biopsy of solid pancreatic lesions after previous nondiagnostic or inconclusive sampling.

OBJECTIVES: Repeated endoscopic ultrasound (EUS)-guided tissue acquisition represents the standard practice for solid pancreatic lesions after previous nondiagnostic or inconclusive results. Since data are lacking, we aimed to evaluate the diagnostic performance of repeated EUS fine-needle biopsy (rEUS-FNB) in this setting. The primary outcome was diagnostic accuracy; sample adequacy, sensitivity, specificity, and safety were secondary outcomes. METHODS: Consecutive patients undergoing rEUS-FNB for solid pancreatic lesions at 23 Italian centers from 2019 to 2021 were retrieved. Pathology on the surgical specimen, malignant histology together with ≥6-month follow-up, and benign pathology together with ≥12-month follow-up were adopted as gold standards. RESULTS: Among 462 patients, 56.5% were male, with a median age of 68 (59-75) years, malignancy prevalence 77.0%. Tumor size was 26 (20-35) mm. Second-generation FNB needles were used in 89.6% cases. Diagnostic accuracy, sensitivity, and specificity of rEUS-FNB were 89.2%, 91.4%, and 81.7%, respectively (19 false-negative and 12 false-positive results). On multivariate analysis, rEUS-FNB performed at high-volume centers (odds ratio [OR] 2.12; 95% confidence interval [CI] 1.10-3.17; P = 0.03) and tumor size (OR 1.03; 95% CI 1.00-1.06; P = 0.05) were independently related to diagnostic accuracy. Sample adequacy was 94.2%. Use of second-generation FNB needles (OR 5.42; 95% CI 2.30-12.77; P < 0.001) and tumor size >23 mm (OR 3.04; 95% CI 1.31-7.06; P = 0.009) were independently related to sample adequacy. CONCLUSION: Repeated EUS-FNB allowed optimal diagnostic performance after nondiagnostic or inconclusive results. Patients' referral to high-volume centers improved diagnostic accuracy. The use of second-generation FNB needles significantly improved sample adequacy over standard EUS-FNB needles.

Proof-of-Concept Study on the Use of Tangerine-Derived Nanovesicles as siRNA Delivery Vehicles toward Colorectal Cancer Cell Line SW480.

In the last years, the field of nanomedicine and drug delivery has grown exponentially, providing new platforms to carry therapeutic agents into the target sites. Extracellular vesicles (EVs) are ready-to-use, biocompatible, and non-toxic nanoparticles that are revolutionizing the field of drug delivery. EVs are involved in cell-cell communication and mediate many physiological and pathological processes by transferring their bioactive cargo to target cells. Recently, nanovesicles from plants (PDNVs) are raising the interest of the scientific community due to their high yield and biocompatibility. This study aims to evaluate whether PDNVs may be used as drug delivery systems. We isolated and characterized nanovesicles from tangerine juice (TNVs) that were comparable to mammalian EVs in size and morphology. TNVs carry the traditional EV marker HSP70 and, as demonstrated by metabolomic analysis, contain flavonoids, organic acids, and limonoids. TNVs were loaded with DDHD1-siRNA through electroporation, obtaining a loading efficiency of 13%. We found that the DDHD1-siRNA complex TNVs were able to deliver DDHD1-siRNA to human colorectal cancer cells, inhibiting the target expression by about 60%. This study represents a proof of concept for the use of PDNVs as vehicles of RNA interference (RNAi) toward mammalian cells.

Impact of colonoscopy on working productivity: a prospective multicenter observational study.

BACKGROUND AND AIMS: Patients undergoing colonoscopy are often in the workforce. Therefore, colonoscopy may affect patients' work productivity in terms of missed working days and/or reduced working efficiency. We aimed to investigate the impact of colonoscopy on work productivity and factors influencing this impact. METHODS: We conducted a prospective, observational, multicenter study in 10 Italian hospitals between 2016 and 2017. We collected information on individual characteristics, work productivity, symptoms, and conditions before, during, and after the procedure from patients undergoing colonoscopy for several indications using validated tools. Outcomes were interference of preparation with work, absenteeism, and impaired work performance after the procedure. We fitted multivariate logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for potential predictors of the outcomes. RESULTS: Among 1137 subjects in the study, 30.5% reported at least 1 outcome. Impaired work performance was associated with bowel preparation regimen (full dose on the day of colonoscopy vs split dose: OR, 4.04; 95% CI, 1.43-11.5), symptoms during bowel preparation (high symptom score: OR, 3.21; 95% CI, 1.15-8.95), and pain during the procedure (OR, 2.47; 95% CI, 1.40-4.35). Increasing number of working hours and less comfortable jobs were associated with absenteeism (P for trend = .06) and impairment of working performance (P for trend = .01) and GI symptoms both before and after colonoscopy. CONCLUSIONS: Occupational and individual characteristics of patients should be considered when scheduling colonoscopy because this procedure may impair work productivity in up to one-third of patients. Split-dose bowel preparation, performing a painless colonoscopy, and preventing the occurrence of GI symptoms may minimize the impact of colonoscopy on work productivity.

Neuroserpin: structure, function, physiology and pathology.

Neuroserpin is a serine protease inhibitor identified in a search for proteins implicated in neuronal axon growth and synapse formation. Since its discovery over 30 years ago, it has been the focus of active research. Many efforts have concentrated in elucidating its neuroprotective role in brain ischemic lesions, the structural bases of neuroserpin conformational change and the effects of neuroserpin polymers that underlie the neurodegenerative disease FENIB (familial encephalopathy with neuroserpin inclusion bodies), but the investigation of the physiological roles of neuroserpin has increased over the last years. In this review, we present an updated and critical revision of the current literature dealing with neuroserpin, covering all aspects of research including the expression and physiological roles of neuroserpin, both inside and outside the nervous system; its inhibitory and non-inhibitory mechanisms of action; the molecular structure of the monomeric and polymeric conformations of neuroserpin, including a detailed description of the polymerisation mechanism; and the involvement of neuroserpin in human disease, with particular emphasis on FENIB. Finally, we briefly discuss the identification by genome-wide screening of novel neuroserpin variants and their possible pathogenicity.

Factors That Affect Adequacy of Colon Cleansing for Colonoscopy in Hospitalized Patients.

BACKGROUND & AIMS: Hospitalization is associated with inadequate colon cleansing before colonoscopy. We aimed to identify factors associated to inadequate colon cleansing among inpatients, and to derive and validate a model to identify inpatients with inadequate cleansing. METHODS: We performed a prospective observational study at 12 hospitals in Italy. Consecutive adult inpatients scheduled for colonoscopy for any indication were enrolled from February through May 2019 (derivation cohort, n = 1016) and from June through August 2019 (validation cohort, n = 508). Inadequate cleansing was defined as Boston bowel preparation scale scores below 2 in any colon segment. We performed multivariate logistic regression to identify factors associated with inadequate cleansing. RESULTS: In the combined cohorts, 1032 patients (68%) had adequate colon cleansing. Physicians' meetings to optimize bowel preparation (odds ratio [OR], 0.42; 95% CI, 0.27-0.65), written and oral instructions to patients (OR, 0.48; 95% CI, 0.36-0.65), admission to gastroenterology unit (OR, 0.71; 95% CI, 0.51-0.98), split-dose regimens (OR, 0.27; 95% CI, 0.20-0.35), a 1-liter polyethylene glycol-based bowel purge (OR, 0.39; 95% CI, 0.23-0.65), and 75% or more intake of bowel preparation (OR, 0.09; 95% CI, 0.05-0.15) significantly reduced odds of inadequate colon cleansing. Alternatively, bedridden status (OR, 2.14; 95% CI, 1.55-2.98), constipation (OR, 2.16; 95% CI, 1.55-3.0), diabetes mellitus (OR, 1.61; 95% CI, 1.18-2.20), use of anti-psychotic drugs (OR, 3.26; 95% CI, 1.62-6.56), and 7 or more days of hospitalization (OR, 1.02; 95% CI, 1.00-1.04) increased risk of inadequate colon cleansing. We developed a model to identify patients with inadequate cleaning using data from patients in the derivation cohort and tested it in the validation cohort. Calibration values were P = .218 for the discrimination cohort and P = .232 for the validation cohort. Discrimination values were c-statistic, 0.78 (95% CI, 0.74-0.81) for the discrimination cohort and c-statistic, 0.73 (95% CI, 0.69-0.78) for the validation cohort. We developed app for use by clinicians. CONCLUSIONS: In a prospective observational study, we identified setting-, patient- and preparation-related factors that affect colon cleansing among inpatients. We derived and validated a model to identify patients with inadequate preparation and developed an app for clinicians. ClinicalTrials.gov no: NCT03925506.

Risk of Covert Submucosal Cancer in Patients With Granular Mixed Laterally Spreading Tumors.

BACKGROUND AND AIMS: Granular mixed laterally spreading tumors (GM-LSTs) have an intermediate level of risk for submucosal invasive cancer (SMICs) without clear signs of invasion (covert); the optimal resection method is uncertain. We aimed to determine the risk of covert SMIC in GM-LSTs based on clinical and endoscopic factors. METHODS: We collected data from 693 patients (50.6% male; median age, 69 years) with colorectal GM-LSTs, without signs of invasion, who underwent endoscopic resection (74.2%) or endoscopic submucosal dissection (25.2%) at 7 centers in Italy from 2016 through 2019. We performed multivariate and univariate analyses to identify demographic and endoscopic factors associated with risk of SMIC. We developed a multivariate model to calculate the number needed to treat (NNT) to detect 1 SMIC. RESULTS: Based on pathology analysis, 66 patients (9.5%) had covert SMIC. In multivariate analyses, increased risk of covert SMIC were independently associated with increasing lesion size (odds ratio per mm increase, 1.02, 95% CI, 1.01-1.03; P = .003) and rectal location (odds ratio, 3.08; 95% CI, 1.62-5.83; P = .004). A logistic regression model based on lesion size (with a cutoff of 40 mm) and rectal location identified patients with covert SMIC with 47.0% sensitivity, 82.6% specificity, and an area under the curve of 0.69. The NNT to identify 1 patient with a nonrectal SMIC smaller than 4 cm was 20; the NNT to identify 1 patient with a rectal SMIC of 4 cm or more was 5. CONCLUSIONS: In an analysis of data from 693 patients, we found the risk of covert SMIC in patients with GM-LSTs to be approximately 10%. GM-LSTs of 4 cm or more and a rectal location are high risk and should be treated by en-bloc resection. ClinicalTrials.gov, Number: NCT03836131.

Novel 1-L polyethylene glycol + ascorbate versus high-volume polyethylene glycol regimen for colonoscopy cleansing: a multicenter, randomized, phase IV study.

BACKGROUND AND AIMS: Adequate bowel cleansing is critical to ensure quality and safety of a colonoscopy. A novel 1-L polyethylene glycol plus ascorbate (1L-PEG+ASC) regimen was previously validated against low-volume regimens but was never compared with high-volume regimens. METHODS: In a phase IV study, patients undergoing colonoscopy were randomized 1:1 to receive split-dose 1L PEG+ASC or a split-dose 4-L PEG-based regimen (4L-PEG) in 5 Italian centers. Preparation was assessed with the Boston Bowel Preparation Scale (BBPS) by local endoscopists and centralized reading, both blinded to the randomization arm. The primary endpoint was noninferiority of 1L-PEG+ASC in colon cleansing. Secondary endpoints were superiority of 1L-PEG+ASC, patient compliance, segmental colon cleansing, adenoma detection rate, tolerability, and safety. RESULTS: Three hundred eighty-eight patients (median age, 59.8 years) were randomized between January 2019 and October 2019: 195 to 1L-PEG+ASC and 193 to 4L-PEG. Noninferiority of 1L-PEG+ASC was demonstrated for cleansing in both the entire colon (BBPS ≥ 6: 97.9% vs 93%; relative risk [RR], 1.03; 95% confidence interval [CI], 1.001-1.04; P superiority = .027) and in the right-sided colon segment (98.4% vs 96.0%; RR, 1.02; 95% CI, .99-1.02; P noninferiority = .013). Compliance was higher with 1L-PEG+ASC than with 4L-PEG (178/192 [92.7%] vs 154/190 patients [81.1%]; RR, 1.10; 95% CI, 1.05-1.12), whereas no difference was found regarding safety (moderate/severe side effects: 20.8% vs 25.8%; P = .253). No difference in adenoma detection rate (38.8% vs 43.0%) was found. CONCLUSIONS: One-liter PEG+ASC showed noninferiority compared with 4L-PEG in achieving adequate colon cleansing and provided a higher patient compliance. No differences in tolerability and safety were detected. (Clinical trial registration number: NCT03742232.).