tbuckley/cabot-search huggingface dataset:
Prevalence, severity, and risk factors of liver disease in blood donors positive in a second-generation anti?hepatitis c virus screening test*1, *2
Authors: L SERFATY
Journal: Hepatology (1995)

In a cohort of 483 blood donors positive for antibody to hepatitis C virus on second-generation enzyme-linked immunosorbent, the confirmatory second-generation recombinant immunoblot assay (Ortho Diagnostic Systems) was positive in 172 cases (36%), indeterminate in 113 (23%), and negative in 198 (41%). We further studied 94 of the donors (recombinant immunoblot assay positive in 85, indeterminate in 6, and negative in 3). Alanine transaminase (ALT) activity, assayed on three occasions, was elevated in at least one assay in 85% of the 85 recombinant immunoblot assay-positive donors. Liver disease was present in 95% of these patients (chronic persistent hepatitis, 35%; chronic active hepatitis, 53%; cirrhosis, 7%). Ten of the 13 recombinant immunoblot assay-positive donors with normal ALT activity had liver disease; polymerase chain reaction testing for viral RNA was predictive of liver disease in most cases. Donors with cirrhosis differed significantly from cirrhosis-free donors in terms of age, sex ratio, ALT activity, and excessive alcohol consumption. Three of the 6 recombinant immunoblot assay-indeterminate donors (isolated C 22) who underwent histological examination had elevated ALT activity and liver disease. The 3 recombinant immunoblot assay-negative donors evaluated were free of liver disease. This study shows that anti-HCV second-generation enzyme-linked immunosorbent positivity is confirmed in fewer than 40% of blood donors by the second-generation recombinant immunoblot assay, and that liver disease is present in 95% of recombinant immunoblot assay-positive donors. Recombinant immunoblot assay positivity combined with viremia is frequently associated with the existence of liver disease, regardless of transaminase activity. Excessive alcohol consumption may be an important factor in the onset of cirrhosis in anti-HCV-positive blood donors.
Response to: ‘Is non-industrial society undergoing an energy balance transition predisposed to accumulate abdominal adipose tissue and susceptible to knee osteoarthritis?’ by Yu<i>et al</i>
Authors: Ian J Wallace, David T Felson, Steven Worthington, Daniel E Lieberman
Journal: Annals of the Rheumatic Diseases (2020)

Many thanks to Yu and colleagues1 for their interest in our recent paper on knee osteoarthritis (OA) susceptibility among the Tarahumara, an indigenous population of subsistence farmers in Mexico undergoing rapid lifestyle changes that promote positive energy balance.2 We welcome their constructive comments and are happy to respond.

As Yu et al point out, a key prediction of the model we proposed for knee OA risk among non-industrial societies is that people born under conditions of limited energy availability are prone to accumulate and maintain excess abdominal adipose tissue if they later experience chronic positive energy balance.3 4 As a result, such people are vulnerable to developing a relatively low body mass index (BMI) but high abdominal adiposity,5 which we hypothesised puts them at greater risk of knee OA for a given BMI.

Yu et al do not disagree that the Tarahumara men we studied had significantly lower BMIs, on average, than the individuals in our comparative sample, urban American men from Framingham, Massachusetts. However, they question whether the Tarahumara had relatively larger abdomens and were prone to accumulating and maintaining abdominal adipose tissue. Average overall body size among the Tarahumara was much smaller than among Framingham individuals, which we needed to account for when comparing abdomen sizes between the two groups. In our paper, we showed that after controlling statistically for body weight and age, Tarahumara’s abdomen circumferences were significantly larger than …
Marrow Transplantation for Treatment of Aplastic Anemia
Authors: Rainer Storb, Ross L. Prentice, E. Donnall Thomas
Journal: New England Journal of Medicine (1977)

Seventy-three consecutive patients with severe aplastic anemia were treated by marrow grafts from normal, HLA-identical siblings, and 68 lived long enough to demonstrate engraftment. In 21 patients the graft was rejected, and 19 of these patients died. This analysis, using a binary logistic regression model, was aimed at identifying factors that predicted marrow-graft rejection. Of the 24 factors entered into the analysis, only two strongly correlated with graft rejection: a positive relative response index in mixed leukocyte culture indicating sensitization of patient against donor (P<0.01); and a low number of marrow cells (<3 x 108 cells per kilogram) used for transplantation (P<0.01). These findings suggest that more powerful immunosuppressive conditioning regimens should be used in patients who are sensitized, and that the greatest possible amount of donor marrow, perhaps supplemented by stem cells derived from the peripheral blood, should be obtained. (N Engl J Med 296:61–66, 1977)
PTH-031 The outcomes of ERCP for common bile duct gallstones in england between 2003 and 2015
Authors: Philip Harvey, Simon Baldwin, Jemma Mytton, Ben Coupland, Felicity Evison, Prashant Patel, Nigel Trudgill
Journal: Endoscopy (2018)

<h3>Introduction</h3> The BSG ERCP standards suggest duct clearance should be achieved in &gt;85% of ERCPs for common bile duct gallstones. However recent data on ERCP for palliation of malignant biliary obstruction demonstrated significant variation in outcomes between providers related to procedure volume. We have therefore examined outcomes of ERCPs for common bile duct gallstones. <h3>Methods</h3> Hospital Episode Statistics (HES) include diagnostic and procedural data for all hospital attendances in England. All subjects undergoing their first ERCP, with the ICD10 code K80 (cholelithiasis) were included. Subjects with a relevant cancer diagnosis 2 years before, or after ERCP were excluded. Associations between demographics, co-morbidities and unit ERCP volume were examined by logistic regression analysis. Not needing to undergo repeat ERCP within 90 days was considered a surrogate for successful duct clearance. <h3>Results</h3> 98 887 subjects were included, 65.5% were female, their median age was 68(IQR 52–79) and 72.3%, 13.8% and 13.9% had a Charlson co-morbidity score of 0, 1–4 and &gt;4 respectively. Approximately half were elective procedures(50.8%). 86.6% did not require repeat ERCP within 90 days; 12.1% required 1 repeat; and 1.3% required 2 or more repeats. The following factors were associated with not needing a repeat ERCP; Charlson co-morbidity score &gt;4 (OR 0.83 (95% CI:0.78–0.88),p&lt;0.001), age &gt;81 (0.82(0.77–0.88),p&lt;0.001), and outpatient procedures (0.80 (0.76–0.84),p&lt;0.001). Provider volume, (volume knot 1 (1.00(1.00–1.00),p=0.135), knot 2 (1.00(1.00–1.00),p=0.523), knot 3 (1.00(1.00–1.01),p=0.333)), year of procedure and emergency admission type were not associated with needing a repeat ERCP within 90 days. Needing a repeat ERCP was associated with; Asian ethnicity (1.18 (1.06–1.31),p=0.002), Black ethnicity (1.22 (1.03–1.45),p=0.023), mixed ethnicity (1.51 (1.14–2.01),p=0.005), age quintile 47–62 (1.10(1.04–1.17),p=0.001), age 63–72 (1.09(1.03–1.16),p=0.004) and male gender (1.12 (1.02–1.45),p&lt;0.001). <h3>Conclusions</h3> The BSG key performance indicator for stone clearance at first ERCP (&gt;85%) appears to be achieved overall, assuming that no repeat ERCP within 3 months is a marker of successful stone clearance. Not needing a repeat ERCP for common bile duct stones was associated with outpatient procedures, very old and co-morbid subjects. Increased ERCP volume and year of ERCP (2003–2015) did not change the apparent of success rate of stone clearance at ERCP.
Interpreting Diagnostic Tests for SARS-CoV-2
Authors: Nandini Sethuraman, Sundararaj Stanleyraj Jeremiah, Akihide Ryo
Journal: JAMA (2020)

Lan Lan, MD; Dan Xu, MD; Guangming Ye, MD; Chen Xia, MS; Shaokang Wang, MS; Yirong Li, MD, PhD; Haibo Xu, MD, PhD
Material-driven fibronectin assembly rescues matrix defects due to mutations in collagen IV in fibroblasts
Authors: Elie Ngandu Mpoyi, Marco Cantini, Yuan Yan Sin, Lauren Fleming, Dennis W. Zhou, Mercedes Costell, Yinhui Lu, Karl Kadler, Andrés J. García, Tom Van Agtmael, Manuel Salmeron-Sanchez
Journal: Biomaterials (2020)

Basement membranes (BMs) are specialised extracellular matrices that provide structural support to tissues as well as influence cell behaviour and signalling. Mutations in COL4A1/COL4A2, a major BM component, cause a familial form of eye, kidney and cerebrovascular disease, including stroke, while common variants in these genes are a risk factor for intracerebral haemorrhage in the general population. These phenotypes are associated with matrix defects, due to mutant protein incorporation in the BM and/or its absence by endoplasmic reticulum (ER) retention. However, the effects of these mutations on matrix stiffness, the contribution of the matrix to the disease mechanism(s) and its effects on the biology of cells harbouring a collagen IV mutation remain poorly understood. To shed light on this, we employed synthetic polymer biointerfaces, poly(ethyl acrylate) (PEA) and poly(methyl acrylate) (PMA) coated with ECM proteins laminin or fibronectin (FN), to generate controlled microenvironments and investigate their effects on the cellular phenotype of primary fibroblasts harbouring a COL4A2+/G702D mutation. FN nanonetworks assembled on PEA induced increased deposition and assembly of collagen IV in COL4A2+/G702D cells, which was associated with reduced ER size and enhanced levels of protein chaperones such as BIP, suggesting increased protein folding capacity of the cell. FN nanonetworks on PEA also partially rescued the reduced stiffness of the deposited matrix and cells, and enhanced cell adhesion through increased actin-myosin contractility, effectively rescuing some of the cellular phenotypes associated with COL4A1/4A2 mutations. The mechanism by which FN nanonetworks enhanced the cell phenotype involved integrin β1-mediated signalling. Collectively, these results suggest that biomaterials and enhanced integrin signalling via assembled FN are able to shape the matrix and cellular phenotype of the COL4A2+/G702D mutation in patient-derived cells.
PTH-072 Training future interventional endoscopists:outcomes of trainee performed colorectal complex EMR/PEMR in a tertiary centre
Authors: Andrew Emmanuel, Shraddha Gulati, Margaret Burt, Bu Hayee, Amyn Haji
Journal: Endoscopy (2018)

<h3>Introduction</h3> Despite the widespread use of endoscopic mucosal resection (EMR) and piecemeal EMR (pEMR) to treat large colorectal superficial neoplastic lesions, training and competence in complex endoscopic resection (ER) in western centres takes place almost exclusively during specialist practice after the completion of residency. There are no accredited western training programs in advanced ER and no reports of outcomes of complex EMR performed by trainees. However, as the use of advanced ER to treat CSNL increases, it is conceivable that training in complex EMR takes place during residency for selected trainees. Our tertiary referral unit has been training 2 residents in advanced colorectal lesion assessment and EMR since January 2016. We evaluated the outcomes of complex EMR performed by trainees during this period. <h3>Methods</h3> All EMR and pEMR of large (≥2 cm) CSNL performed from January 2016 to October 2017 were included. Lesions resected using ESD were excluded. ER were performed by 2 specialist interventional endoscopist trainers and 2 residents. The residents were already accredited for independent practice for diagnostic colonoscopy and polypectomy &lt;2 cm. Patient and lesion characteristics were described and outcomes including failed ER, complications and recurrence for EMR performed by residents and trainers were compared. <h3>Results</h3> 238 ER of colorectal lesions≥2 cm were performed during the study period. After excluding procedures for recurrent lesions (n=16) and procedures using ESD/Hybrid ESD (n=78), 144 lesions resected using EMR/pEMR were included. 60 ER were performed by residents (42%). The mean patient age was 69.5 years (male=40). The mean size of resident performed EMR was 34.3 mm ±10.7 mm (range 20 mm-60 mm) <i>versus</i> 52.6 mm ±32.3 mm for ER performed by trainers (p&lt;0.001). Lesions were located in the right colon (n=33), left colon (n=20) and rectum (n=7). Compared to ER performed by trainers, there were no differences in failure to achieve endoscopic clearance(p=0.09), complications (p=0.67), intraprocedural bleeding (p=0.32) or recurrence (p=0.42). <h3>Conclusions</h3> These results show that, in a specialist unit with experienced trainers, it is safe to train residents in complex EMR/pEMR who can perform the techniques safely in large CSNL with good outcomes. Significant prior experience in diagnostic colonoscopy is important but the skills for advanced assessment and EMR can subsequently be acquired in the right setting.
Changes in Prevalence of Vaping Among Youths in the United States, Canada, and England from 2017 to 2019
Authors: David Hammond, Vicki L. Rynard, Jessica L. Reid
Journal: JAMA Pediatrics (2020)

Among Youths in the United States, Canada, and England from 2017 to 2019There are concerns over increases in vaping among North American youths. [1]2][3] In the US in 2019, one-fifth of 10th-grade students and one-quarter of 12th-grade students reported using e-cigarettes in the past 30 days. 2 The extent to which similar increases have been observed in countries with different regulatory environments, such as Canada and England, is an important question.In 2018, Canada loosened restrictions on the sale and marketing of nicotine-containing e-cigarettes, whereas e-cigarettes in England are subject to more comprehensive regulations than in either Canada or the US.
Abstract B03: E-cigarette vapor exposure skews competition between colonizing oral <i>Streptococci</i> to allow biofilm formation of <i>S. mutans</i> and activation of stress and survival pathways in the oral cavity
Authors: Matthew Caldwell, Alma Catala Valentin, Joshua Bernard, Sean Moore, Claudia D. Andl
Journal: Cancer Research (2020)

Abstract E-cigarette (e-cig) use is rising, but much is unknown about the effects of its vapor. This vapor contains chemicals such as propylene glycol, a known antimicrobial, and nicotine, whose derivatives are carcinogenic. Here, we study the effects of vaping on resident bacteria of the oral cavity and on oral cell inflammation, which is linked to tumorigenesis. Streptococcus mutans, Streptococcus sanguinis, and Streptococcus gordonii species are significant residents in the oral cavity, with S. mutans the primary cause of dental caries. Growth and biofilm formation is enhanced upon exposure to traditional cigarette smoke in vitro. We aim to analyze the interplay between e-cigarette vapor and oral streptococci colonizing of the oral epithelium. S. mutans, S. sanguinis, and S. gordonii were treated using nicotine-free and 3mg nicotine vapor, as well as double-shot menthol freeze flavored 3mg nicotine vapor in a vape chamber designed to phenocopy physiologically relevant exposure. Next, we analyzed the effects on growth and biofilm formation. Nicotine-independent inhibition of growth occurred upon exposure in all three species. Interestingly, biofilm formation was enhanced in S. mutans while decreased in S. sanguinis and S. gordonii. Upon exposure to the same conditions in the vape chamber, oral epithelial cells showed activation of survival pathways, such as ERK 1/2, by Western blot. Upon coculturing of bacterial and oral epithelial cells at a multiplicity of infection of one for five hours exposed to the same conditions, we observed activation of survival and inflammatory pathways, by Western blot. The pioneer colonizers S. gordonii and S. sanguinis generally antagonize caries-causing S. mutans, which can become a predominant member of the community under appropriate conditions, leading to dental caries formation. The observed decrease in the biofilm formation of the commensals S. sanguinis and S. gordonii upon e-cig vapor exposure indicates the opportunistic colonization of S. mutans, whose biofilm-forming abilities increased. Following e-cig usage, dental caries, periodontitis, and eventually cancer in the oral epithelium may result from this dysbiosis of the microbiome in the oral cavity. Citation Format: Matthew Caldwell, Alma Catala Valentin, Joshua Bernard, Sean Moore, Claudia D. Andl. E-cigarette vapor exposure skews competition between colonizing oral Streptococci to allow biofilm formation of S. mutans and activation of stress and survival pathways in the oral cavity [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr B03.
PTH-048 Diagnostic ERCP in specialist centres: safe and effective for evaluating indeterminate biliary changes following MDT
Authors: Wei On, Laura Dwyer, Rizwan Saleem, Steve Hood, Richard Sturgess, Nick Stern
Journal: Endoscopy (2018)

<h3>Introduction</h3> Indeterminate biliary strictures (BS) may be identified in symptomatic patients or incidentally on imaging. Patients need investigation to exclude cholangiocarcinoma or other significant pathology. The first line investigation is with Magnetic Resonance Cholangio-Pancreatography (MRCP) however this is not always diagnostic. Such cases are all reviewed through our tertiary Multi-disciplinary team (MDT) meeting for further evaluation. Diagnostic Endoscopic Retrograde Cholangio-Pancreatography (ERCP) is often used to further investigate these abnormalities<sup>1</sup> but carries a risk of complications. <h3>Methods</h3> A retrospective analysis was performed of patients reviewed through our regional HPB MDT from October 2014 to December 2016. Patients with indeterminate BS with no mass lesion were identified from our MDT database. Following MDT discussion, all patients were investigated with ERCP ±cholangioscopy (POC). Liver Function Tests (LFTs) and details of suspected BS were obtained from the medical records. Diagnoses were obtained from the endoscopy database and histopathology reports, where applicable. <h3>Results</h3> 66 patients were identified with a mean age of 63.7 (SD 14.5). 47% were male. 82% of patients had abnormal LFTs, 35% had jaundice and 61% had upstream dilatation on radiological imaging. 31 (47%) required POC in addition to ERCP. 85% of patients (n=56) had an abnormal diagnosis. 8 (12.1%) had malignancy, 13 (19.7%) PSC or other cholangiopathy and 10 (15.2%) stone disease. In our centre, complications associated with these ERCPs were low: pancreatitis: 1 (1.6%); cholangitis: 1 (1.6%); bleeding:1 (1.6%). There were 2 delayed bleeds (peptic ulcer and variceal). Upstream dilatation was shown to be a predictor of abnormal diagnosis on both univariate (p=0.004) and multivariate analysis (p=0.01) with a sensitivity of 72.5%, specificity of 72.7%, positive predictive value of 92.5% and negative predictive value of 36.4%. <h3>Conclusions</h3> Of those with suspected BS on imaging, 85% had pathology demonstrated on direct cholangiography ±POC. 15.2% of those reviewed through a tertiary HPB MDT had stone disease evident at ERCP that was not diagnosed on review of MRCP and other imaging modalities. Diagnostic ERCP in appropriate centres still has a role to play in the evaluation of indeterminate biliary strictures following specialist MDT review when non-invasive imaging is inconclusive. <h3>Reference</h3> . British Society of Gastroenterology. <i>ERCP – the way forward, A Standards Framework</i> 2014. https://www.bsg.org.uk/resource/ercp---the-way-forward--a-standards-framework-pdf.html
Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability
Authors: Reihaneh Zarrizi, Martin R. Higgs, Karolin Voßgröne, Maria Rossing, Birgitte Bertelsen, Muthiah Bose, Arne Nedergaard Kousholt, Heike Rösner, the COMPLEXO Network, Bent Ejlertsen, Grant S. Stewart, Finn Cilius Nielsen, Claus S. Sørensen
Journal: Journal of Clinical Investigation (2020)

Haploinsufficiency of factors governing genome stability underlies hereditary breast and ovarian cancer. One significant pathway that is disabled as a result is homologous recombination repair (HRR). With the aim of identifying new candidate genes, we examined early-onset breast cancer patients negative for BRCA1 and BRCA2 pathogenic variants. Here, we focused on CtIP (RBBP8 gene), which mediates HRR through the end resection of DNA double-strand breaks (DSBs). Notably, these patients exhibited a number of rare germline RBBP8 variants. Functional analysis revealed that these variants did not affect DNA DSB end resection efficiency. However, expression of a subset of variants led to deleterious nucleolytic degradation of stalled DNA replication forks in a manner similar to that of cells lacking BRCA1 or BRCA2. In contrast to BRCA1 and BRCA2, CtIP deficiency promoted the helicase-driven destabilization of RAD51 nucleofilaments at damaged DNA replication forks. Taken together, our work identifies CtIP as a critical regulator of DNA replication fork integrity, which, when compromised, may predispose to the development of early-onset breast cancer.
Circular RNA circBFAR promotes the progression of pancreatic ductal adenocarcinoma via the miR-34b-5p/MET/Akt axis
Authors: Xiaofeng Guo, Quanbo Zhou, Dan Su, Yuming Luo, Zhiqiang Fu, Leyi Huang, Zhiguo Li, Decan Jiang, Yao Kong, Zhihua Li, Rufu Chen, Changhao Chen
Journal: Molecular Cancer (2020)

Accumulating evidence suggests that circular RNAs (circRNAs) are important participants in cancer progression. However, the biological processes and underlying mechanisms of circRNAs in pancreatic ductal adenocarcinoma (PDAC) are unclear.CircRNAs were verified by Sanger sequencing. Colony formation, 5-Ethynyl-2'-deoxyuridine (EdU), and Transwell assays were performed to investigate the effect of circBFAR on the proliferation, invasion, and migration of PDAC cells in vitro. RNA pull-down assays were conducted to verify the binding of circBFAR with microRNA miR-34b-5p.In the present study, we identified a novel circRNA (termed as circBFAR, hsa_circ_0009065) that was upregulated in a 208-case cohort of patients with PDAC. The ectopic expression of circBFAR correlated positively with the tumor-node-metastasis (TNM) stage and was related to poorer prognosis of patients with PDAC. Moreover, circBFAR knockdown dramatically inhibited the proliferation and motility of PDAC cells in vitro and their tumor-promoting and metastasis properties in in vivo models. Mechanistically, circBFAR upregulated mesenchymal-epithelial transition factor (MET) expression via sponging miR-34b-5p. Additionally, circBFAR overexpression increased the expression of MET and activated downstream phosphorylation of Akt (Ser 473) and further activated the MET/PI3K/Akt signaling pathway, which ultimately promoted the progression of PDAC cells. Importantly, application of MET inhibitors could significantly attenuate circBFAR-mediated tumorigenesis in vivo.Our findings showed that circBFAR plays an important role in the proliferation and metastasis of PDAC, which might be explored as a potential prognostic marker and therapeutic target for PDAC.
Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial
Authors: Nir Kleinmann, Surena F Matin, Phillip M Pierorazio, John L Gore, Ahmad Shabsigh, Brian Hu, Karim Chamie, Guilherme Godoy, Scott Hubosky, Marcelino Rivera, Michael O'Donnell, Marcus Quek, Jay D Raman, John J Knoedler, Douglas Scherr, Joshua Stern, Christopher Weight, Alon Weizer, Michael Woods, Hristos Kaimakliotis, Angela B Smith, Jennifer Linehan, Jonathan Coleman, Mitchell R Humphreys, Raymond Pak, David Lifshitz, Michael Verni, Mehrad Adibi, Mahul B Amin, Elyse Seltzer, Ifat Klein, Marina Konorty, Dalit Strauss-Ayali, Gil Hakim, Mark Schoenberg, Seth P Lerner
Journal: The Lancet Oncology (2020)