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Patients should be referred for further evaluation if the procedure fails or an insufficient sample is obtained. Postmenopausal women and women with persistent or recurrent symptoms should receive further evaluation even when biopsy results are normal because blind sampling may miss focal lesions.Dyspnea is a symptom arising from a complex interplay of diseases and physiologic states and is commonly encountered in primary care. It is considered chronic if present for more than one month. As a symptom, dyspnea is a predictor for all-cause mortality. The likeliest causes of dyspnea are disease states involving the cardiac or pulmonary systems such as asthma, chronic obstructive pulmonary disease, heart failure, pneumonia, and coronary artery disease. A detailed history and physical examination should begin the workup; results should drive testing. Approaching testing in stages beginning with first-line tests, including a complete blood count, basic chemistry panel, electrocardiography, chest radiography, spirometry, and pulse oximetry, is recommended. If no cause is identified, second-line noninvasive testing such as echocardiography, cardiac stress tests, pulmonary function tests, and computed tomography scan of the lungs is suggested. Final options include more invasive tests that should be done in collaboration with specialty help. There are three main treatment and management goals correctly identify the underlying disease process and treat appropriately, optimize recovery, and improve the dyspnea symptoms. The six-minute walk test can be helpful in measuring the effect of ongoing intervention. Care of patients with chronic dyspnea typically requires a multidisciplinary approach, which makes the primary care physician ideal for management.INTRODUCTION Somatic mutations in BRCA1/2 and other homologous recombination repair (HRR) genes have been associated with sensitivity to PARP inhibitors and/or platinum agents in several cancers, whereas hypermutant tumors caused by alterations in POLE or mismatch repair genes have demonstrated robust responses to immunotherapy. We investigated the relationship between somatic truncations in HRR genes and hypermutation in colorectal cancer (CRC) and endometrial cancer (EC). METHODS We analyzed the mutational spectra associated with somatic BRCA1/2 truncations in multiple genomic cohorts (N = 2,335). From these results, we devised a classifier incorporating HRR genes to predict hypermutator status among microsatellite stable (MSS) tumors. Using additional genomic cohorts (N = 1,439) and functional in vivo assays, we tested the classifier to disambiguate POLE variants of unknown significance and identify MSS hypermutators without somatic POLE exonuclease domain mutations. RESULTS Hypermutator phenotypes were prevalent among CRCs with somatic BRCA1/2 truncations (50/62, 80.6%) and ECs with such mutations (44/47, 93.6%). The classifier predicted MSS hypermutators with a cumulative true-positive rate of 100% in CRC and 98.0% in EC and a false-positive rate of 0.07% and 0.63%. Validated by signature analyses of tumor exomes and in vivo assays, the classifier accurately reassigned multiple POLE variants of unknown significance as pathogenic and identified MSS hypermutant samples without POLE exonuclease domain mutations. DISCUSSION Somatic truncations in HRR can accurately fingerprint MSS hypermutators with or without known pathogenic exonuclease domain mutations in POLE and may serve as a low-cost biomarker for immunotherapy decisions in MSS CRC and EC.INTRODUCTION The burden of hepatocellular carcinoma (HCC) occurring in patients with alcoholic liver disease (ALD) is increasing at an alarming rate. The aims of this study were to compare the patient and tumor characteristics of HCC occurring in ALD-alone relative to and in addition to other chronic liver diseases. METHODS Patients diagnosed with HCC between 2000 and 2014 were identified at 5 US clinical centers. The patients were categorized as ALD-alone, ALD plus viral hepatitis, or a non-ALD etiology. Clinical and tumor characteristics among the 3 groups were compared, and survival probability was estimated by the Kaplan-Meier method. The frequency of noncirrhotic HCC was compared across the 3 groups. RESULTS A total of 5,327 patients with HCC were analyzed. Six hundred seventy (12.6%) developed HCC due to underlying ALD. Ninety-one percent of ALD-related HCC arose in men, in contrast to non-ALD etiologies where men accounted for 70% of HCCs cases (P less then 0.001). Patients with ALD-alone-related HCC were older at diagnosis and had tumors less likely to be detected as part of routine surveillance. The ALD-alone cohort was least likely to be within the Milan criteria and to undergo liver transplantation. Overall survival in the ALD-alone HCC cohort was lower than the other 2 groups (1.07 vs 1.31 vs 1.41 years, P less then 0.001). HCC in the noncirrhotic ALD cohorts occurred in only 3.5% of the patients compared with 15.7% in patients with non-ALD etiologies (P less then 0.001). DISCUSSION HCC occurring in patients with ALD occurred mostly in older men and almost exclusively in a cirrhotic background. They present with advanced tumors, and their survival is lower than HCCs occurring in non-ALD.INTRODUCTION Race, ethnicity, and socioeconomic status are known to influence staging and survival in colorectal cancer (CRC). It is unclear how these relationships are affected by geographic factors and changes in insurance coverage for CRC screening. We examined the temporal trends in the association between sociodemographic and geographic factors and staging and survival among Medicare beneficiaries. METHODS We identified patients 65 years or older with CRC using the 1991-2010 Surveillance, Epidemiology, and End Results-Medicare database and extracted area-level sociogeographic data. We constructed multinomial logistic regression models and the Cox proportional hazards models to assess factors associated with CRC stage and survival in 4 periods with evolving reimbursement and screening practices (i) 1991-1997, (ii) 1998-June 2001, (iii) July 2001-2005, and (iv) 2006-2010. RESULTS We observed 327,504 cases and 102,421 CRC deaths. Blacks were 24%-39% more likely to present with distant disease than whites. High-income areas had 7%-12% reduction in distant disease. 17β-estradiol concentration Compared with whites, blacks had 16%-21% increased mortality, Asians had 32% lower mortality from 1991 to 1997 but only 13% lower mortality from 2006 to 2010, and Hispanics had 20% reduced mortality only from 1991 to 1997. High-education areas had 9%-12% lower mortality, and high-income areas had 5%-6% lower mortality after Medicare began coverage for screening colonoscopy. No consistent temporal trends were observed for the associations between geographic factors and CRC survival. DISCUSSION Disparities in CRC staging and survival persisted over time for blacks and residents from areas of low socioeconomic status. Over time, staging and survival benefits have decreased for Asians and disappeared for Hispanics.OBJECTIVES Although early biliary drainage improves outcomes in patients with acute cholangitis, the optimal time to perform endoscopic retrograde cholangiopancreatography (ERCP) is controversial. Our aim was to evaluate the impact of timing of ERCP on mortality in hospitalized patients with acute cholangitis. METHODS We searched PubMed, EMBASE, and The Cochrane Library (until February 2019) for studies evaluating the impact of timing of ERCP ( less then 24, less then 48, and less then 72 hours from hospitalization) on outcomes in patients with acute cholangitis. The primary outcome was in-hospital mortality. RESULTS Fourteen observational studies, including 84,063 patients (mean age = 66 ± 18), met the study criteria. The overall pooled in-hospital mortality with acute cholangitis was 1.9% (95% confidence interval [CI] 1.8%-7.6%), which increased to 4.3% (95% CI 1.8%-8.7%) when administrative database studies were excluded. In 9 studies, ERCP performed less then 24 compared with ≥24 hours decreased in-hospital mortality (odds ratio [OR] = 0.81, 95% CI 0.73-0.90; I = 0%). In 8 studies, ERCP performed less then 48 compared with ≥48 hours decreased in-hospital mortality (OR = 0.57, 95% CI 0.51-0.63; I = 0%). In 4 studies, ERCP performed less then 72 compared with ≥72 hours decreased in-hospital mortality (OR = 0.32, 95% CI 0.15-0.68; I = 0%). Furthermore, hospital stay was reduced in patients receiving ERCP less then 24 compared with ≥24 hours (mean difference [MD] = 3.2 days, 95% CI 2.3-4.1; I = 78%), less then 48 compared with ≥48 hours (MD = 3.6 days, 95% CI 2.1-5.1; I = 98%), and less then 72 compared with ≥72 hours (MD = 4.1 days, 95% CI 0.9-7.3; I = 63%). DISCUSSION In observational studies, earlier ERCP performed in patients with acute cholangitis, even urgently performed less then 24 hours from presentation, was associated with reduced mortality. A randomized trial evaluating the impact of urgent ERCP on outcomes is needed.OBJECTIVES Chronic pancreatitis (CP) is a serious condition whose pathogenic mechanism is unclear. Interactions of host genetic factors with gut microbiota have a role, but little is known, especially in children with CP (CCP), in which the external factors are less important. Our objective was to identify the main gut microbiota genera in CCP and to characterize the functional mutations of these patients. METHODS We used 16S rRNA sequencing to compare the gut microbiota of healthy controls with patients who had CCP and different functional gene mutations. RESULTS CCP is characterized by gut microbiota with remarkably reduced alpha diversity. Receiver operating characteristic curve analyses indicated that the abundances of 6 genera-Faecalibacterium, Subdoligranulum, Phascolarctobacterium, Bifidobacterium, Eubacerium, and Collinsella-were significantly decreased in CCP, with an area under curve (AUC) of 0.92 when considering all 6 genera together. Functional analysis of gut microbiota in CCP indicated reduced ribosomal activity, porphyrin and chlorophyll metabolism, starch and sucrose metabolism, and aminoacyl-tRNA biosynthesis, but an enrichment of phosphotransferase system pathways. link2 The abundance of Butyricicoccus was significantly decreased in CCP in the presence of CFTR mutations when combined with mutations in CASR, CTSB, SPINK1, and/or PRSS1. The abundance of Ruminococcaceae was significantly increased in CCP when there were mutations in CASR, CTSB, SPINK1, and/or PRSS1. Patients with CCP but no gene mutations had greater abundances of Veillonella and reduced abundances of Phascolarctobacterium. DISCUSSION CCP is associated with a depletion of probiotic gut microbiota, and CCP patients with different functional gene mutations have different gut microbiota.OBJECTIVES A superficial nonampullary duodenal epithelial tumor (SNADET) is defined as a mucosal or submucosal sporadic tumor of the duodenum that does not arise from the papilla of Vater. SNADETs rarely metastasize to the lymph nodes, and most can be treated endoscopically. However, SNADETs are sometimes missed during esophagogastroduodenoscopic examination. In this study, we constructed a convolutional neural network (CNN) and evaluated its ability to detect SNADETs. METHODS A deep CNN was pretrained and fine-tuned using a training data set of the endoscopic images of SNADETs (duodenal adenomas [N = 65] and high-grade dysplasias [HGDs] [N = 31] [total 531 images]). The CNN evaluated a separate set of images from 26 adenomas, 8 HGDs, and 681 normal tissue (total 1,080 images). The gold standard for both the training data set and test data set was a "true diagnosis" made by board-certified endoscopists and pathologists. A detected tumor was marked with a rectangular frame on the endoscopic image. link3 If it overlapped at least a part of the "true tumor" diagnosed by board-certified endoscopists, the CNN was considered to have "detected" the SNADET.