Idiopathic orthostatic hypotension: Recent data (eleven cases) and review of the literature

Eight cases of Shy-Drager syndrome and three of Bradbury-Eggleston idiopathic orthostatic hypotension were examined. In all cases, examination of circulatory reflexes showed major dysfunction of the sympathetic vasoconstrictor system. Anomalies in the vagal cardiomoderator system were less constant. Normal urinary elimination of catecholamines was recorded daily. Characteristically, no elevation of blood or urine norepinephrine levels were found in orthostatism. Insulin hypoglycemia normally raised urinary adrenalin elimination in three of ten patients. Plasma dopa-beta-hydroxylase activity was normal. Renin-angiotensin-aldosterone system showed variable activity at basal state but usually rose during orthostatism. On the average, very low homovanillic acid levels were found in cerebrospinal fluid before and after probenecid; hydroxyindolacetic acid was normal. Cerebral autoregulation had deteriorated in two of four cases. Physiopathologically the two clinical types are indistinguishable with or without central neurological signs

Introduction to 2D and 3D tomographic methods based on straight line propagation: X-ray, emission and ultrasonic tomography

This paper presents the basic principles of computerized tomography (CT), and its evolution towards three dimensional (3D ) imaging . Since the modelisation of CT reconstruction relies on the Radon transform, its definition and major properties are firs t recalled. After a brief summary on conventional 2D methods, we present the imaging principles for two modalities appropriate d to this modelisation : X-Ray and emission tomography. We describe the evolution of the instrumentation for these two techniques , and emphasize the approximations introduced by a modelisation using the Radon transform taking into account the physics o f the problem . We also describe the principles of ultrasonic tomography systems, and their major differences with the two previou s technics . At last, we formulate the general problematic of 3D image reconstruction from 2D projections . We consider four classe s of reconstruction methods corresponding to the classification chosen for the synthetic presentation of methods, accompanying thi s paper.Cet article présente les principes de base de la tomographie assistée par ordinateur, ainsi que son évolution vers le tridimen - sionnel (3D) . La modélisation mathématique du problème de reconstruction tomographique s'appuie sur la transformatio n de Radon dont la définition et quelques propriétés sont rappelées . Après un bref résumé sur les méthodes conventionnelle s 2D, nous présentons les principes physiques pour deux modalités bien appropriées à cette modélisation : la tomographie de transmission par rayons X et la tomographie d'émission par rayons ,y . Nous nous attachons à décrire l'évolution de l'instru - mentation dans ces deux techniques, ainsi que les approximations introduites par une modélisation de type Transformée de Radon par rapport à la physique du problème . Nous décrivons également les principes des systèmes de tomographie ultrasonore, et leurs différences majeures par rapport aux deux techniques précédentes . Enfin, nous reprenons la problématiqu e générale des méthodes de reconstruction 3D à partir de projections 2D . Nous faisons apparaître quatre classes correspondan t au découpage choisi pour la présentation des fiches techniques accompagnant cet article

Composite Outcomes in Observational Studies of Ulcerative Colitis: a Systematic Review and Meta‐Analysis

Background: Ulcerative colitis (UC) has been the focus of numerous observational studies over the years and a common strategy employed in their design is the use of composite and aggregate outcomes. Objective: This systematic review and meta-analysis aims to identify composite and aggregate outcomes of observational studies in UC and to evaluate how the number and type of variables included and the length of follow-up affect the frequency of patients that achieve these outcomes. Methods: A systematic literature search was carried out using MEDLINE [via PubMed], Scopus, and Web of Science online databases. Observational studies that included UC patients and reported composite or aggregate outcomes were identified. A set of variables considered to be representative of progressive or disabling UC was defined, the proportion of patients attaining the outcomes was determined and a random-effects meta-analysis was performed by dividing the identified studies into subgroups according to different criteria of interest. Results: A total of 10,264 records were identified in the systematic search, of which 33 were retained for qualitative analysis and 20 were included in the meta-analysis. The mean frequency for composite outcomes was 0.363 [95% confidence interval (CI) 0.323-0.403]. The frequency of composite outcome for the subgroup of studies that included the variable "Biologics" was significantly higher than for those in which this variable was not reported [0.410; 95% CI 0.364-0.457 versus 0.298; 95% CI 0.232-0.364; p = 0.006]. Composite outcomes were also more frequent as the follow-up duration increased. Conclusion: The frequency of composite outcomes in observational studies of UC is dependent on the specific identity of the variables being reported. Moreover, longer follow-up periods are associated with higher frequencies of composite outcomes. The evidence provided here is useful for the design of future observational studies of UC that aim to maximize the frequency of patients that achieve composite outcomes.info:eu-repo/semantics/publishedVersio

Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data

© 2019, The Author(s). Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers

Unmet Medical Needs in Ulcerative Colitis: An Expert Group Consensus

BACKGROUND The authors aimed to conduct an extensive literature review and consensus meeting to identify unmet needs in ulcerative colitis (UC) and ways to overcome them. UC is a relapsing and remitting inflammatory bowel disease with varied, and changing, incidence rates worldwide. UC has an unpredictable disease course and is associated with a high health economic burden. During 2016 and 2017, a panel of experts was convened to identify, discuss and address areas of unmet need in UC. METHODS PubMed and Cochrane Library databases were searched for relevant articles describing studies performed in patients with UC. These findings were used to generate a set of statements relating to unmet needs in UC. Consensus on these statements was then sought from a panel of 9 expert gastroenterologists using a modified Delphi review process that consisted of anonymous surveys followed by live meetings. RESULTS In 2 literature reviews, over 5,000 unique records were identified and a total of 138 articles were fully reviewed. These were used to consider 26 areas of unmet need, which were explored in 2 face-to-face meetings, in which the statements were debated and amended, resulting in consensus on 30 final statements. The unmet needs identified were categorised into 7 areas: impact of UC on patients' daily life; importance of early diagnosis and treatment; drawbacks of existing treatments; urgent need for new treatments; and disease-, practice- or patient-focused unmet needs. CONCLUSIONS These expert group meetings found a number of areas of unmet needs in UC, which is an important first step in tackling them in the future. Future research and development should be focused in these areas for the management of patients with UC

Development of Red Flags Index for Early Referral of Adults with Symptoms and Signs Suggestive of Crohn's Disease: An IOIBD Initiative

International audience; BACKGROUND AND AIMS:Diagnostic delay is frequent in patients with Crohn's disease (CD). We developed a tool to predict early diagnosis.METHODS:A systematic literature review and 12 CD specialists identified 'Red Flags', i.e. symptoms or signs suggestive of CD. A 21-item questionnaire was administered to 36 healthy subjects, 80 patients with irritable bowel syndrome (non-CD group) and 85 patients with recently diagnosed (<18 months) CD. Patients with CD were asked to recall symptoms and signs they experienced during the 12 months before diagnosis. Multiple logistic regression analyses selected and weighted independent items to construct the Red Flags index. A receiver operating characteristic curve was used to assess the threshold that discriminated CD from non-CD. Association with the Red Flags index relative to this threshold was expressed as the odds ratios (OR).RESULTS:Two hundred and one subjects, CD and non-CD, answered the questionnaire. The multivariate analysis identified eight items independently associated with a diagnosis of CD. A minimum Red Flags index value of 8 was highly predictive of CD diagnosis with sensitivity and specificity bootstrap estimates of 0.94 (95% confidence interval 0.88-0.99) and 0.94 (0.90-0.97), respectively. Positive and negative likelihood ratios were 15.1 (9.3-33.6) and 0.066 (0.013-0.125), respectively. The association between CD diagnosis and a Red Flags index value of ≥8 corresponds to an OR of 290 (p < 0.0001).CONCLUSIONS:The Red Flags index using early symptoms and signs has high predictive value for the diagnosis of CD. These results need prospective validation prior to introduction into clinical practice

Quality of Life and Work Productivity Improvements with Upadacitinib: Phase 2b Evidence from Patients with Moderate to Severe Crohn’s Disease

Introduction: In the phase 2 CELEST study, positive efficacy results were obtained with the Janus kinase 1 inhibitor upadacitinib for adult patients with moderate to severe Crohn’s disease. We present the health-related quality of life and work productivity improvement results with upadacitinib from CELEST. Methods: CELEST (NCT02365649) was a double-blind study where patients were randomized 1:1:1:1:1:1 in the 16-week induction period to placebo or upadacitinib 3 mg twice daily (BID), 6 mg BID, 12 mg BID, 24 mg BID, or 24 mg once daily (QD). Patients completing the induction period were re-randomized 1:1:1 to receive upadacitinib 3 mg BID, 12 mg BID, or 24 mg QD for 36 weeks or 3 mg BID, 6 mg BID, or 12 mg BID (after amendment). Inflammatory Bowel Disease Questionnaire (IBDQ), European Quality of Life-5 Dimensions visual analog scale (EQ-5D VAS), and Work Productivity and Activity Impairment (WPAI) questionnaire outcomes were assessed at baseline and Weeks 8, 16, and 52. Results: At Week 16, a significant percentage (P ≤ 0.05) of patients receiving upadacitinib 6-mg BID dose or higher achieved IBDQ response (IBDQ score change ≥ 16 points; 49%–57% for upadacitinib vs. 24% for placebo) and IBDQ remission, except 24 mg QD (IBDQ score ≥ 170; 26%–39% for upadacitinib vs. 11% for placebo). Greater improvements in IBDQ total score, EQ-5D VAS, and activity impairment from baseline (P ≤ 0.1) versus placebo were also observed. Larger improvements (P ≤ 0.1) in IBDQ response and total score and EQ-5D VAS were observed at Week 8 with 6 and 24 mg BID versus placebo, with improvements for all dosages maintained or greater at Week 52 for IBDQ, EQ-5D VAS, and WPAI endpoints, in particular for the 12-mg BID group. Conclusion: Improvements in health-related quality of life and work productivity were achieved and sustained with upadacitinib in patients with moderate to severe Crohn’s disease. Trial Registration: ClinicalTrials.gov identifier, NCT02365649. © 2021, The Author(s)

Innovative approaches to biologic development on the trail of CT-P13: biosimilars, value-added medicines, and biobetters.

The biosimilar concept is now well established. Clinical data accumulated pre- and post-approval have supported biosimilar uptake, in turn stimulating competition in the biologics market and increasing patient access to biologics. Following technological advances, other innovative biologics, such as "biobetters" or "value-added medicines," are now reaching the market. These innovative biologics differ from the reference product by offering additional clinical or non-clinical benefits. We discuss these innovative biologics with reference to CT-P13, initially available as an intravenous (IV) biosimilar of reference infliximab. A subcutaneous (SC) formulation, CT-P13 SC, has now been developed. Relative to CT-P13 IV, CT-P13 SC offers clinical benefits in terms of pharmacokinetics, with comparable efficacy, safety, and immunogenicity, as well as increased convenience for patients and reduced demands on healthcare system resources. As was once the case for biosimilars, nomenclature and regulatory pathways for innovative biologics require clarification to support their uptake and ultimately benefit patients

A systematic review of factors associated with non-adherence to treatment for immune-mediated inflammatory diseases.

Background: Non-adherence impacts negatively on patient health outcomes and has associated economic costs. Understanding drivers of treatment adherence in immune-mediated inflammatory diseases is key for the development of effective strategies to tackle non-adherence. Objective: To identify factors associated with treatment non-adherence across diseases in three clinical areas: rheumatology, gastroenterology, and dermatology. Design: Systematic review Data sources: Articles published in PubMed, Science Direct, PsychINFO and the Cochrane Library from 1 January 1980 to 14 February 2014. Study selection: Studies were eligible if they included patients with a diagnosis of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, or psoriasis and included statistics to examine associations of factors with non-adherence. Data extraction: Data were extracted by the first reviewer using a standardised 23-item form and verified by a second/ third reviewer. Quality assessment was carried out for each study using a 16-item quality checklist. Results: 73 studies were identified for inclusion in the review. Demographic or clinical factors were not consistently associated with non-adherence. Limited evidence was found for an association between non-adherence and treatment factors such as dosing frequency. Consistent associations with adherence were found for psychosocial factors, with the strongest evidence for the impact of the healthcare professional-patient relationship, perceptions of treatment concerns and depression, lower treatment self-efficacy and necessity beliefs, and practical barriers to treatment. Conclusions: While examined in only a minority of studies, the strongest evidence found for non-adherence were psychosocial factors. Interventions designed to address these factors may be most effective in tackling treatment non-adherence