bluuebunny/crossref_metadata_2025_split huggingface dataset:
P651 Diagnostic delay, effectiveness and safety outcomes in a real-world cohort of patients with Crohn’s disease: data from administrative databases in Tuscany, Italy
Authors: Bertani L , Ferraro S , Bartolini C , Convertino I , Giometto S , Cappello E , Valdiserra G , Tillati S , Blandizzi C , Lucenteforte E , Gini R , Tuccori M , Costa F 
Published: May 2021

Abstract

Background
Diagnostic delay (DD) of Crohn’s disease (CD) is poorly investigated in the real-world setting, and could affect significantly the outcome of CD. The aim of the present study was to quantify the possible DD of CD in CD patients in Tuscany region of Italy, evaluating effectiveness and safety outcomes in CD patients with DD.

Methods
We conducted a retrospective cohort study on data extracted from administrative databases of Tuscany. We included patients &gt;18 years old (yo) with a record of ICD-9 diagnosis for CD or disease exemption or a dispensation of oral budesonide from 6/1/2011 to 6/30/2016 (index date, ID) whichever came first. Patients with a look-back period (time before ID) &lt; 5 y and follow-up (FUP) &lt; 3 y were excluded. Patients with at least one Emergency Department (ED) access or hospitalisation for gastrointestinal causes in the lookback period (excluding 6 months before ID) could have a possible DD. DD was classified in short (up to 18 months) and long (up to 60 months). We performed survival analyses (Kaplan-Meier curves) for effectiveness (time free from the first: dispensation of azathioprine, biologic drug and ileocecal resection surgery) and safety outcomes (time free from first: ED access and/or hospitalization for any cause). Hazard ratio (HR) was calculated by using Cox models adjusted for age, gender and number of concomitant drugs in the month before ID. Both outcomes were evaluated for dichotomous (No DD and DD) and categorical variables of DD (No DD, short DD and long DD).

Results
Among 3342 CD patients, 584 (17,5%) had a suspected DD: 212 and 372 patients had short and long DD, respectively, p&lt;0.001. The effectiveness analysis revealed that about the 20% of patients with long DD were treated with a biologic within 3 years, as compared with those with short DD or no DD (10%), p=0.0007. The adjusted (a)HR for biologic drug was 1.30 (Confidence Interval, CI 95%: 1.12–1.56) for patients with long DD and 1.02 (CI 95%:0.82–1.30) for those with short DD. No significant aHRs were found for the other effectiveness outcomes. The safety analysis showed that 75% of patients with DD had first ED access or hospitalization for any causes with the FUP, as compared with those without (about 60%), p&lt;0.001. The aHR showed an increased risk for safety outcomes in patients with DD: 1.71 (CI 95%:1.61–1.91) for the ED accesses, 1.31 (CI 95%:1.19–1.49) for hospitalization, and 1.54 (CI 95%:1.41–1.71) for the composite outcome.

Conclusion
More than 17% of patients had a putative DD (mostly long DD). A risk of treatment with biologic drug, ED accesses and hospitalizations for any cause was found for patients with DD compared with those timely diagnosed.
P676 The small intestinal microbiome in Crohn’s disease is characterised by increased luminal diversity and stable mucosa-associated communities
Authors: Wauters L , Tito R , Ceulemans M , Moens A , Outtier A , Sabino J , Ferrante M , Vermeire S , Vanuytsel T , Raes J 
Published: May 2021

Abstract

Background
Crohn’s disease (CD) may affect the entire gut but the composition and optimal sampling of the small intestinal microbiome are understudied. We assessed the variation in small intestinal luminal and mucosal microbiota in CD compared to healthy volunteers (HV) and functional dyspepsia (FD) patients.

Methods
Duodenal biopsies were collected with the Brisbane aseptic biopsy device1 followed by sterile brushing of the lumen/mucus layer. Aseptic ileal biopsies and brushes were also collected in CD patients with synchronous lower endoscopy. Acid- (proton pump inhibitors, PPIs) or immune-suppression (IS) and macro- (erosions/ulcers) and/or microscopic inflammation (CD) were recorded. Contamination was minimised during sample and data processing2 with further analysis at genus level. Microbiota covariates were studied using distance-based redundancy analysis (dbRDA, genus-level Aitchison distance) and PERMANOVA. Alpha-diversity (α) was compared between sampling types (biopsy/brush), disease groups, PPIs (off/on), IS (yes/no) or location (CD). Genera abundance profiles were compared transversally (sampling type) and regionally (CD) with correction for multiple testing (FDR&lt;.1).

Results
A total of 99 participants (21 CD, 48 FD and 30 HV) with similar demographics were included. Only sampling type and subject were associated with duodenal community variation (table). Transversal variation was also evident from the more significant clustering for sampling type vs. groups (fig 1). Within CD, sampling type (8.5%) and location (17.8%, both p=.005) but not treatment or inflammation were associated with community variation. Duodenal α-diversity of brushes was lower vs. biopsies (p&lt;2*10–9) and higher in CD vs. controls (fig 2). Compared to untreated subjects, α-diversity was lower with PPI in brushes (fig 3) and higher with IS in biopsies (CD) (fig 4). The 42 differentially abundant genera between sampling types of the duodenum were largely shared between groups vs. only 3 different genera for the ileum (CD). In CD, regional differences were found for 24 genera in brushes vs. only 6 in biopsies, with inflammation driving minor changes in brush and not biopsy samples of the duodenum only.

Conclusion
Small intestinal microbiota variation is significant, especially between duodenal luminal and mucosal communities. Luminal α-diversity was highest in CD but lower than that of the mucosa with an effect of treatment. Despite regional variation, mucosal genera profiles were more conserved and less affected by inflammation in CD.
References
1. Shanahan et al., AP&T 2016
2. Davis et al., Microbiome 2018
P686 Novel grape-derived prebiotic selectively enhances abundance and metabolic activity of IBD and IBS faecal butyrate producing bacteria in an in vitro model of intestinal fermentation
Authors: Oliver L , Ramió-Pujol S , Amoedo J , Malagón M , Serrano M , Bahí A , Lluansí A , Busquets D , Pardo L , Serra-Pagès M , Aldeguer X , Garcia-Gil J 
Published: May 2021

Abstract

Background
Inflammatory Bowel Disease (IBD) and Irritable Bowel Syndrome (IBS) are two intestinal disorders with unknown aetiology. IBD presents two main forms which are Crohn’s disease (CD) and ulcerative colitis (UC). It has been reported recently that bacterial communities present in the colon of patients with either IBD or IBS are structurally different compared to those found in healthy individuals. This dysbiosis mainly consists of a decrease of butyrate producing bacteria and, therefore, the recovery of this metabolic group should be at the baseline of any successful treatment.
The main goal of this proof-of-concept study was to test the capacity of a new prebiotic of selected dietary fibre obtained from grape to balance the dysbiosis found in patients with different intestinal disorders.

Methods
In this study, fresh faecal samples from 6 healthy subjects, 3 CD, 3 UC, and 3 IBS were collected at the Hospital Universitari Dr. Josep Trueta. Fresh samples were diluted 1:5 with fermentation buffer and incubated with 200 mg of prebiotic at 37 ºC under agitation for 72 h. Results were compared with those obtained with various commercial prebiotics after simulating in vitro digestion: inulin, grape pectin, and grape seed extract (GSPE).
Total DNA was extracted and the abundance of butyrate-producing bacterial markers: F. prausnitzii (Fpra), its two phylogroups (PHGI and PHGII), Roseburia spp. (Ros) and S. variabile (Sva) was analysed by qPCR. Bacterial activity was determined by measuring short chain fatty acids (SCFA) concentration (butyrate, acetate, and propionate) by gas chromatography.

Results
The abundance of all butyrate-producing bacteria analysed increased after incubation with the new prebiotic. Among them, Ros presented significantly higher abundance values with respect to negative control in healthy, CU, and IBS patients. It also showed a significant increase in all individuals analysed compared to inulin, grape pectin, and GSPE.
Fermentation of the tested new prebiotic, produced significantly higher concentrations of SCFA (p &lt; 0.001) when compared to negative control and all other commercial fibres. Acetate concentration was a 241% higher than negative control, followed by butyrate (187%), and propionate (169%).

Conclusion
The studied prebiotic produces in vitro an increase of the abundance and enhancement of the metabolism of butyrate-producing bacteria, when compared to commercial prebiotics. These results suggest that this new fibre is a promising prebiotic to be used in promotion of intestinal microbiota restoration at mucosa.
P687 Development of a panel of microbial markers to distinguish transient from pathological dysbiosis
Authors: Oliver L , Ramió-Pujol S , Malagón M , Serrano M , Bahí A , Busquets D , Torrealba L , Serra-Pagès M , Aldeguer X , Garcia-Gil J 
Published: May 2021

Abstract

Background
Dysbiosis is a widely used but unspecific term. It has been defined as any change in the composition of resident microbial communities relative to the ones found in healthy individuals. But it is still unclear which are the appropriate communities to define it and the reference values to measure it. Different studies have described dysbiosis in various diseases such as Inflammatory Bowel Disease (IBD), diabetes, rheumatoid arthritis, and autism, among others. Besides, the microbiota can be altered by transient factors such as antibiotics, diet, stress, or infections. Therefore, different degrees of severity can be associated with the term dysbiosis from which pathological and transient dysbiosis can be differentiated.
This work aimed at defining more specifically the term intestinal dysbiosis and to differentiate both transient and pathological dysbiosis.

Methods
Fifteen key microbial markers belonging to the principal families, classes and orders found in the human intestinal microbiota were accurately selected based on its functionality: F. prausnitzii (Fpra), E. coli (Eco), Firmicutes (Fir), Bacteroidetes (Bac), A. muciniphila (Akk), Ruminococcus sp. (Rum), Roseburia sp. (Ros), Gammaproteobacteria (Gam), Clostridia cluster I (Clo), Clostridia cluster XIV (XIV), Enterococcus sp., Lactobacillus sp. (Lac), C. albicans (Can), M. smithii (Msm), and the total bacterial load (Eub).
The dysbiosis was defined using stool samples in a cohort of healthy subjects (n=24) and then validated with 9 patients diagnosed with intestinal diseases 4 IBD and 2 Irritable Bowel Syndrome (IBS)). Total DNA was extracted and the abundance of microbial markers was analysed by qPCR.
Together with the establishment of the most common range in which each microbial marker was found, an index to define the pathological dysbiosis was calculated.

Results
Almost all healthy subjects analysed presented one or two slightly altered markers. The affected microbial markers in this “transient dysbiosis” were Fpra, Akk, and Ros, which are indicative of the mucous layer state, Firm as indicative of the lifestyle and fiber intake, Gam as characteristic of the pro-inflammatory state of the gut, and Msm as an altered intestinal habit and gas production.
All patients analyzed (IBD and IBS) presented alterations mainly of the bacteria inhabiting the mucosa and an alteration of the opportunistic species related to the disrupted mucous layer and defining “pathological dysbiosis”.

Conclusion
This study establishes an appropriate abundance range of key microbial markers in the gut, leading to a specific definition of dysbiosis which allows to differentiate the pathological from the transient dysbiosis. These results need further validation in a larger patient cohort.
Provincial Merchants in Eighteenth-Century England: The ‘Great Oaks’ of Manchester
Authors: Maw Peter 
Published: May 2021

Abstract
The importance of overseas trade to England’s national wealth and international reputation in the eighteenth century amplified the public discourse on the social value of merchants. Contemporary conduct books described a hierarchical occupational structure, where merchants enjoyed the highest prestige within the business community, with tradesmen and manufacturers performing distinct and progressively less valued professional functions. These conduct books focused on London, England’s premier port and the beating heart of Europe’s commodity and financial markets. Historians have also given much attention to London but have equally demonstrated the importance of merchants in the ‘outports’, whose participation in England’s foreign trade engendered significant wealth, status and political influence. This article considers a different type of eighteenth-century merchant, one based within English manufacturing regions, and one that has been largely overlooked in the historiography, not least because their businesses elided the separation of production and mercantile activities espoused by contemporary didacts. Focusing on Manchester, the article demonstrates that the town’s ‘Great Oaks’ challenged London’s commercial hegemony in a distinctive way, seeking not to replicate outport merchants’ entrepreneurial verve in risky, multilateral trades, but specialising, as both manufacturers and merchants, in exporting to commercially developed markets, where the ability to supply a precise assortment of locally produced textiles was more important than the capacity to sell imports or to provide financial services to overseas clients. Although little studied, provincial merchant communities were a general feature of the more dynamic English manufacturing regions in the years immediately before, and during the onset of, industrialisation.
Out-of-hours primary care for people with intellectual disabilities: interviews in general practice
Authors: Heutmekers Marloes , Naaldenberg Jenneken , Mastebroek Mathilde , Assendelft Willem J J , van Schrojenstein Lantman-de Valk Henny M J , Leusink Geraline L 
Published: May 2021

Abstract

Background
Out-of-hours primary care for people with intellectual disabilities (ID) involves different groups of health care professionals, who are often not familiar to one another nor to the specific health care needs of this vulnerable population. It is not known to what extend these specific health care needs or organizational factors influence the delivery of out-of-hours primary care for people with ID.

Objective
The objective of this study is to explore the experiences of health care professionals regarding the medical content and the organizational context of out-of-hours primary care for people with ID.

Methods
Semi-structured interviews were conducted with daily care professionals, triage nurses and general practitioners (GPs) involved in out-of-hours primary care for people with ID in the Netherlands. Interviews were thematically analysed for medical content and organizational context.

Results
The analysis resulted in four interconnected themes: (i) uncertainties in the triage assessment of ID patients; (ii) confusion about inter-professional responsibilities; (iii) impact on routines and workflow concerning ID patients and (iv) constraints in the decision-making process. All issues raised were related to the organizational context.

Conclusions
Health care professionals involved in out-of-hours primary care for people with ID indicate that the quality of this care is more influenced by the organizational context than by the medical content. We recommend out-of-hours GP services and care provider services for people with ID to set standards for roles and responsibilities in order to facilitate health care professionals in delivering accessible and high-quality care to this vulnerable population.
Worlds of Labour: Introducing the Standard-Setting, Privileging and Equalising Typology as a Measure of Legal Segmentation in Labour Law
Authors: Dingeldey Irene , Fechner Heiner , Gerlitz Jean-Yves , Hahs Jenny , Mückenberger Ulrich 
Published: May 2021

Abstract
The Standard Employment Relationship (SER) in industrialised countries is associated with strong protection for employees who fulfil its criteria but tends to neglect those who do not. Although the theoretical concept of SER has had repercussions around the world, its global empirical incidence and the variation of regulatory patterns associated with it have not been scrutinised so far. Comparative quantitative research in labour law has mainly focused on the overall level of employment protection in the countries of the Northern Hemisphere. Against this background, we ask how legal segmentation in labour law, that is, the exclusion from and gradation in employment protection which seems to be connected with the SER, can be conceptualised and measured in a global perspective. Drawing on leximetrics, a method to measure and quantify norms, we make use of and extend existing data sets such as the Centre for Business Research Labour Regulation Index (CBR-LRI) and Employment Protection Legislation Index (EPLex) in order to grasp the nature of legal segmentation. We identify three main functions of individual employment law in the protection/segmentation context: the standard-setting (S), the privileging (P) and the equalising (E) functions. We develop the SPE-employment law model on the assumption that the three functions are mutually independent in normative terms. The SPE typology offers a genuinely new perspective for comparative labour regulation research, making it possible to see the differentiation of patterns of legal segmentation and their path dependencies in 115 countries. First findings on a global scale show that in 2013 no fundamental difference between the levels of regulation in the Global South and North can be found. Moreover, familiar patterns can be observed such as a tendency to stable and low protection levels in liberal welfare states, and a tendency to universalist types of regulation in former socialist countries.
“What Do You Mean It’s Not Cancer?” A Review of Autoimmune and Systemic Inflammatory Diseases Involving the Breast
Authors: Limninart Narisara , Harvey Jennifer A , Schultz Katherine J , Mills Anne M , Noland Mary Margaret B , Schroen Anneke T , Rochman Carrie M 
Published: May 2021

AbstractAutoimmune and systemic inflammatory diseases represent a heterogeneous group of immune-mediated conditions with a wide range of clinical presentations and various affected organs. Autoimmune diseases can present in the breast as localized disease or as part of systemic involvement. Although breast involvement is uncommon, the spectrum of imaging findings can include breast masses, axillary adenopathy, calcifications, and skin changes, the appearance of which can mimic breast cancer. Common etiologies include diabetic mastopathy, systemic lupus erythematosus, scleroderma, rheumatoid arthritis, idiopathic granulomatous mastitis, sarcoidosis, and Immunoglobulin-G4 related mastopathy. This educational review will present multimodality imaging findings of breast manifestations of systemic inflammatory and autoimmune diseases and coexisting complications. It will also review how these disorders may affect breast cancer risk and breast cancer treatment options, including radiation therapy.
Could the Crime of Aggression Undermine Deterrence?
Authors: Whiting Alex 
Published: May 2021

Abstract
There is a hopeful story to be told with respect to the activation of the crime of aggression at the International Criminal Court (ICC). Activation will either add to deterrence, or at worst will be harmlessly symbolic. But what if the premise is wrong? What if there is a risk that activation of the crime of aggression will undermine rather than advance deterrence? It matters not that the crime is activated, but how it is activated — the narrow definitional and jurisdictional scope of the crime as it has been enacted at the ICC, may undermine the deterrence effect of the Court by further encouraging cynicism about what the Court can and cannot do. Recognizing this risk both enriches the debate and raises larger questions about strategies for building and expanding international criminal law and its institutions.
Safety of measles, rubella and mumps vaccines in adults: a prospective cohort study
Authors: Ami Neuberger , Eyal Nadir , Asaf Biber , Chen Avni , Adi Brom , Drorit Attias , Neta Petersiel , Hajar Dallashi , Stav Rakedzon , Eli Schwartz 
Published: May 2021

Abstract

Background
In recent years, multiple outbreaks of measles associated with vaccine hesitancy occurred in high-income countries, where measles incidence had previously been low. Most safety data about the measles, mumps and rubella (MMR) vaccine are derived from studies conducted among children, whereas evidence regarding the safety profile of the vaccine in adults is scarce.

Methods
In 2017, during an outbreak of measles in Europe, Israeli travellers to high-risk locations who were incompletely vaccinated, were urged to complete the two MMR vaccination schedule before their travel. In this prospective cohort study, we analysed adverse events (AEs) of MMR and MMRV (measles, mumps, rubella and varicella) vaccines among these travellers. All participants were followed up using structured questionnaires 2–4 weeks after vaccination.

Results
Seven hundred and eighty-five adult travellers whose median age was 49.2 years were vaccinated and followed up. Any AEs were reported by 25.2% of all participants; 11.6% reported local AEs, and 18.6% reported systemic AEs, none of which were severe. In general, AEs were much more common among female travellers (19.4% of males vs 30.1% of females (P &lt; 0.001)). Local AEs, overall systemic AEs, headache and arthralgia were much more common among females, whereas rates of general malaise and fever were not statistically different between genders. We did not observe any significant differences in the rates of total, local or systemic AEs between the MMR and MMRV vaccines. Higher rates of systemic AEs were observed among participants who were younger and probably immunized once with MMR compared to older vaccines immunized once to measles only and to those who were never immunized.

Conclusions
The current study demonstrated low rates of systemic AEs and no serious AEs following either MMR or MMRV administration. More AEs were reported among females, and rates of AEs were similar after either MMR or MMRV.