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Objectives To analyze trends in the incidence and use of diagnostic modalities for GCA in a population-based cohort over the past seven decades. To explore survival trends in patients with GCA compared with the general population. Methods A population-based cohort of patients diagnosed with GCA was extended with new incident cases from 2010 to 2019. Three time periods were compared: Period One (1950–1979), Period Two (1980–1999), and Period Three (2000–2019). Cases were classified as: Diagnostic Group One, temporal artery biopsy (TAB) positive; Diagnostic Group Two, TAB-negative or not done with positive large-vessel imaging; or Diagnostic Group Three, clinical diagnosis of GCA. Survival was evaluated by comparing Kaplan-Meier estimated mortality rates for cases of GCA against expected mortality rates from Minnesota life tables Results Age- and sex-adjusted incident rates per 100,000 ≥ 50 years of age (95% CI) were 13.5 (10.1, 16.9) in Period One, 21.0 (17.1, 25.0) in Period Two, and 15.0 (12.4, 17.5) in Period Three. The percent of patients in Diagnostic Group One decreased over the three time periods (89%, 86%, and 72%) while the patients in Diagnostic Group Three increased (11%, 14%, and 17%). Standardized mortality ratios (95% CI) were 1.03 (0.79, 1.32), 1.11 (0.91, 1.34), and 0.82 (0.64, 1.04) across Periods 1–3, respectively. Conclusions Incidence of GCA in females in the population declined, resulting in a decreasing overall incidence. More patients have been identified by large-vessel imaging and fewer by positive TABs. No significant difference in survival between patients with GCA and the general population was observed.

Gastrointestinal single-organ vasculitis is a vasculitis restricted to one organ in the gastrointestinal system and without systemic manifestations. These diseases are rare and true incidence and prevalence are difficult to determine. Most patients will have predominantly gastrointestinal symptoms although some will be asymptomatic, and in these cases the diagnosis is incidental. The diagnosis typically relies on pathology and/or imaging studies. Systemic vasculitis must be excluded in all cases. Cases of limited single-organ vasculitis can sometimes be managed with surgery alone whereas cases of diffuse disease often require immunosuppressive therapy. The disease has been associated with significant morbidity and mortality, particularly in the first year after diagnosis. All cases should be monitored closely for the possible evolution to systemic vasculitis.

Introduction Anastomotic biliary strictures (ABS) have been reported in approximately 13% of patients undergoing orthotopic liver transplantation (OLT). Without treatment these can lead to progressive graft failure. Endoscopic management of these strictures with temporary fully covered self-expanding metal stents (SEMS) offers a non-surgical option for their management. This retrospective case series describes the outcomes of ABS managed using SEMS at our centre. Unit standard practice is to reserve endoscopic management for early ABS and undertake a biliary sphincterotomy to reduce pancreatitis risk. Methods The electronic records of all patients who underwent both OLT and endoscopic retrograde cholangiopancreatography (ERCP) between January 2013 and March 2020 were reviewed. Patients were selected from this group if they were found to have an ABS as diagnosed by biochemical liver function test derangement and corresponding characteristic radiological findings. Demographic data, technical aspects of the procedure, success rate, and complications were recorded. Results A total of 36 transplant recipients were diagnosed with ABS. This group underwent a total of 45 ERCP procedures. The median time from transplant to ABS diagnosis was 6 months (interquartile range (IQR) 2 – 22 months). There was a balloon dilatation prior to stent placement in 13 procedures (29%). There was a sphincterotomy either at the time of stent placement or during a preceding procedure in 33 cases (92%). There were ten cases of pancreatitis (22%), four cases of cholangitis (9%) and two of bile leak (4%). There were eight cases of pancreatitis in the group of 33 who had undergone sphincterotomy (24%) and two cases of pancreatitis in the group of three who had not (67%). There was one case of bleeding following sphincterotomy (3%) that occurred immediately and did not require transfusion. The median time to stent removal was 105 days (IQR 67 – 125). Only one case (3%) required surgical biliary reconstruction. The avoidance of the need for biliary reconstruction was regarded as the key outcome for successful endoscopic management of ABS and this was achieved in 35 cases (97%). Conclusion Early ABS following OLT were effectively managed using endoscopically placed biliary stents in the majority of cases. The rate of pancreatitis was lower in the sphincterotomy group. These data support the practice of temporary SEMS placement for early ABS and sphincterotomy to reduce pancreatitis risk.

Giant cell arteritis (GCA) is the most common primary systemic vasculitis in adults 50 years or older. Expanded use of advanced arterial imaging has assisted both in the diagnosis of GCA and recognition of disease subsets. Although glucocorticoids have been the mainstay of treatment for almost 7 decades, new therapeutic options have emerged. This review aims to provide the clinician with a pragmatic approach to evaluating and managing patients with GCA while also addressing recent diagnostic and therapeutic developments.

Background:Diagnostic methods for giant cell arteritis (GCA) have evolved over recent decades, and large vessel imaging plays an increasing role in disease detection.Objectives:This study aims to estimate the incidence of GCA over the past 10 years in a population and compare it to preceding incidence estimates. It also explores trends in the diagnostic modalities used to identify GCA.Methods:A pre-existing population-based cohort of patients diagnosed with GCA between 1950 and 2009 was extended with incident cases from 2010 to 2019. The diagnosis of GCA was confirmed by review of medical records of patients with ICD9/10 codes for GCA between 1/1/2010 and 12/31/2019. Incident cases that met either one of the following sets of inclusion criteria were added to the cohort: one, American College of Rheumatology 1990 GCA classification criteria; or two, patients aged ≥50 years with elevation of erythrocyte sedimentation rate or C-reactive protein and radiographic evidence of large vessel vasculitis attributed to GCA. Incident cases were classified into one of three groups: group 1, temporal artery biopsy (TAB) positive; group 2, TAB negative or not done with positive large-vessel imaging; or group 3, clinical diagnosis of GCA.Results:The study cohort included 305 patients diagnosed with GCA from 1950 until 2019. Fifty-five incident cases were diagnosed between 2010 and 2019; 37 females (67%) and 18 males (33%). The age and sex adjusted incidence rates (95% CI) per 100,000 between 2010 and 2019 for females, males, and the total population were 13.0 (8.8, 17.3), 8.6 (4.6, 12.7), and 10.8 (8.0, 13.7), respectively. The corresponding incidence rates from 2000-2009 were 28.0 (21.0, 35.1), 10.2 (5.0, 15.5), and 20.5 (15.9, 25.1), respectively. This represents a significant decline in the incidence rates in females (pConclusion:In this population-based cohort of patients with GCA diagnosed over a 70-year period, the incidence of GCA has declined in recent years. The total decline is driven by a decline in females but not in males. The reasons for this are unclear but should be followed over time and investigated in other population-based cohorts. There has also been a shift in the diagnostic modalities for GCA. In recent years, there are fewer TAB positive patients, and more patients diagnosed with large vessel imaging. This is the first population-based incidence cohort demonstrating a trend towards increased use of large vessel imaging for the diagnosis of GCA.References:[1]Chandran AK, et al. Incidence of Giant Cell Arteritis in Olmsted County, Minnesota, over a 60-year period 1950-2009. Scand J Rheumatol. 2015;44(3):215-218.[2]Gonzalez-Gay MA, et al. Giant cell arteritis: is the clinical spectrum of the disease changing? BMC Geriatr. 2019; Jul 29;19(1):200.[3]Rubenstein E, et al. Sensitivity of temporal artery biopsy in the diagnosis of giant cell arteritis: a systemic literature review and meta-analysis. Rheumatology (Oxford). 2020 May 1:59(5):1011-1020.Figure 1.Trends in the incidence of GCA in Olmsted County by sex (1950-2019).Acknowledgements:This study was made possible using the resources of the Rochester Epidemiology Project, which is supported by the National Institute on Aging of the National Institutes of Health (NIH) under Award Number R01 AG034676, and CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.Disclosure of Interests:Thomas Garvey: None declared, Cynthia S. Crowson: None declared, Matthew Koster: None declared, Kenneth J Warrington Grant/research support from: Clinical research support from Eli Lilly and Kiniksa

Background:In previous studies patients with giant cell arteritis (GCA) have had survival rates that are similar to the general population.Objectives:To investigate survival trends and cause-specific mortality in patients diagnosed with GCA over a 60-year period.Methods:We assembled a population-based incidence cohort of patients with GCA diagnosed between 1950 and 2009. All patients were included if they met the American College of Rheumatology (ACR) 1990 Criteria for the Classification of GCA. Patients diagnosed between 2000 and 2009 could also be included if they met the following criteria: age greater than or equal to 50 years, elevated inflammatory markers, and radiographic evidence of large-vessel vasculitis attributed to GCA. A non-GCA comparison cohort was assembled from the same underlying population for each patient with GCA. Patients were followed until death, last contact, or December 31st, 2018. Survival trends were analyzed by grouping patients into the following categories according to year of GCA diagnosis: Group A 1950-1979; Group B 1980-1989; Group C 1990-1999; and Group D 2000-2009. Mortality rates were estimated using the Kaplan-Meier method and were compared with expected mortality rates for persons of the same age, sex, and calendar year, as estimated by regional population life tables. Cause-specific mortality was obtained from death certificates for patients in both cohorts. The causes were grouped according to ICD-9 chapters and hazard ratios were estimated against the non-GCA comparators.Results:The study population included 245 incident cases of GCA: 194 (79%) women and 51 (21%) men with mean age (±SD) of 76.2 (±8.3) years and median follow-up of 10.6 years. There was no overall difference in survival between the GCA cohort and the general population. The 2-, 5-, and 10-year survival rates (95% CI) were 89% (86, 93), 76% (70, 81), and 56% (50, 63) respectively with a standardized mortality ratio of 0.99 (0.86, 1.14). The standardized mortality ratios for Groups A, B, C, and D were 0.83 (0.57, 1.17), 0.92 (0.63, 1.3), 1.21 (0.85, 1.69), 0.70 (0.50, 0.95), respectively. The overall all-cause mortality adjusted for age, sex, and calendar-year was similar between the GCA patients and their comparators with a hazard ratio of 1.03 (0.84, 1.24). Mortality due to neoplasms was significantly lower in the GCA cohort with a hazard ratio of 0.53 (0.3, 0.92). Other cause-specific mortalities were not significantly different between the groups.Conclusion:In this population-based cohort of patients with GCA diagnosed over a 60-year period, the survival of patients diagnosed in recent years was significantly better than that of the general population. The explanation for this novel finding is unclear, but likely to be multifactorial. In this study the number of deaths due to neoplasm in the GCA group was significantly lower.References:[1]Chandran AK, et al. Incidence of Giant Cell Arteritis in Olmsted County, Minnesota, over a 60-year period 1950-2009. Scand J Rheumatol. 2015;44(3):215-218.[2]Mohammad A. et al. Rate of comorbidities in Giant Cell Arteritis: A Population-based Study. J Rheumatol. 2017;44(1):84-90.[3]Salvarani C. et al. Reappraisal of the epidemiology of giant cell arteritis in Olmsted County, Minnesota, over a fifty-year period. Arthritis Rheum. 2004;51(2):264-8.Acknowledgments:This study was made possible using the resources of the Rochester Epidemiology Project, which is supported by the National Institute on Aging of the National Institutes of Health (NIH) under Award Number R01 AG034676, and CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.Disclosure of Interests:Thomas Garvey: None declared, Cynthia S. Crowson Grant/research support from: Pfizer research grant, Matthew Koster: None declared, Eric Matteson Grant/research support from: Pfizer, Consultant of: Boehringer Ingelheim, Gilead, TympoBio, Arena Pharmaceuticals, Speakers bureau: Simply Speaking, Kenneth J Warrington: None declared

Importance: Patients with cervical cytology abnormalities may require surveillance for many years, which increases the risk of management error, especially in clinics with multiple managing clinicians. National Committee for Quality Assurance (NCQA) Patient-Centered Medical Home (PCMH) certification requires tracking of abnormal results and communicating effectively with patients.The purpose of this study was to determine whether a computer-based tracking system that is not embedded in the electronic medical record improves (1) accurate and timely communication of results and (2) patient adherence to follow-up recommendations.Design: Pre/post study using data from 2005-2012. Intervention implemented in 2008. Data collected via chart review for at least 18 months after index result. Participants: Pre-intervention: all women (N = 72) with first abnormal cytology result from 2005-2007. Post-intervention: all women (N = 128) with first abnormal cytology result from 2008-2010. Patients were seen at a suburban, university-affiliated, family medicine residency clinic. Intervention: Tracking spreadsheet reviewed monthly with reminders generated for patients not in compliance with recommendations. Main Outcome and Measures: (1) rates of accurate and timely communication of results and (2) rates of patient adherence to follow-up recommendations.Intervention decreased absent or erroneous communication from clinician to patient (6.4% pre- vs 1.6% post-intervention [P = 0.04]), but did not increase patient adherence to follow-up recommendations (76.1% pre- vs 78.0% post-intervention [ P= 0.78]).Use of a spreadsheet tracking system improved communication of abnormal results to patients, but did not significantly improve patient adherence to recommended care. Although the tracking system complies with NCQA PCMH requirements, it was insufficient to make meaningful improvements in patient-oriented outcomes.

Background & Aims: Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide. Improved treatments for advanced HCC are urgently needed. The recently identified human sulfatase 1 enzyme (SULF1) desulfates cell surface heparan sulfate glycosaminoglycans and down-regulates cell growth signaling in HCC cells in vitro. While investigating the epigenetic regulation of SULF1, we discovered that histone H4 acetylation is up-regulated by SULF1 in HCC cells. Histone deacetylase (HDAC) inhibitors reprogram cellular gene expression through the acetylation of nucleosomal histones and promote cell growth arrest and apoptosis. Hence, they are a promising modality for cancer treatment. Methods: To explore the interaction between SULF1 expression and HDAC inhibitor action, we examined the effects of SULF1 expression on HCC cells and xenografts treated with HDAC inhibitors. Results: (1) Forced expression of SULF1 significantly delayed the growth of Huh7 and Hep3B xenografts in nude mice in vivo. (2) SULF1 increased histone H4 acetylation by modulation of cellular HDAC and histone acetyltransferase activities. (3) SULF1 enhanced the induction of apoptosis by the HDAC inhibitors apicidin and scriptaid. (4) SULF1 enhanced the inhibition of tumor growth, migration, and angiogenesis by HDAC inhibitors. We also demonstrate that knockdown of SULF1 with shRNA constructs up-regulates phosphorylation of AKT and Erk and attenuates apicidin-induced apoptosis. The interaction between SULF1 and apicidin was confirmed in vivo in Huh7 and Hep3B xenografts. Conclusions: These results show that SULF1 promotes histone H4 acetylation, potentiates the effects of HDAC inhibitors, and inhibits HCC tumorigenesis.

The goal of the BioSPICE program is to create a framework that provides biologists access to the most current computational tools. At the program midpoint, the BioSPICE member community has produced a software system that comprises contributions from approximately 20 participating laboratories integrated under the BioSPICE Dashboard and a methodology for continued software integration. These contributed software modules are the BioSPICE Dashboard, a graphical environment that combines Open Agent Architecture and NetBeans software technologies in a coherent, biologist-friendly user interface. The current Dashboard permits data sources, models, simulation engines, and output displays provided by different investigators and running on different machines to work together across a distributed, heterogeneous network. Among several other features, the Dashboard enables users to create graphical workflows by configuring and connecting available BioSPICE components. Anticipated future enhancements to BioSPICE include a notebook capability that will permit researchers to browse and compile data to support model building, a biological model repository, and tools to support the development, control, and data reduction of wet-lab experiments. In addition to the BioSPICE software products, a project website supports information exchange and community building.

Evidential reasoning is a body of techniques that supports automated reasoning from evidence. It is based upon the Dempster-Shafer theory of belief functions. Both the formal basis and a framework for the implementation of automated reasoning systems based upon these techniques are presented. The formal and practical approaches are divided into four parts (1) specifying a set of distinct propositional spaces, each of which delimits a set of possible world situations (2) specifying the interrelationships among these propositional spaces (3) representing bodies of evidence as belief distributions over these propositional spaces and (4) establishing paths for the bodies of evidence to move through these propositional spaces by means of evidential operations, eventually converging on spaces where the target questions can be answered.

Multilevel relational database systems store information at different security classifications. An inference problem exists if it is possible for a user with a low-level clearance to draw conclusions about information at higher classifications. The authors are developing DISSECT, a tool for analyzing multilevel relational database schemas to assist in the detection and elimination of inference problems. A translation is defined from schemas to an equivalent graph representation, which can be presented graphically in DISSECT. The initial focus is on detection of inference problems that depend only on information all of which is stored in the database. In particular, potential inference problems are identified as different sequences of foreign key relationships that connect the same entities. Inferences can be blocked by upgrading the security classification of some of foreign key relationships. A global optimization approach to upgrading is suggested to block a set of inference problems that allows upgrade costs to be considered, and supports security categories as well as levels. >

A serious problem in computer database and knowledge base security is detecting and eliminating so-called inference channels. The existence of such channels enables a user with access to information classified at a low level to infer information classified at a high level, and through the transformation of low level data to high level data may provide an unacceptable information flow. In order to estimate the presence of inference channels, determine the degree of risk which they present, and find ways to eliminate them, one needs a formal model to describe them. The authors introduce abductive reasoning. Abduction provides both the basis for a formal model for the inference problem and a computational mechanism for detecting inference channels. Abduction additionally provides a framework for reasoning with approximate and uncertain information, which enables them to extend the model for inference channels by taking into account the likelihood that a person might believe some statement of interest. >

In order to plan operations where knowledge of significant elements is imprecise and uncertain, a means of characterizing the situation in terms of the various factors that may influence those operations must be provided. In this paper we discuss an approach to that characterization that uses evidential reasoning to handle the uncertainty, imprecision, and incompleteness typical of sources of real-world information and knowledge, to support planning routes for military helicopters. Evidential reasoning is a maturing collection of inference techniques for reasoning with uncertain information. Based on the Shafer-Dempster theory of evidence, evidential reasoning uses a non-Bayesian updating scheme to combine evidence provided by multiple diverse knowledge sources. Knowledge sources in an evidential reasoning system are not required to attribute their belief to a universe of discourse comprised solely of mutually exclusive, exhaustive, singleton events, as required by a classical probability approach. Rather, they may express levels of ignorance explicitly by allocating belief to disjunctions of propositions, thereby leading directly to an interval measure of belief; ignorance is expressed by the width of this interval. Evidential reasoning evolved from consideration of appropriate models for reasoning about information acquired from sensors, and therefore seems natural for drawing conclusions from sensor data and prestored maps regarding the degree to which a selected geographic area will support certain activities. Here, we discuss evidential reasoning and illustrate the utility of the technology for classifying geographic areas by describing our current map-and-sensor-based research in which we estimate the utility of land areas for concealing helicopter operations.