ACG Clinical Guideline: Diagnosis and Management of Gastrointestinal Subepithelial Lesions.

Subepithelial lesions (SEL) of the GI tract represent a mix of benign and potentially malignant entities including tumors, cysts, or extraluminal structures causing extrinsic compression of the gastrointestinal wall. SEL can occur anywhere along the GI tract and are frequently incidental findings encountered during endoscopy or cross-sectional imaging. This clinical guideline of the American College of Gastroenterology was developed using the Grading of Recommendations Assessment, Development, and Evaluation process and is intended to suggest preferable approaches to a typical patient with a SEL based on the currently available published literature. Among the recommendations, we suggest endoscopic ultrasound (EUS) with tissue acquisition to improve diagnostic accuracy in the identification of solid nonlipomatous SEL and EUS fine-needle biopsy alone or EUS fine-needle aspiration with rapid on-site evaluation sampling of solid SEL. There is insufficient evidence to recommend surveillance vs resection of gastric gastrointestinal stromal tumors (GIST) <2 cm in size. Owing to their malignant potential, we suggest resection of gastric GIST >2 cm and all nongastric GIST. When exercising clinical judgment, particularly when statements are conditional suggestions and/or treatments pose significant risks, health-care providers should incorporate this guideline with patient-specific preferences, medical comorbidities, and overall health status to arrive at a patient-centered approach.

Differential Developmental Neurotoxicity and Tissue Uptake of the Per- and Polyfluoroalkyl Substance Alternatives, GenX and PFBS.

Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals with several applications. Multiple adverse health effects are reported for longer carbon chain (≤C8) PFAS. Shorter carbon chain PFAS, [e.g., hexafluoropropylene oxide dimer acid (HFPO-DA; GenX) and perfluorobutanesulfonic acid (PFBS)] were introduced as alternatives. Past studies indicate that longer-chain PFAS are neurotoxic targeting the dopamine pathway, but it is not known if shorter-chain PFAS act similarly. This study aimed to evaluate developmental neurotoxicity and tissue uptake of GenX and PFBS using the zebrafish (Danio rerio). First, acute toxicity was assessed by measuring LC50 at 120 h postfertilization (hpf). Body burden was determined after embryonic exposure (1-72 hpf) to sublethal concentrations of GenX or PFBS by LC-ESI-MS/MS. Locomotor activity using a visual motor response assay at 120 hpf and dopamine levels at 72 hpf was assessed after embryonic exposure. PFBS was more acutely toxic and bioaccumulative than GenX. GenX and PFBS caused hyperactivity at 120 hpf, but stronger behavioral alterations were observed for PFBS. An increase in whole organism dopamine occurred at 40 ppb of GenX, while a decrease was observed at 400 ppb of PFBS. Differences detected in dopamine for these two PFAS indicate differential mechanisms of developmental neurotoxicity.

Electric Field-Assisted Nanofiltration for PFOA Removal with Exceptional Flux, Selectivity, and Destruction.

Per- and polyfluoroalkyl substances (PFAS) pose significant environmental and human health risks and thus require solutions for their removal and destruction. However, PFAS cannot be destroyed by widely used removal processes like nanofiltration (NF). A few scarcely implemented advanced oxidation processes can degrade PFAS. In this study, we apply an electric field to a membrane system by placing a nanofiltration membrane between reactive electrodes in a crossflow configuration. The performance of perfluorooctanoic acid (PFOA) rejection, water flux, and energy consumption were evaluated. The reactive and robust SnO2-Sb porous anode was created via a sintering and sol-gel process. The characterization and analysis techniques included field emission scanning electron microscopy (FE-SEM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), ion chromatography, mass spectroscopy, porosimeter, and pH meter. The PFOA rejection increased from 45% (0 V) to 97% (30 V) when the electric field and filtration were in the same direction, while rejection capabilities worsened in opposite directions. With saline solutions (1 mM Na2SO4) present, the induced electro-oxidation process could effectively mineralize PFOA, although this led to unstable removal and water fluxes. The design achieved an exceptional performance in the nonsaline feed of 97% PFOA rejection and water flux of 68.4 L/m2 hr while requiring only 7.31 × 10-5 kWh/m3/order of electrical energy. The approach's success is attributed to the proximity of the electrodes and membrane, which causes a stronger electric field, weakened concentration polarization, and reduced mass transfer distances of PFOA near the membrane. The proposed electric field-assisted nanofiltration design provides a practical membrane separation method for PFAS removal from water.

Chronic Exposure to a PFAS Mixture Resembling AFFF-Impacted Surface Water Decreases Body Size in Northern Leopard Frogs (Rana pipiens).

Per- and polyfluoroalkyl substances (PFAS) occur in the environment as mixtures, yet mixture toxicity remains poorly understood. Aqueous film-forming foams (AFFFs) are a common source of PFAS. Our objective was to examine chronic effects of a complex PFAS mixture on amphibian growth and development. We tested toxicity of a five-chemical PFAS mixture summing to 10 µg/L and that accounts for >90% of the PFAS in AFFF-affected surface waters: perfluorooctane sulfonate (PFOS, 40%), perfluorohexane sulfonic acid (PFHxS, 30%), perflurooctanoic acid (PFOA, 12.5%), perfluorohexanoic acid (PFHxA, 12.5%), and perfluoropentanoic acid (PFPeA, 5%). We also included treatments to determine whether PFOS drove mixture toxicity and whether PFOS and mixture components act additively. We exposed Northern leopard frog (Rana pipiens) larvae through metamorphosis (∼130 d) in outdoor mesocosms. After 21 days of exposure, the larval body condition fell ∼5% relative to controls in the 4 µg/L PFOS treatment and mixtures lacking PFOS. At metamorphosis, the full 5-component 10 µg/L PFAS mixture reduced mass by 16% relative to controls. We did not observe effects on development. Our results indicate that toxicity of PFOS and other PFAS mixtures typical of AFFF sites act additively and that PFOS is not more inherently toxic than other mixture components.

High Persistence of Novel Polyfluoroalkyl Betaines in Aerobic Soils.

Some contemporary aqueous film-forming foams (AFFFs) contain n:3 and n:1:2 fluorotelomer betaines (FTBs), which are often detected at sites impacted by AFFFs. As new chemical replacements, little is known about their environmental fate. For the first time, we investigated the biotransformation potential of 5:3 and 5:1:2 FTBs and a commercial AFFF that mainly contains n:3 and n:1:2 FTBs (n = 5, 7, 9, 11, and 13). Although some polyfluoroalkyl compounds are precursors to perfluoroalkyl acids, 5:3 and 5:1:2 FTBs exhibited high persistence, with no significant changes even after 120 days of incubation. While the degradation of 5:3 FTB into suspected products such as fluorotelomer acids or perfluoroalkyl carboxylic acids (PFCAs) could not be conclusively confirmed, we did identify a potential biotransformation product, 5:3 fluorotelomer methylamine. Similarly, 5:1:2 FTB did not break down or produce short-chain hydrogen-substituted polyfluoroalkyl acids (n:2 H-FTCA), hydrogen-substituted PFCA (2H-PFCA), or any other products. Incubating the AFFF in four soils with differing properties and microbial communities resulted in 0.023-0.25 mol % PFCAs by day 120. Most of the products are believed to be derived from n:2 fluorotelomers, minor components of the AFFF. Therefore, the findings of the study cannot be fully explained by the current understanding of structure-biodegradability relationships.

Toxicities of Legacy and Current-Use PFAS in an Anuran: Do Larval Exposures Influence Responses to a Terrestrial Pathogen Challenge?

Legacy polyfluoroalkyl substances (PFAS) [perfluorooctanesulfonate (PFOS) and perfluorooctanoic acid (PFOA)] are being replaced by various other fluorinated compounds, such as hexafluoropropylene oxide dimer acid (GenX). These alternatives are thought to be less bioaccumulative and, therefore, less toxic than legacy PFAS. Contaminant exposures occur concurrently with exposure to natural stressors, including the fungal pathogen Batrachocytrium dendrobatidis (Bd). Despite evidence that other pollutants can increase the adverse effects of Bd on anurans, no studies have examined the interactive effects of Bd and PFAS. This study tested the growth and developmental effects of PFOS, PFOA, and GenX on gray treefrog (Hyla versicolor) tadpoles, followed by a Bd challenge after metamorphosis. Despite PFAS exposure only occurring during the larval stage, carry-over effects on growth were observed post metamorphosis. Further, PFAS interacted with Bd exposure to influence growth; Bd-exposed animals had significantly shorter SVL [snout-vent length (mm)] with significantly increased body condition, among other time-dependent effects. Our data suggest that larval exposure to PFAS can continue to impact growth in the juvenile stage after exposure has ended. Contrary to predictions, GenX affected terrestrial performance more consistently than its legacy congener, PFOA. Given the role of Bd in amphibian declines, further investigation of interactions of PFAS with Bd and other environmentally relevant pathogens is warranted.

Perfluoroalkyl acid transformation and mitigation by nNiFe-activated carbon nanocomposites in steady-state flow column studies.

The ongoing contamination of groundwater with per- and polyfluoroalkyl substances (PFAS) has resulted in a global and rapidly growing interest in PFAS groundwater remediation. Preferred technologies that lead to PFAS destruction are often limited by not addressing all PFAS, being energy-intensive or not being suited for in-situ application. We developed nNiFe-activated carbon (AC) nanocomposites and demonstrated varying degrees of PFAS reduction and fluoride generation with these nanocomposites in batch reactors for several PFAS. Here we explore nNiFe-AC's effectiveness to transform perfluoroalkyl acid acids (PFAAs) under steady-state flow (0.0044 to 0.15 mL/min) in nNiFe-AC:sand packed columns. Column experiments included, two perfluorooctane sulfonate (PFOS) in deionized water and two PFAA mixtures in deionized water or bicarbonate buffer containing five perfluoroalkyl carboxylates (PFCAs, C5-C9) and three perfluoroalkyl sulfonates (PFSAs, C4, C6 and C8) at temperatures of 50 or 60°C were evaluated. PFOS transformation was similar in PFOS-only and PFAA mixture column experiments. Overall, % PFAA transformation under flow conditions exceeded what we observed previously in batch reactors with up to 53% transformation of a PFAA mixture with ∼ 8% defluorination. Longer chain PFAS dominated the PFAAs transformed and a bicarbonate matrix appeared to reduce overall transformation. PFAA breakthrough was slower than predicted from only sorption due to transformation; some longer chain PFAS like PFOS did not breakthrough. Here, nNiFe-AC technology with both in-situ and ex-situ potential application was shown to be a plausible part of a treatment train needed to address the ongoing challenge for cleaning up PFAS-contaminated waters.

Lead-Time Trajectory of CA19-9 as an Anchor Marker for Pancreatic Cancer Early Detection.

BACKGROUND & AIMS: There is substantial interest in liquid biopsy approaches for cancer early detection among subjects at risk, using multi-marker panels. CA19-9 is an established circulating biomarker for pancreatic cancer; however, its relevance for pancreatic cancer early detection or for monitoring subjects at risk has not been established. METHODS: CA19-9 levels were assessed in blinded sera from 175 subjects collected up to 5 years before diagnosis of pancreatic cancer and from 875 matched controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. For comparison of performance, CA19-9 was assayed in blinded independent sets of samples collected at diagnosis from 129 subjects with resectable pancreatic cancer and 275 controls (100 healthy subjects; 50 with chronic pancreatitis; and 125 with noncancerous pancreatic cysts). The complementary value of 2 additional protein markers, TIMP1 and LRG1, was determined. RESULTS: In the PLCO cohort, levels of CA19-9 increased exponentially starting at 2 years before diagnosis with sensitivities reaching 60% at 99% specificity within 0 to 6 months before diagnosis for all cases and 50% at 99% specificity for cases diagnosed with early-stage disease. Performance was comparable for distinguishing newly diagnosed cases with resectable pancreatic cancer from healthy controls (64% sensitivity at 99% specificity). Comparison of resectable pancreatic cancer cases to subjects with chronic pancreatitis yielded 46% sensitivity at 99% specificity and for subjects with noncancerous cysts, 30% sensitivity at 99% specificity. For prediagnostic cases below cutoff value for CA19-9, the combination with LRG1 and TIMP1 yielded an increment of 13.2% in sensitivity at 99% specificity (P = .031) in identifying cases diagnosed within 1 year of blood collection. CONCLUSION: CA19-9 can serve as an anchor marker for pancreatic cancer early detection applications.

Effects of Per- and Polyfluoroalkyl Substance Mixtures on the Susceptibility of Larval American Bullfrogs to Parasites.

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants known to adversely affect health and development in many taxa. Although PFAS generally occur as mixtures in the environment, little is known about the effects of PFAS mixtures on organisms compared to single chemical exposures. Moreover, PFAS exposure in nature occurs alongside biotic factors such as parasitism. Even though host-parasite interactions are common in natural systems, there is little information about how PFAS affect these interactions. Here, we examined the effects of PFAS mixtures on the susceptibility of larval American bullfrogs (Rana catesbeiana) to echinostomes. Our PFAS treatments included perfluorooctanesulfonic acid (PFOS) at 4 and 10 ppb, two mixtures without PFOS as a component at 6 and 10 ppb total PFAS, and a mixture containing PFOS at 10 ppb total PFAS. We found that a 62-day PFAS exposure increased parasite loads by 42-100% in all treatments relative to the control. Additionally, we found that the singular exposure to PFOS increased parasite loads by ∼40% compared to a mixture containing PFOS suggesting antagonism among PFAS in mixtures. Our results highlight the need for further investigation into the effects of PFAS mixtures on organisms and how PFAS affect common ecological interactions.

Acute Toxicity of Eight Aqueous Film-Forming Foams to 14 Aquatic Species.

Researchers have developed numerous per- and polyfluoroalkyl substances (PFAS)-free aqueous film-forming foam (AFFF) formulations to replace PFAS-containing AFFF used for fire suppression. As part of the Department of Defense's Strategic Environmental Research and Development Program (SERDP), we examined the direct lethal effects of seven PFAS-free AFFF and a PFAS-containing AFFF on 14 aquatic species using a series of lethal concentration (LC50) tests. We assessed the LC10, LC50, and LC90 values using log-logistic and logit analyses. Across all aquatic species tested, we discovered that exposure to at least one PFAS-free AFFF was more or as toxic as exposure to the PFAS-containing AFFF. For most cases, National Foam Avio F3 Green KHC 3% and Buckeye Platinum Plus C6MILSPEC 3% were the most and least toxic formulations, respectively. Moreover, we found consistency among results from multiple experiments using the same minnow species (Pimephales promelas) and among closely related taxa (e.g., daphnids, amphibians). Lastly, the LC50 values for AFFF formulations trended lower for tested marine species as compared to those of freshwater species. These results dramatically increase the current knowledge on the potentially toxic effects of AFFF but also highlight the need for additional research and the development of new PFAS-free AFFF that are more "ecologically friendly" than those containing persistent PFAS.

State-of-the-Art Update of Pancreatic Cysts.

Andrew Canakis.

COVID-19 related pancreatic cancer surveillance disruptions amongst high-risk individuals.

BACKGROUND: COVID-19 pandemic-related disruptions to EUS-based pancreatic cancer surveillance in high-risk individuals remain uncertain. METHODS: Analysis of enrolled participants in the CAPS5 Study, a prospective multicenter study of pancreatic cancer surveillance in high-risk individuals. RESULTS: Amongst 693 enrolled high-risk individuals under active surveillance, 108 (16%) had an EUS scheduled during the COVID-19 pandemic-related shutdown (median length of 78 days) in the spring of 2020, with 97% of these procedures being canceled. Of these canceled surveillance EUSs, 83% were rescheduled in a median of 4.1 months, however 17% were not rescheduled after 6 months follow-up. Prior history of cancer was associated with increased likelihood of rescheduling. To date no pancreatic cancer has been diagnosed among those whose surveillance was delayed. CONCLUSIONS: COVID-19 delayed pancreatic cancer surveillance with no adverse outcomes in efficiently rescheduled individuals. However, 1 in 6 high-risk individuals had not rescheduled surveillance, indicating the need for vigilance to ensure timely surveillance rescheduling.

Comparison of zebrafish in vitro and in vivo developmental toxicity assessments of perfluoroalkyl acids (PFAAs).

Perfluoroalkyl acids (PFAAs) are persistent environmental contaminants that are associated with various adverse health outcomes. Perfluorooctanoic acid (PFOA) is one of the most prominently detected PFAAs in the environment, which is now replaced with shorter chain carbon compounds including perfluorohexanoic acid (PFHxA) and perfluorobutyric acid (PFBA). The aim of this study was to compare the toxicity of four PFAAs as a function of chain length and head group (carboxylate versus sulfonate) with in vitro and in vivo zebrafish assessments, which were subsequently compared to other cell and aquatic models. Mortality rate increased with chain length (PFOA > PFHxA ≫ PFBA) in both whole embryo/larvae and embryonic cell models. The sulfonate group enhanced toxicity with perfluorobutane sulfonate (PFBS) showing higher toxicity than PFBA and PFHxA in both larvae and cells. Toxicity trends were similar among different aquatic models, but sensitivities varied. Discrepancies with other zebrafish studies were confirmed to be associated with a lack of neutralization of acidic pH of dosing solutions in these other investigations, demonstrating the need for rigor in reporting pH of exposure solutions in all experiments. The zebrafish embryonic cell line was also found to be similar to most other cell lines regardless of exposure length. Overall, results agree with findings in other cell lines and organisms where longer chain length and sulfonate group increase toxicity, except in investigations not neutralizing the exposure solutions for these acidic compounds.

Prospective evaluation of an assessment tool for technical performance of duodenoscopes.

OBJECTIVE: While single-use and detachable-tip duodenoscopes have been recently developed to overcome risks of infection transmission, there are no reliable tools to objectively assess their technical performance. We evaluated the reliability and validity of a newly developed tool to assess the technical performance of reusable duodenoscopes. METHODS: An assessment tool was developed to measure duodenoscope performance based on three distinct criteria: maneuverability, mechanical/imaging characteristics and ability to perform requisite interventions. The assessment tool was tested prospectively on duodenoscopes used in endoscopic retrograde cholangiopancreatography (ERCP) procedures at nine academic medical centers over a 6-month period. The main outcome was reliability of the duodenoscope assessment tool, which was estimated using Cronbach's coefficient alpha (α). The secondary outcome was validity of the assessment tool. RESULTS: The assessment tool evaluated technical performance of reusable duodenoscopes in 1080 ERCP procedures. Indications were biliary in 92.8% and pancreatic in 7.2% procedures. The overall Cronbach's coefficient α for maneuverability was 0.81, assessment of mechanical/imaging characteristics was 0.92, and ability to perform requisite interventions was 0.87. On multiple linear regression analysis, prolonged procedure duration, older patient age and pancreatic interventions were significantly positively associated with higher (worse) scores. CONCLUSIONS: The newly developed assessment tool appears reliable and valid for evaluating the technical performance of duodenoscopes. Registration: ClinicalTrials.gov Identifier: NCT04004533.

Best Practices in Teaching Endoscopy Based on a Delphi Survey of Gastroenterology Program Directors and Experts in Endoscopy Education.

BACKGROUND AND AIMS: Teaching endoscopy is a key objective of gastroenterology (GI) fellowship programs but the best approach is not known. We sought to characterize which teaching competencies experts considered most critical for endoscopy education. METHODS: We developed and refined 18 endoscopy teaching competencies based on literature review, personal experience, and interviews with experts. We invited GI fellowship program directors and endoscopy education experts to participate in a Delphi process to rate each proposed competency as essential, important but not essential, or not important using a 70% agreement threshold for consensus. Thirty-four GI fellowship program directors and 2 experts in endoscopy education participated (n = 36). RESULTS: Most survey participants were male (61.8%), associate professors (55.9%), and had performed at least a quarter of procedures with fellows (80.6%). Survey response rates were 94% (34 of 36) for round 1 and 91% (31 of 34) for round 2 (overall 31 of 36; 86.1%). After 2 rounds we achieved the predefined consensus level for most competencies. Fourteen of 18 competencies (77.8%) reached consensus after round 2: 10 (55.6%) were deemed essential and 4 (22.2%) were deemed important but not essential. Essential competencies included the following: discusses patient history and plans for procedure with trainee (100%), assumes control of procedure when trainee is unable to progress or if patient safety concerns arise (100%), maintains attention throughout the case (96.8%), and discusses the next steps in management for the patient (96.8%). CONCLUSIONS: In a national Delphi survey of endoscopy education experts, we identified 10 essential endoscopy teaching competencies. These can be used to frame faculty development and standardize GI fellowship programs to promote high-quality endoscopy education.

EUS-guided fine-needle biopsy sampling versus FNA in the diagnosis of subepithelial lesions: a large multicenter study.

BACKGROUND AND AIMS: Although conventional EUS-guided FNA (EUS-FNA) has previously been considered first-line for sampling subepithelial lesions (SELs), variable accuracy has resulted in increased use of fine-needle biopsy (FNB) sampling to improve diagnostic yield. The primary aim of this study was to compare FNA versus FNB sampling for the diagnosis of SELs. METHODS: This was a multicenter, retrospective study to evaluate the outcomes of EUS-FNA and EUS-guided FNB sampling (EUS-FNB) of SELs over a 3-year period. Demographics, lesion characteristics, sensitivity, specificity, accuracy, number of needle passes, diagnostic adequacy of rapid on-site evaluation (ROSE), cell block accuracy, and adverse events were analyzed. Subgroup analyses were performed comparing FNA versus FNB sampling by location and diagnostic yield with or without ROSE. Multivariable logistic regression was also performed. RESULTS: Two hundred twenty-nine patients with SELs (115 FNA and 114 FNB sampling) underwent EUS-guided sampling. Mean patient age was 60.86 ± 12.84 years. Most lesions were gastric in location (75.55%) and from the fourth layer (71.18%). Cell block for FNB sampling required fewer passes to achieve conclusive diagnosis (2.94 ± 1.09 vs 3.55 ± 1.55; P = .003). The number of passes was not different for ROSE adequacy (P = .167). Immunohistochemistry was more able to be successfully performed in more FNB sampling samples (69.30% vs 40.00%; P < .001). Overall, sensitivity and accuracy were superior for FNB sampling versus FNA (79.41% vs 51.92% [P = .001] and 88.03% vs 77.19% [P = .030], respectively). On subgroup analysis, sensitivity and accuracy of FNB sampling alone was superior to FNA + ROSE (79.03% vs 46.67% [P = .001] and 87.25% vs 68.00% [P = .024], respectively). There was no significant difference in diagnostic yield of FNB sampling alone versus FNB sampling + ROSE (P > .05). Multivariate analysis showed no predictors associated with accuracy. One minor adverse event was reported in the FNA group. CONCLUSIONS: EUS-FNB was superior to EUS-FNA in the diagnosis of SELs. EUS-FNB was also superior to EUS-FNA alone and EUS-FNA + ROSE. These results suggest EUS-FNB should be considered a first-line modality and may suggest a reduced role for ROSE in the diagnosis of SELs. However, a large randomized controlled trial is required to confirm our findings.

Characterizing and Comparing Per- and Polyfluoroalkyl Substances in Commercially Available Biosolid and Organic Non-Biosolid-Based Products.

There is increasing concern over the presence of per- and polyfluoroalkyl substances (PFAS) in biosolids, while sales in commercially available biosolid-based products used as soil amendments are also increasing. Here, the occurrence of 17 perfluoroalkyl acids (PFAAs) present in 13 commercially available biosolid-based products, six organic composts (manure, mushroom, peat, and untreated wood), and one food and yard waste compost were studied. The PFAA concentration ranges observed are as follows: biosolid-based products (9.0-199 µg/kg) > food and yard waste (18.5 µg/kg) > other organic products (0.1-1.1 µg/kg). Analysis of 2014, 2016, and 2018 bags produced from one product line showed a temporal decrease in the total PFAAs (181, 101, and 74 µg/kg, respectively). The total oxidizable precursor (TOP) assay revealed the presence of PFAA precursors in the biosolid-based products at much higher levels, when the soluble carbon was removed by the ENVI-Carb clean-up prior to the TOP assay. Time-of-flight mass spectrometry confirmed the presence of three sulfonamides, two fluorotelomer sulfonates, and several polyfluoroalkyl phosphate diesters. Pore-water concentrations of water-saturated products were primarily of short-chain PFAAs and increased with increasing PFAA concentrations in the products. A strong positive log-linear correlation between organic carbon (OC)-normalized PFAA partition coefficients and the number of CFn units indicates that OC is a good predictor of PFAA release concentrations.

Competence in Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography, From Training Through Independent Practice.

BACKGROUND & AIMS: It is unclear whether participation in competency-based fellowship programs for endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) results in high-quality care in independent practice. We measured quality indicator (QI) adherence during the first year of independent practice among physicians who completed endoscopic training with a systematic assessment of competence. METHODS: We performed a prospective multicenter cohort study of invited participants from 62 training programs. In phase 1, 24 advanced endoscopy trainees (AETs), from 20 programs, were assessed using a validated competence assessment tool. We used a comprehensive data collection and reporting system to create learning curves using cumulative sum analysis that were shared with AETs and trainers quarterly. In phase 2, participating AETs entered data into a database pertaining to every EUS and ERCP examination during their first year of independent practice, anchored by key QIs. RESULTS: By the end of training, most AETs had achieved overall technical competence (EUS 91.7%, ERCP 73.9%) and cognitive competence (EUS 91.7%, ERCP 94.1%). In phase 2 of the study, 22 AETs (91.6%) participated and completed a median of 136 EUS examinations per AET and 116 ERCP examinations per AET. Most AETs met the performance thresholds for QIs in EUS (including 94.4% diagnostic rate of adequate samples and 83.8% diagnostic yield of malignancy in pancreatic masses) and ERCP (94.9% overall cannulation rate). CONCLUSIONS: In this prospective multicenter study, we found that although competence cannot be confirmed for all AETs at the end of training, most meet QI thresholds for EUS and ERCP at the end of their first year of independent practice. This finding affirms the effectiveness of training programs. Clinicaltrials.gov ID NCT02509416.

Novel Methylated DNA Markers Discriminate Advanced Neoplasia in Pancreatic Cysts: Marker Discovery, Tissue Validation, and Cyst Fluid Testing.

OBJECTIVES: Pancreatic cystic lesions (PCLs) may be precancerous. Those likely to harbor high-grade dysplasia (HGD) or pancreatic cancer (PC) are targets for surgical resection. Current algorithms to predict advanced neoplasia (HGD/PC) in PCLs lack diagnostic accuracy. In pancreatic tissue and cyst fluid (CF) from PCLs, we sought to identify and validate novel methylated DNA markers (MDMs) that discriminate HGD/PC from low-grade dysplasia (LGD) or no dysplasia (ND). METHODS: From an unbiased whole-methylome discovery approach using predefined selection criteria followed by multistep validation on case (HGD or PC) and control (ND or LGD) tissues, we identified discriminant MDMs. Top candidate MDMs were then assayed by quantitative methylation-specific polymerase chain reaction on archival CF from surgically resected PCLs. RESULTS: Of 25 discriminant MDMs identified in tissue, 13 were selected for validation in 134 CF samples (21 cases [8 HGD, 13 PC], 113 controls [45 ND, 68 LGD]). A tree-based algorithm using 2 CF-MDMs (TBX15, BMP3) achieved sensitivity and specificity above 90%. Discrimination was significantly better by this CF-MDM panel than by mutant KRAS or carcinoembryonic antigen, with areas under the receiver operating characteristic curve of 0.93 (95% confidence interval: 0.86-0.99), 0.71 (0.57-0.85), and 0.72 (0.60-0.84), respectively. Cutoffs for the MDM panel applied to an independent CF validation set (31 cases, 56 controls) yielded similarly high discrimination, areas under the receiver operating characteristic curve = 0.86 (95% confidence interval: 0.77-0.94, P = 0.2). DISCUSSION: Novel MDMs discovered and validated in tissue accurately identify PCLs harboring HGD/PC. A panel of 2 MDMs assayed in CF yielded results with potential to enhance current risk prediction algorithms. Prospective studies are indicated to optimize and further evaluate CF-MDMs for clinical use.

Developmental exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) selectively decreases brain dopamine levels in Northern leopard frogs.

Per- and polyfluoroalkyl substances (PFAS) are synthetic compounds that are a major public health concern due to widespread use, long environmental and biological half-lives, detection in most human plasma samples, and links to multiple adverse health outcomes. The literature suggests that some PFAS may be neurotoxic. However, there are major gaps in the literature with respect to how environmentally-relevant doses during development may influence the nervous system. To address this gap, we utilized a sentinel species, Northern leopard frogs (Lithobates pipiens) to determine the effects of developmental exposure to environmentally relevant perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) on major neurotransmitter systems. Frog larvae at Gosner stage 25 were exposed to 10, 100, or 1000 ppb PFOS or PFOA for 30 days before neurochemical analysis. High performance liquid chromatography (HPLC) with electrochemical detection or fluorescent detection assays was used to measure neurotransmitter levels, which were normalized to protein levels in each sample. Dopamine (DA) decreased significantly in the brains of frogs treated with PFOA (1000 ppb) and PFOS (100 and 1000 ppb). Significant increases in DA turnover also resulted from PFOA and PFOS treatment. Neither PFOS, nor PFOA produced detectable alterations in serotonin (nor its metabolite), norepinephrine, gamma-amino butyric acid (GABA), glutamate, or acetylcholine. PFAS body burdens showed that PFOS accumulated relative to dose, while PFOA did not. These data suggest that DArgic neurotransmission is selectively affected in developmentally exposed amphibians and that PFAS should be evaluated for a potential role in diseases that target the DA system.