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Background and Aims Tesnatilimab, a monoclonal antibody targeting NKG2D, was evaluated in Crohn’s disease [CD] patients who had failed or were intolerant to biologic or conventional therapy. Methods TRIDENT was a phase 2b, two-part, randomised, double-blind, placebo-controlled, parallel-arm, multicenter study. In Part 1 [proof of concept], 145 patients who were biologic intolerant or refractory [Bio-IR] or had not failed biologic therapy [Bio-NF] were randomised in a 1:1 ratio to placebo subcutaneously [SC] or tesnatilimab 400 mg SC. In Part 2 [dose ranging], 243 Bio-IR and Bio-NF patients were randomised in a 1:1:1:1:1 ratio to placebo, tesnatilimab [50 mg, 150 mg, 400 mg], or intravenous infusion of ustekinumab ~6 mg/kg at Week 0 and 90 mg SC at Weeks 8 and 16. The primary endpoint was mean change from baseline in Crohn’s Disease Activity Index [CDAI] at Week 8 [Part 1] and Week 12 [Part 2]. Clinical and endoscopic remission/response were evaluated. Efficacy analyses were also assessed by NKG2D and MICB single nucleotide polymorphism [SNP] status [SNP-positive means positive in at least one of two SNPs]. Safety events were summarised. Results In Part 1, mean change from baseline in CDAI score was significantly greater with tesnatilimab vs placebo at Week 8 [-103.6 vs -60.0; p Conclusions Tesnatilimab was well tolerated. The efficacy of tesnatilimab in patients with CD was significant for the primary endpoint in Part 1; however, no dose-response signal was detected for the primary endpoint in Part 2. Based on these inconsistent findings, tesnatilimab was not considered an effective treatment for patients with CD and no further development is planned. ClinicalTrials.gov Identifier NCT02877134

Background Inflammatory bowel disease (IBD) is a complex disease with variable presentation, progression, and response to therapies. Current disease classification is based on subjective clinical phenotypes. The peripheral blood immunophenome can reflect local inflammation, and thus we measured 39 circulating immune cell types in a large cohort of IBD and control subjects and performed immunotype:phenotype associations. Methods We performed fluorescence-activated cell sorting or CyTOF analysis on blood from 728 Crohn’s disease, 464 ulcerative colitis, and 334 non-IBD patients, with available demographics, endoscopic and clinical examinations and medication use. Results We observed few immune cell types commonly affected in IBD (lowered natural killer cells, B cells, and CD45RA– CD8 T cells). Generally, the immunophenome was distinct between ulcerative colitis and Crohn’s disease. Within disease subtype, there were further distinctions, with specific immune cell types associating with disease duration, behavior, and location. Thiopurine monotherapy altered abundance of many cell types, often in the same direction as disease association, while anti-tumor necrosis factor (anti-TNF) monotherapy demonstrated an opposing pattern. Concomitant use of an anti-TNF and thiopurine was not synergistic, but rather was additive. For example, thiopurine monotherapy use alone or in combination with anti-TNF was associated with a dramatic reduction in major subclasses of B cells. Conclusions We present a peripheral map of immune cell changes in IBD related to disease entity and therapies as a resource for hypothesis generation. We propose the changes in B cell subsets could affect antibody formation and potentially explain the mechanism behind the superiority of combination therapy through the impact of thiopurines on pharmacokinetics of anti-TNFs., Graphical abstract

ObjectivesThe use of external control arms to study treatment effects is growing in interest among drug sponsors and regulators. However, experience with performing these kinds of studies for complex, immune-mediated diseases is limited. We sought to analyze a retrospective cohort of Crohn’s patients to predict the outcome of a prospective cohort.MethodsWe queried electronic health records databases and screened records at the University of California, San Francisco to identify patients meeting the eligibility criteria of TRIDENT, a concurrent trial involving ustekinumab as a reference arm. Timepoints were defined to balance the tradeoff between missing disease activity and bias. We compared two imputation models by their impacts on cohort membership and outcomes. We compared the results of ascertaining disease activity using structured data algorithms against manual review. We used these data to estimate ustekinumab’s real-world effectiveness.ResultsScreening identified 183 patients. 30% of the cohort had missing baseline data. Two imputation models were tested and had similar effects on cohort definition and outcomes. Algorithms for ascertaining non-symptom-based elements of disease activity were similar in accuracy to manual review. The final cohort consisted of 56 patients. 34% of the cohort was in steroid-free clinical remission by week 24.ConclusionsWe predict that a third of the ustekinumab-treated cohort in TRIDENT will be in steroid-free remission by week 24. However, our prediction is limited by substantial missing data. Efforts to improve real-world data capture and align trial design with clinical practice may enable more robust future studies and improve trial efficiency.STUDY HIGHLIGHTSWHAT IS KNOWNExternal control arm studies are receiving growing interest from drug sponsors and regulators as a potential source of real-world evidenceHowever, the feasibility and robustness of this approach is currently limitedUstekinumab is an FDA-approved treatment of moderately to severely active Crohn’s diseaseWHAT IS NEW HEREWe derived a retrospective cohort of patients designed to resemble the participants of TRIDENT, a concurrent phase 2b trial using ustekinumab as a reference armWe predict that about 34% of the ustekinumab-assigned participants in TRIDENT will be in steroid-free clinical remission by week 24.EHR structured data algorithms may be an accurate and less laborious alternative to manual abstraction of non-symptom-based components of the Crohn’s Disease Activity IndexReal-world practice differs from controlled studies in important ways, including the treatment goals and the timing of encountersThese differences can pose challenges to the feasibility of external control arm studies, and must be addressed to enable this novel study designThe methods, data, and code used in this pilot study are shared here for reproducibility and enhancement by others

Precision medicine is part of five focus areas of the Challenges in IBD research document, which also includes preclinical human IBD mechanisms, environmental triggers, novel technologies, and pragmatic clinical research. The Challenges in IBD Research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of a multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the precision medicine section is focused on highlighting the main gap areas that must be addressed to get closer to treatments tailored to the biological and clinical characteristics of each patient, which is the aim of precision medicine. The main gaps were identified in: 1) understanding and predicting the natural history of IBD: disease susceptibility, activity, and behavior; 2) predicting disease course and treatment response; and 3) optimizing current and developing new molecular technologies. Suggested approaches to bridge these gaps include prospective longitudinal cohort studies to identify and validate precision biomarkers for prognostication of disease course, and prediction and monitoring of treatment response. To achieve this, harmonization across studies is key as well as development of standardized methods and infrastructure. The implementation of state-of-the-art molecular technologies, systems biology and machine learning approaches for multi-omics and clinical data integration and analysis will be also fundamental. Finally, randomized biomarker-stratified trials will be critical to evaluate the clinical utility of validated signatures and biomarkers in improving patient outcomes and cost-effective care.

Objectives: Lysyl oxidase like 2 (LOXL2) is associated with poor prognosis in idiopathic pulmonary disease (IPF) and cancer. We developed an Enzyme-linked immunosorbent assay (ELISA) targeting the LOXL2 neo-epitope generated through the release of the signal peptide during LOXL2 maturation. Design and methods: An ELISA targeting the N-terminal site of the human LOXL2 was developed including technical optimization and validation steps. Serum LOXL2 was measured in patients with breast, colorectal, lung, ovarian, pancreatic and prostate cancer, melanoma, IPF and in healthy controls (n = 16). Results: A technically robust and specific assay was developed. LOXL2 was detectable in serum from healthy controls and showed reactivity towards recombinant LOXL2. Compared to controls, LOXL2 levels were significantly (p 0.001) Conclusions: A specific ELISA towards the N-terminal neo-epitope site in LOXL2 was developed which detected significantly elevated serum levels from patients with above-mentioned cancer types or IPF compared to healthy controls. Keywords: Lysyl Oxidase like-2, Neoepitope, Extracellular matrix, Cancer, Idiopathic pulmonary fibrosis, Serological biomarker

ObjectiveIBD therapies and treatments are evolving to deeper levels of remission. Molecular measures of disease may augment current endpoints including the potential for less invasive assessments.DesignTranscriptome analysis on 712 endoscopically defined inflamed (Inf) and 1778 non-inflamed (Non-Inf) intestinal biopsies (n=498 Crohn’s disease, n=421 UC and 243 controls) in the Mount Sinai Crohn’s and Colitis Registry were used to identify genes differentially expressed between Inf and Non-Inf biopsies and to generate a molecular inflammation score (bMIS) via gene set variance analysis. A circulating MIS (cirMIS) score, reflecting intestinal molecular inflammation, was generated using blood transcriptome data. bMIS/cirMIS was validated as indicators of intestinal inflammation in four independent IBD cohorts.ResultsbMIS/cirMIS was strongly associated with clinical, endoscopic and histological disease activity indices. Patients with the same histologic score of inflammation had variable bMIS scores, indicating that bMIS describes a deeper range of inflammation. In available clinical trial data sets, both scores were responsive to IBD treatment. Despite similar baseline endoscopic and histologic activity, UC patients with lower baseline bMIS levels were more likely treatment responders compared with those with higher levels. Finally, among patients with UC in endoscopic and histologic remission, those with lower bMIS levels were less likely to have a disease flare over time.ConclusionTranscriptionally based scores provide an alternative objective and deeper quantification of intestinal inflammation, which could augment current clinical assessments used for disease monitoring and have potential for predicting therapeutic response and patients at higher risk of disease flares.

In the interview, Mark Curran and Rune Peitersen talk about topics of the artist’s visual explorations, which in his past projects (which concern the usage of military drones), revolve around physical distance and the powerlessness of drone operators and their targets, while considering whether the visua lrepresentations of drone warfare has any power to elicit empathy. On the other hand, in another system of control, the same distance and its relationship to the viewer is stressed in the interplay between human interest and interference with nature in Peitersen’s latest ongoing project, in which he questions systematization again, this time not due to artificial algorithmic intelligence, but as a human-made system of attempted ownership of nature.

Background And Aims Disease extent varies in ulcerative colitis (UC) from proctitis to left-sided colitis to pancolitis and is a major prognostic factor. When the extent of UC is limited there is often a sharp demarcation between macroscopically involved and uninvolved areas and what defines this or subsequent extension is unknown. We characterized the demarcation site molecularly and determined genes associated with subsequent disease extension. Methods We performed RNA sequence analysis of biopsy specimens from UC patients with endoscopically and histologically confirmed limited disease, of which a subset later extended. Biopsy specimens were obtained from the endoscopically inflamed upper (proximal) limit of disease, immediately adjacent to the uninvolved colon, as well as at more proximal, endoscopically uninflamed colonic segments. Results Differentially expressed genes were identified in the endoscopically inflamed biopsy specimens taken at each patient's most proximal diseased site relative to healthy controls. Expression of these genes in the more proximal biopsy specimens transitioned back to control levels abruptly or gradually, the latter pattern supporting the concept that disease exists beyond the endoscopic disease demarcation site. The gradually transitioning genes were associated with inflammation, angiogenesis, glucuronidation, and homeodomain pathways. A subset of these genes in inflamed biopsy specimens was found to predict disease extension better than clinical features and were responsive to biologic therapies. Network analysis revealed critical roles for interferon signaling in UC inflammation and poly(ADP-ribose) polymerase 14 (PARP14) was a predicted key driver gene of extension. Higher PARP14 protein levels were found in inflamed biopsy specimens of patients with limited UC that subsequently extended. Conclusion Molecular predictors of disease extension reveal novel strategies for disease prognostication and potential therapeutic targeting.

Activation of the innate immune system is commonly associated with depression. Immunomodulatory drugs may have efficacy for depressive symptoms that are co-morbidly associated with inflammatory disorders. We report a large-scale re-analysis by standardized procedures (mega-analysis) of patient-level data combined from 18 randomized clinical trials conducted by Janssen or GlaxoSmithKline for one of nine disorders (N = 10,743 participants). Core depressive symptoms (low mood, anhedonia) were measured by the Short Form Survey (SF-36) or the Hospital Anxiety and Depression Scale (HADS), and participants were stratified into high (N = 1921) versus low-depressive strata based on baseline ratings. Placebo-controlled change from baseline after 4–16 weeks of treatment was estimated by the standardized mean difference (SMD) over all trials and for each subgroup of trials targeting one of 7 mechanisms (IL-6, TNF-α, IL-12/23, CD20, COX2, BLγS, p38/MAPK14). Patients in the high depressive stratum showed modest but significant effects on core depressive symptoms (SMD = 0.29, 95% CI [0.12–0.45]) and related SF-36 measures of mental health and vitality. Anti-IL-6 antibodies (SMD = 0.8, 95% CI [0.20–1.41]) and an anti-IL-12/23 antibody (SMD = 0.48, 95% CI [0.26–0.70]) had larger effects on depressive symptoms than other drug classes. Adjustments for physical health outcome marginally attenuated the average treatment effect on depressive symptoms (SMD = 0.20, 95% CI: 0.06–0.35), but more strongly attenuated effects on mental health and vitality. Effects of anti-IL-12/23 remained significant and anti-IL-6 antibodies became a trend after controlling for physical response to treatment. Novel immune-therapeutics can produce antidepressant effects in depressed patients with primary inflammatory disorders that are not entirely explained by treatment-related changes in physical health.

Background and Aims The presence of gastrointestinal symptoms and high levels of viral RNA in the stool suggest active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication within enterocytes. Methods Here, in multiple, large cohorts of patients with inflammatory bowel disease (IBD), we have studied the intersections between Coronavirus Disease 2019 (COVID-19), intestinal inflammation, and IBD treatment. Results A striking expression of ACE2 on the small bowel enterocyte brush border supports intestinal infectivity by SARS-CoV-2. Commonly used IBD medications, both biologic and nonbiologic, do not significantly impact ACE2 and TMPRSS2 receptor expression in the uninflamed intestines. In addition, we have defined molecular responses to COVID-19 infection that are also enriched in IBD, pointing to shared molecular networks between COVID-19 and IBD. Conclusions These data generate a novel appreciation of the confluence of COVID-19– and IBD-associated inflammation and provide mechanistic insights supporting further investigation of specific IBD drugs in the treatment of COVID-19. Preprint doi: https://doi.org/10.1101/2020.05.21.109124

Polygenic and environmental factors are underlying causes of inflammatory bowel disease (IBD). We hypothesized that integration of the genetic loci controlling a metabolite's abundance, with known IBD genetic susceptibility loci, may help resolve metabolic drivers of IBD.We measured the levels of 1300 metabolites in the serum of 484 patients with ulcerative colitis (UC) and 464 patients with Crohn's disease (CD) and 365 controls. Differential metabolite abundance was determined for disease status, subtype, clinical and endoscopic disease activity, as well as IBD phenotype including disease behavior, location, and extent. To inform on the genetic basis underlying metabolic diversity, we integrated metabolite and genomic data. Genetic colocalization and Mendelian randomization analyses were performed using known IBD risk loci to explore whether any metabolite was causally associated with IBD.We found 173 genetically controlled metabolites (metabolite quantitative trait loci, 9 novel) within 63 non-overlapping loci (7 novel). Furthermore, several metabolites significantly associated with IBD disease status and activity as defined using clinical and endoscopic indexes. This constitutes a resource for biomarker discovery and IBD biology insights. Using this resource, we show that a novel metabolite quantitative trait locus for serum butyrate levels containing ACADS was not supported as causal for IBD; replicate the association of serum omega-6 containing lipids with the fatty acid desaturase 1/2 locus and identify these metabolites as causal for CD through Mendelian randomization; and validate a novel association of serum plasmalogen and TMEM229B, which was predicted as causal for CD.An exploratory analysis combining genetics and unbiased serum metabolome surveys can reveal novel biomarkers of disease activity and potential mediators of pathology in IBD.

Background: Recent studies reported conflicting results on the relationship between antenatal magnesium sulfate (MgSO4) exposure and neonatal intestinal injury. Most studies have not assessed MgSO4 exposure quantitatively and none reported the exposure timing. Objectives: The aim of this work was to assess whether there is a temporal or dose-dependent relationship between antenatal MgSO4 exposure and intestinal injury in extremely preterm neonates. Methods: A retrospective study was made of inborn neonates with gestational age ≤28 weeks and/or birth weights ≤1,000 g. Primary outcomes included necrotizing enterocolitis (NEC), spontaneous intestinal perforation (SIP), and/or death prior to discharge or in the first 2 weeks of life. Outcome comparisons were made based on the timing of MgSO4 exposure, within 7 days (Mg7D) or within 3 days (Mg3D) of birth. Total cumulative doses for the Mg3D group were also computed. Results: A total of 302 neonates were included, 210 in the Mg7D group, out of whom 179 (85.2%) constituted the Mg3D group. There were no differences noted when comparing MgSO4 exposure timing and the likelihood of NEC, SIP, and/or death. This remained the same for subgroup analysis of neonates < 26 weeks’ gestation. Each 10-g increase in MgSO4 cumulative dose correlated with a decrease in SIP/NEC/death by 18.9% prior to discharge and by 21.9% in the first 2 weeks of life. Small for gestational age (SGA) was a potential effect modifier by a likelihood ratio test with p = 0.07. Conclusions: Antenatal MgSO4 exposure in extremely preterm neonates was not associated with an increased risk of intestinal injury or death, and might have reduced these complications in a dose-dependent manner in our study. This protective effect was more noticeable in SGA neonates.

This chapter reflects on Mark Curran’s documentary photography project SOUTHERN CROSS. Completed between 1999 and 2001, the project was a critical response to the rapid economic development witnessed in the Republic of Ireland at the turn of the new millenium. Focused on Dublin and the surrounding region, it critically mapped and surveyed the spaces of development and finance, presenting the newly globalised landscape transformed in response to the migration of global capital. Addressing projects documenting the impact of the Celtic Tiger, Colin Graham described SOUTHERN CROSS as ‘evidence of the rasping, clawing deformation of the landscape, the visceral human individual in the midst of burgeoning idea of progress-as-building, propped up by finance-as-economics…it stands as an extraordinary warning of the future that was then yet to come’.

Objectives Elastin is a signature protein of the lungs. Matrix metalloproteinase-7 (MMP-7) is important in lung defence mechanisms and degrades elastin. However, MMP-7 activity in regard to elastin degradation has never been quantified serologically in patients with lung diseases. An assay for the quantification of MMP-7 generated elastin fragments (ELM7) was therefore developed to investigate MMP-7 derived elastin degradation in pulmonary disorders such as idiopathic pulmonary fibrosis (IPF) and lung cancer. Design and methods Monoclonal antibodies (mABs) were raised against eight carefully selected MMP-7 cleavage sites on elastin. After characterisation and validation of the mABs, one mAB targeting the ELM7 fragment was chosen. ELM7 fragment levels were assessed in serum samples from patients diagnosed with IPF (n = 123, baseline samples, CTgov reg. NCT00786201 ), and lung cancer (n = 40) and compared with age- and sex-matched controls. Results The ELM7 assay was specific towards in vitro MMP-7 degraded elastin and the ELM7 neoepitope but not towards other MMP-7 derived elastin fragments. Serum ELM7 levels were significantly increased in IPF (113%, p Conclusions MMP-7-generated elastin fragments can be quantified in serum and may reflect pathological lung tissue turnover in several important lung diseases.

Objective B lymphoid kinase (BLK) is associated with rheumatoid arthritis (RA) and several other B cell–associated autoimmune disorders. BLK risk variants are consistently associated with reduced BLK expression, but the mechanisms by which reduced expression alters human B cell function to confer autoimmune disease susceptibility are unknown. This study was undertaken to characterize the BLK risk haplotype and to determine associated B cell functional phenotypes involved in autoimmunity. Methods The BLK risk haplotype association with RA (determined using whole-genome sequencing data) was confirmed in 2,526 RA cases and 2,134 controls. Peripheral blood mononuclear cells (PBMCs) from RA patients, healthy adults, and umbilical cord blood were used to study B cell functional phenotypes associated with the BLK risk genotype. Association of the BLK haplotype with B cell phenotypes was analyzed using cell culture and flow cytometry. Results Two insertion/deletions were found on the RA risk haplotype in BLK, and the reduction in BLK expression associated with the risk haplotype was confirmed in primary B lymphocytes. Carriers of the RA-associated haplotype had evidence of lower basal B cell receptor (BCR) signaling activity, yet their B cells were hyperactivatable, with enhanced up-regulation of CD86 after BCR crosslinking and greater T cell stimulatory capacity. The number of isotype-switched memory B cells was also significantly increased in subjects carrying the risk haplotype. Conclusion A major mechanism underlying the BLK association with autoimmune disease involves lowered thresholds for BCR signaling, enhanced B cell–T cell interactions, and altered patterns of isotype switching.

Objective To establish whether the analysis of whole blood gene expression can be useful in predicting or monitoring response to anti-TNF therapy in RA.

Golimumab, a tumor necrosis factor antagonist, is an effective treatment for patients with moderate-to-severe ulcerative colitis (UC); however, more than 50% of initial responders lose their response to the drug within the first year of therapy. A gene expression signature identified in colon biopsies collected before treatment was associated with response to infliximab, and was subsequently refined to associate with mucosal healing in response to golimumab. We performed a phase 2a open-label study of 103 golimumab-treated patients with moderate-to-severe UC to test whether the baseline gene expression signature could be used to predict which patients would achieve mucosal healing, clinical response, and clinical remission at weeks 6 and 30 of treatment. The gene expression signature identified patients who went on to achieve mucosal healing at treatment week 6 with an area under the receiver operating characteristic curve (AUCROC) of 0.688 (P = .002) and at week 30 with an AUCROC of 0.671 (P = .006). The signature identified patients with mucosal healing with 87% sensitivity, but only 34% specificity, limiting its clinical utility. The baseline gene expression signature did not identify patients who went on to achieve clinical remission or clinical response with statistical significance. Further studies are needed to identify biomarkers that can be used to predict which patients with UC will respond to treatment with anti–tumor necrosis factor agents. ClinicalTrials.gov no: NCT01988961 .

This chapter presents a case study of how Nike got to the point of practical implementation of an effective management system within the footwear-manufacturing supply chain. It focuses on the evolution of traditional environmental, safety and health (ESH) management at Nike to the model that is being used. At the core of Nike's sustainability values are The Natural Step (TNS) system conditions and natural capitalism principles. As facilities achieve successes with their Management Environment, Safety and Health (MESH) implementation, the challenge will be to continually integrate sustainability criteria into the tools. Developed in 1997, MESH represents Nike's commitment to corporate responsibility. The uniqueness of MESH lies in raising the bar of ISO 14001 to include management, safety and health along with environmental issues. MESH has also encouraged manufacturers to get more involved in manufacturing and technological innovations, order management and environmental processes and procedures.

Background: Lysyl oxidase like 2 (LOXL2) activity is elevated in idiopathic pulmonary fibrosis (IPF) and cancer affecting collagen stability, desmoplastic- and scar tissue stiffness associated with poor prognosis. An ELISA targeting the LOXL2 neo-epitope generated through release of the signal peptide during LOXL2 maturation was developed and evaluated in patients with various cancers or IPF. Methods: The N-terminal site of the human LOXL2 was selected as target for ELISA development. A range of technical optimizations and validation steps were performed. Serum LOXL2 was measured in cohort 1: healthy controls (n=16) and in patients with stage 1-3 cancer of the breast (n=20), colon (n=7) lung (n=26), ovary (n=9), pancreas (n=5), prostate (n=14) and malignant melanoma (n=7); as well as in cohort 2: IPF (n=120) and healthy controls (n=51) Results: A technically robust and specific assay was developed showing a lower limit of detection of 5.7 ng/ml and intra- and inter-assay variations of 8% and 12%, respectively. LOXL2 was detectable in serum from healthy controls and showed reactivity towards recombinant LOXL2. Compared to controls, LOXL2 was significantly (p Conclusion: A technically robust assay specific towards a neo-epitope in LOXL2 was developed and shown to be elevated in patients with various cancer types and IPF compared to controls.

Background Decorin is one of the most abundant proteoglycans of the extracellular matrix and is mainly secreted and deposited in the interstitial matrix by fibroblasts where it plays an important role in collagen turnover and tissue homeostasis. Degradation of decorin might disturb normal tissue homeostasis contributing to extracellular matrix remodeling diseases. Here, we present the development and validation of a competitive enzyme-linked immunosorbent assay (ELISA) quantifying a specific fragment of degraded decorin, which has potential as a novel non-invasive serum biomarker for fibrotic lung disorders. Methods A fragment of decorin cleaved in vitro using human articular cartilage was identified by mass-spectrometry (MS/MS). Monoclonal antibodies were raised against the neo-epitope of the cleaved decorin fragment and a competitive ELISA assay (DCN-CS) was developed. The assay was evaluated by determining the inter- and intra-assay precision, dilution recovery, accuracy, analyte stability and interference. Serum levels were assessed in lung cancer patients, patients with idiopathic pulmonary fibrosis (IPF), patients with chronic obstructive pulmonary disease (COPD) and healthy controls. Results The DCN-CS ELISA was technically robust and was specific for decorin cleaved by cathepsin-S. DCN-CS was elevated in lung cancer patients (p

Background Interleukin-6 (IL-6) is one of the known neuroactive-cytokines involved in neuronal plasticity and stress coping and is associated with depression. Depressive symptoms are common in patients with rheumatoid arthritis (RA), a disease characterized by high peripheral IL-6. Previous analysis of a Phase II study1 showed that sirukumab, a human monoclonal antibody that selectively binds to the IL-6 cytokine with high affinity, can help reduce depressive symptoms in RA patients. Objectives To further assess and validate the effects of sirukumab on relieving depressive symptoms in RA patients. Methods We conducted a post-hoc analysis of 2 Phase III, randomized, double-blind, placebo-controlled trials evaluating efficacy and safety of sirukumab in the treatment of RA. SIRROUND-D enrolled patients with active RA despite disease-modifying anti-rheumatic drugs and having serum C-reactive protein (CRP)≥8mg/L at baseline. SIRROUND-T enrolled patients with active RA despite anti-TNF therapy and having serum CRP≥8mg/L or erythrocyte sedimentation rate≥28mm/h at baseline. Patients using antidepressants were excluded from the analysis. Patients were grouped by presence/absence of prevalent depressed mood and anhedonia (PDMA), based on the self-reported frequencies of these 2 core depressive symptoms in the SF-36, requiring one present at least “most of the time” and the other “some of the time” in the past 4 weeks. A depression score was derived based on the 2 core depressive symptoms of SF-36. Relief of depressive symptoms in patients with PDMA was evaluated by comparing changes in the depression score from baseline to week 8 between the placebo and combined sirukumab groups directly and with adjustment for RA activity as measured by the Disease Activity Score-28 with CRP. Changes in depression score were also analyzed in RA patients who did not have an ACR50 response to sirukumab. The combined effect of anti-IL-6 treatment was estimated using meta-analysis of 2 Phase III, 1 Phase II studies of sirukumab and 1 Phase II study of the anti-IL-6 cytokine antibody siltuximab. Results At baseline, 19% and 22% of patients were classified as PDMA in the 2 studies, respectively. Sirukumab treatment, compared to placebo, significantly improved depressive symptoms by week 8 among PDMA patients (p=0.022 and 0.046 for the 2 studies, respectively) before adjusting for changes in RA activity. Within the sirukumab group, the reduction in depressive symptoms remained significant after adjusting for changes in RA activity (p Conclusions Our findings are consistent with previous results from a phase II RA study. Peripheral anti-IL-6 cytokine treatment is associated with improvement in depressive symptoms in RA patients, possibly supporting a role for IL-6 dysfunction in depression. References Ann Rheum Dis2015;74(Suppl2): 720. Disclosure of Interest Y. Sun Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Develoment, LLC, B. Hsu Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Develoment, LLC, D. Wang Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Develoment, LLC, M. Curran Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Develoment, LLC, W. Drevets: None declared, G. Chen: None declared, G. Wittenberg: None declared

This chapter uses the remarkable case of the publication of the works of Theodore Rilliet de Saussure by the Societe typographique de Neuchâtel in the 1780s to examine how censorship functioned and how ‘illegality’ was constructed across the various regions of francophone Europe in the pre-Revolutionary period. Where previous studies have largely concentrated upon the size of the underground, this chapter shifts the focus to the multiple layers of the underground book market and, especially, the extent to which its operations were widely tolerated. The chapter argues that the limits of the true underground were not imposed from above but instead emerged through the interactions of all book trade actors, from lowly shipping agents to printers and authors.

Centrally informed through the application of photography, my multi-media practice has evolved to one conversant in ethnography and the principles of a critically reflexive practice. Ethnography can be viewed as an epistemological position or “a commitment”, as Zsuzsa Gille states, “to study an issue at hand by understanding it from the perspectives of people whose lives are tied up with or affected by it”. The thematic concerns within my research practice have critically addressed the predatory context resulting from the flows and migrations of global capital. To this end, and drawing upon my own practice-led fieldwork in the Lausitz (Lusatia), Brandenburg in the former East Germany (Deutsche Demokratische Republik), this article and the illustrations frame a long-term research project constructed in a landscape inscribed with the utopic “wounds of modernity” (Berman) — Industrialisation, Socialism, and now at great cost, Globalisation — and the re-representational strategies employed to evoke the “wound...

Robert Darnton's acclaimed 1995 work on the late eighteenth-century francophone illegal book trade, The forbidden best-sellers of pre-revolutionary France, has become one of the most cited and studied texts in its field. The culmination of thirty years' archival research and reflection, it roots Darnton's previous case-study-driven articles and monographs in a wide-ranging empirical survey of the order books of the Swiss printer-booksellers, the Société typographique de Neuchâtel. It claims to offer readers a picture of what illegal books went into bookshops everywhere in pre-revolutionary France. The first fruits of the French Book Trade in Enlightenment Europe project, a digital humanities initiative that has created an on-line database revealing the STN's entire trade, this article challenges Darnton's interpretation of the nature and utility of the Neuchâtel archive. It demonstrates that the STN's order books are an unreliable gauge of general French demand. It goes further. It argues for a nuanced polycentric understanding of the eighteenth-century Francophone book trade, and outlines a bibliometric digital humanities pathway that might lead us there.

Background An individual patient’s response to a particular drug is influenced by multiple factors, which may include genetic predisposition. Pharmacogenetic studies attempt to discover and estimate the contributions of genetic variants to the variability in response to a drug treatment. The task of identifying the genetic contribution is often complicated by response phenotypes that are based on imprecise or subjective clinical observations. Because the success of a pharmacogenetic study depends on the analysis of a heritable phenotype, it is important to identify phenotypes with a significant heritable component to ensure reliable and reproducible results in subsequent genetic association studies. Methods We retrospectively analyzed data collected from 436 rheumatoid arthritis patients treated with golimumab during the phase III GO-FURTHER study. We investigated the reliability of several potential response outcomes after golimumab treatment. Using whole-genome sequencing of the clinical trial cohort, we estimated the heritability of each potential outcome measure. We further performed a longitudinal analysis of the clinical data to estimate variability of outcome measures over time and the degree to which each response metric could be confounded by placebo response. Results We determined that the high degree of within-patient variation over time makes a single follow-up visit insufficient to assess an individual patient’s response to golimumab treatment. We found that different potential response outcomes had varying degrees of heritability and that averaging across multiple follow-up visits yielded higher heritability estimates than single follow-up estimates. Importantly, we found that the change in swollen and tender joint counts were the most heritable outcome metrics we tested; however, we showed that they are also more likely to be confounded by a placebo response than objective phenotypes like the change in C-reactive protein levels. Conclusions Our rigorous approach to finding robust and heritable response phenotypes could be beneficial to all pharmacogenetic studies and may lead to more reliable and reproducible results. Trial Registration Clinicaltrials.gov NCT00973479. Registered 4 September 2009. Electronic supplementary material The online version of this article (doi:10.1186/s13075-017-1299-8) contains supplementary material, which is available to authorized users.

Background & Aims Severe forms of inflammatory bowel disease (IBD) that develop in very young children can be caused by variants in a single gene. We performed whole-exome sequence (WES) analysis to identify genetic factors that might cause granulomatous colitis and severe perianal disease, with recurrent bacterial and viral infections, in an infant of consanguineous parents. Methods We performed targeted WES analysis of DNA collected from the patient and her parents. We validated our findings by a similar analysis of DNA from 150 patients with very-early-onset IBD not associated with known genetic factors analyzed in Toronto, Oxford, and Munich. We compared gene expression signatures in inflamed vs noninflamed intestinal and rectal tissues collected from patients with treatment-resistant Crohn's disease who participated in a trial of ustekinumab. We performed functional studies of identified variants in primary cells from patients and cell culture. Results We identified a homozygous variant in the tripartite motif containing 22 gene (TRIM22) of the patient, as well as in 2 patients with a disease similar phenotype. Functional studies showed that the variant disrupted the ability of TRIM22 to regulate nucleotide binding oligomerization domain containing 2 (NOD2)−dependent activation of interferon-beta signaling and nuclear factor−κB. Computational studies demonstrated a correlation between the TRIM22−NOD2 network and signaling pathways and genetic factors associated very early onset and adult-onset IBD. TRIM22 is also associated with antiviral and mycobacterial effectors and markers of inflammation, such as fecal calprotectin, C-reactive protein, and Crohn's disease activity index scores. Conclusions In WES and targeted exome sequence analyses of an infant with severe IBD characterized by granulomatous colitis and severe perianal disease, we identified a homozygous variant of TRIM22 that affects the ability of its product to regulate NOD2. Combined computational and functional studies showed that the TRIM22-NOD2 network regulates antiviral and antibacterial signaling pathways that contribute to inflammation. Further study of this network could lead to new disease markers and therapeutic targets for patients with very early and adult-onset IBD.

Background Although genome-wide association studies (GWAS) have identified over 100 genetic loci associated with rheumatoid arthritis (RA), our ability to translate these results into disease understanding and novel therapeutics is limited. Most RA GWAS loci reside outside of protein-coding regions and likely affect distal transcriptional enhancers. Furthermore, GWAS do not identify the cell types where the associated causal gene functions. Thus, mapping the transcriptional regulatory roles of GWAS hits and the relevant cell types will lead to better understanding of RA pathogenesis. Results We combine the whole-genome sequences and blood transcription profiles of 377 RA patients and identify over 6000 unique genes with expression quantitative trait loci (eQTLs). We demonstrate the quality of the identified eQTLs through comparison to non-RA individuals. We integrate the eQTLs with immune cell epigenome maps, RA GWAS risk loci, and adjustment for linkage disequilibrium to propose target genes of immune cell enhancers that overlap RA risk loci. We examine 20 immune cell epigenomes and perform a focused analysis on primary monocytes, B cells, and T cells. Conclusions We highlight cell-specific gene associations with relevance to RA pathogenesis including the identification of FCGR2B in B cells as possessing both intragenic and enhancer regulatory GWAS hits. We show that our RA patient cohort derived eQTL network is more informative for studying RA than that from a healthy cohort. While not experimentally validated here, the reported eQTLs and cell type-specific RA risk associations can prioritize future experiments with the goal of elucidating the regulatory mechanisms behind genetic risk associations. Electronic supplementary material The online version of this article (doi:10.1186/s13059-016-0948-6) contains supplementary material, which is available to authorized users.

Several small studies suggest that the presence of the human leukocyte antigen (HLA)-Cw6 (C*06:02) allele may be a predictor of improved response to ustekinumab. This study was designed to assess the association of the HLA-C*06:02 allele with response to ustekinumab in large cohorts of patients from the phase 3 studies of ustekinumab in moderate-to-severe psoriasis. In this retrospective study, both HLA-C*06:02-positive and -negative patients demonstrated good responses to ustekinumab (86% vs. 76%, respectively, achieved at least a 75% improvement from baseline in Psoriasis Area and Severity Index [PASI 75] at week 24). A modestly higher proportion of HLA-C*06:02-positive than HLA-C*06:02-negative patients achieved PASI 75/90 responses at weeks 12 and 24. The largest response difference between the positive and negative patients (17.9%) was observed for PASI 75 (week 12), with smaller differences noted at later time points for PASI 90 (11.8% at week 24) and PASI 100 (10.2% at week 28). A differential response to ustekinumab has been confirmed in HLA-C*06:02-positive versus HLA-C*06:02-negative patients; however, this difference is modest, particularly at the higher response rate thresholds (PASI 90/100) and later time points (weeks 24/28).

We survey recent results on reaction-diffusion equations with discontinuous hysteretic nonlinearities. We connect these equations with free boundary problems and introduce a related notion of spatial transversality for initial data and solutions. We assert that the equation with transverse initial data possesses a unique solution, which remains transverse for some time, and also describe its regularity. At a moment when the solution becomes nontransverse, we discretize the spatial variable and analyze the resulting lattice dynamical system with hysteresis. In particular, we discuss a new pattern formation mechanism—rattling, which indicates how one should reset the continuous model to make it well posed.

In 2005, the Republic of Ireland, was defined as the ‘most globalised economy in the world’ (IDA Ireland). The significance of this position is amplified by the fact that the South of Ireland never...

Rationale: The ADEPT study aimed to correlate clinical features and accessible biomarkers with molecular characteristics by profiling asthmatics across severities and healthy nonatopic volunteers (HVs). This report focuses on the identification of mucosal Th2 phenotype (based on IL-13 driven gene expression), using accessible biomarkers, such as exhaled nitric oxide (FENO), blood eosinophils (bEOS) and serum analytes. Methods: Assessments included questionnaires, pulmonary function tests, airway hyperresponsiveness, FENO, and biomarkers from sputum, blood, and endobronchial biopsy (EBBX). Th2 phenotype was evaluated by EBBX gene expression of CCL26, periostin, or an IL-13 in vitro gene signature (IVS). Results: Relative to HVs, EBBX gene expression of CCL26 provided the best segregation into Th2-high and Th2-low asthmatics compared to periostin or IL-13 IVS. Most EBBX-Th2-CCL26-high subjects with moderate-severe asthma were FENO≥35ppb (69%) and bEOS≥300/ul (77%), compared to a minority of EBBX-Th2-CCL26-low subjects (24% for each). Classifying subjects to EBBX-Th2-CCL26-high status based on FENO-high or bEOS-high status gave 100% sensitivity but only 64% specificity. Serum CCL17-high status added to FENO/bEOS model improved specificity to 93% for identification of Th2 status, with 85% sensitivity. Conclusions: Combinations of accessible biomarkers (FENO, bEOS, and serum CCL17) can accurately predict Th2 status measured by EBBX expression of CCL26. Eosinophilic inflammation was associated with but not limited to persistent airway Th2 gene expression. The ability to identify distinct asthma phenotypes using accessible biomarkers will be important in developing novel therapeutic agents.

Motivation Next-generation sequencing (NGS) technologies have become much more efficient, allowing whole human genomes to be sequenced faster and cheaper than ever before. However, processing the raw sequence reads associated with NGS technologies requires care and sophistication in order to draw compelling inferences about phenotypic consequences of variation in human genomes. It has been shown that different approaches to variant calling from NGS data can lead to different conclusions. Ensuring appropriate accuracy and quality in variant calling can come at a computational cost. Results We describe our experience implementing and evaluating a group-based approach to calling variants on large numbers of whole human genomes. We explore the influence of many factors that may impact the accuracy and efficiency of group-based variant calling, including group size, the biogeographical backgrounds of the individuals who have been sequenced, and the computing environment used. We make efficient use of the Gordon supercomputer cluster at the San Diego Supercomputer Center by incorporating job-packing and parallelization considerations into our workflow while calling variants on 437 whole human genomes generated as part of large association study. Conclusions We ultimately find that our workflow resulted in high-quality variant calls in a computationally efficient manner. We argue that studies like ours should motivate further investigations combining hardware-oriented advances in computing systems with algorithmic developments to tackle emerging ‘big data’ problems in biomedical research brought on by the expansion of NGS technologies. Electronic supplementary material The online version of this article (doi:10.1186/s12859-015-0736-4) contains supplementary material, which is available to authorized users.