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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

We describe a fetus at 24 3/7 weeks' gestation that showed ultrasound evidence of anemia, hydrops, and severe growth restriction. Both parents were known to be cis heterozygous carriers for SEA α-thalassemia deletion (αα/–). Cordocentesis confirmed fetal anemia and homozygous α-thalassemia (−/−) in the fetus. Fetal intrauterine transfusions corrected the anemia, treated the hydrops, and improved fetal growth. The postnatal course was complicated by hypoxic respiratory failure and persistent pulmonary hypertension of the newborn, which resolved only after partial volume exchange transfusion. This case report is presented to point out the potential unintended outcomes with transplacental transfusion via delayed cord clamping and cord milking at delivery in the setting of congenital Bart's hemoglobinopathy, and demonstrates that partial exchange transfusion of the newborn may optimize oxygen delivery due to the more favorable oxygen affinity of transfused adult hemoglobin compared with the Bart's hemoglobin.

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

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

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

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.

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 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

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.

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).

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.

While a heterogeneous network increases the system performance in terms of coverage and capacity, if it is deployed without being well planned and without making use of optimized configurations, it could potentially lead to tough requirements on the mobility performance. The system level simulations shows that in typical scenarios the small separated cell deployment (each low power node is deployed as a separate cell) meets mobility requirements from the regular network operations perspective. However, in challenging mobility scenarios, small separated cell deployment might suffer from the degradation in mobility performance due to the non-optimal handover settings. The proposed combined cell deployment (low power nodes and macro cell use the same cell identity) provides an effective alternative to improve mobility in terms of reduced handover numbers and improved transmission robustness for handover signaling, therefore simplifying the network planning and management.

Background 14–3-3η is an emerging soluble Rheumatoid Arthritis (RA) biomarker that activates intracellular pathways that lead to the upregulation of inflammatory and joint damage factors. It is reported to be highly specific and sensitive for RA as a diagnostic marker, higher levels are associated with greater joint damage progression risk and 14–3-3η9s modulation with treatment suggests a role in disease monitoring. Objectives In this study, we examine the specificity of 14–3-3η in an independent, clinically well-characterized cohort of moderate to severe RA and disease control subjects. Methods Serum 14–3-3η levels were measured in a total of 147 patients using the Augurex 14–3-3η ELISA. The patient set comprised 36 with RA and 111 controls consisting of 20 with asthma (A), 20 with Crohn9s Disease (CD), 12 presumed healthy (H), 16 with psoriasis (PsO), 20 with sarcoid arthritis (S), and 23 with spondylarthropathies (SpA). Sample testing was done independently of Augurex. Mann-Whitney testing together with Kruskal-Wallis analysis with the post-hoc Dunn9s multiple comparison test was performed to assess group differences. Receiver operator characteristic curve (ROC) analysis was performed to assess the specificity of 14–3-3η for RA. Results Median (IQR) serum 14–3-3η levels were significantly higher in RA [2.35ng/ml (0.28–19.41)] than all controls [0 (0–0)], p Conclusions Serum 14–3-3η is a highly specific RA biomarker. As a novel mechanistic disease factor, 14–3-3η is expected to provide new insights and approaches to RA management and clinical studies. References Arthritis Res Ther 2014; 16(2):R99; J Rheumatol 2014; 41(11):2104. Disclosure of Interest B. Dasgupta Employee of: Janssen R & D, LLC, Y. Cherkas Employee of: Janssen R & D, LLC, S. Lamberth Employee of: Janssen R & D, LLC, K. Hayden Employee of: Janssen R & D, LLC, C. Brodmerkel Employee of: Janssen R & D, LLC, A. Marotta Grant/research support from: Janssen R & D, LLC, M. Curran Employee of: Janssen R & D, LLC

OBJECTIVES: Genome-wide association studies (GWAS) have identified loci reproducibly associated with inflammatory bowel disease (IBD) and other immune-mediated diseases; however, the molecular mechanisms underlying most of genetic susceptibility remain undefined. Expressional quantitative trait loci (eQTL) of disease-relevant tissue can be employed in order to elucidate the genes and pathways affected by disease-specific genetic variance. METHODS: In this study, we derived eQTLs for human whole blood and intestine tissues of anti-tumor necrosis factor-resistant Crohn's disease (CD) patients. We interpreted these eQTLs in the context of published IBD GWAS hits to inform on the disease process. RESULTS: At 10% false discovery rate, we discovered that 5,174 genes in blood and 2,063 genes in the intestine were controlled by a nearby single-nucleotide polymorphism (SNP) (i.e., cis-eQTL), among which 1,360 were shared between the two tissues. A large fraction of the identified eQTLs were supported by the regulomeDB database, showing that the eQTLs reside in regulatory elements (odds ratio; OR=3.44 and 3.24 for blood and intestine eQTLs, respectively) as opposed to protein-coding regions. Published IBD GWAS hits as a whole were enriched for blood and intestine eQTLs (OR=2.88 and 2.05; and P value=2.51E-9 and 0.013, respectively), thereby linking genetic susceptibility to control of gene expression in these tissues. Through a systematic search, we used eQTL data to inform 109 out of 372 IBD GWAS SNPs documented in National Human Genome Research Institute catalog, and we categorized the genes influenced by eQTLs according to their functions. Many of these genes have experimentally validated roles in specific cell types contributing to intestinal inflammation. CONCLUSIONS: The blood and intestine eQTLs described in this study represent a powerful tool to link GWAS loci to a regulatory function and thus elucidate the mechanisms underlying the genetic loci associated with IBD and related conditions. Overall, our eQTL discovery approach empirically identifies the disease-associated variants including their impact on the direction and extent of expression changes in the context of disease-relevant cellular pathways in order to infer the functional outcome of this aspect of genetic susceptibility.

Background Interleukin-6 (IL-6) is among the known neuroactive cytokines involved in stress coping and neuronal plasticity. Clinical and preclinical studies suggest a role for IL-6 in the pathophysiology of depression; it is unclear whether peripheral anti-IL-6 treatment can directly alleviate depressive symptoms. Depressive symptoms and fatigue commonly affect RA patients, particularly those with high disease activity. Objectives To assess the effects of sirukumab, a human IL6 antibody, on measures of depressed mood and anhedonia, and fatigue from a Ph2 trial in patients with active RA. Methods This was a post-hoc analysis of the SF-36 Mental Health and Vitality domain items from a Ph2, multicenter, randomized, double-blind, placebo-controlled study evaluating efficacy and safety of 4 dose regimens of sirukumab (25mg q4wks up to 100mg q2wks) administered SC in patients with active RA despite MTX. Serum CRP ≥10mg/L was required for enrollment, and history of an uncontrolled psychiatric or emotional disorder that was of sufficient severity to interfere with study participation was excluded. Patients using anti-depressants were excluded from analysis. Patients were grouped by presence or absence of prevalent depressed mood and anhedonia (PDMA) at entry, defined as self-reported depressed mood and anhedonia on the SF-36 with >1 item designated “most of the time” and the other at least “some of the time” for 4wks. Sirukumab treatment was defined as receiving any sirukumab regimen. Change from baseline in PDMA and fatigue at wk12 were analyzed unadjusted and adjusted for baseline and wk12 DAS28-CRP score; to investigate the relationship between depressive symptoms improvement and RA clinical response, change in PDMA symptoms was also investigated separately in ACR50 responders and non-responders Results At entry, about 26% of patients were classified as having PDMA. This group also experienced significantly more fatigue and nervousness than those without PDMA. The severity of PDMA symptoms in this group was not significantly correlated with RA chronicity or severity, or with baseline serum levels of inflammatory biomarkers. Clinical efficacy of sirukumab on RA disease symptoms as measured with the DAS28-CRP occurred in patients with and without PDMA at entry. Patients in the PDMA group receiving sirukumab but not PBO achieved significant improvements at wk12 in PDMA symptoms (p=0.0006), and fatigue (p=0.0157). In patients with PDMA, significant improvements on PDMA symptoms upon sirukumab treatment, but not PBO, were observed in both ACR50 responders (p=0.0024) and non-responders (p=0.0014). In patients with PDMA treated with sirukumab, baseline soluble IL-6 receptor (sIL-6R) level significantly correlated with improvement at wk12 in PDMA symptoms (Spearman r=0.44, p=0.015). Conclusions These novel findings link IL-6 signaling pathway dysregulation to depressive symptoms and fatigue, and suggest that peripheral anti-IL-6 treatment can improve depressive symptoms in RA patients independently of clinical response. References Hodes GE et al,PNAS 2014;111(45):16136-16141. Smolen JS et al,ARD 2014;73:1616-1625. Disclosure of Interest B. Hsu Employee of: Janssen, D. Wang Employee of: Janssen, Y. Sun Employee of: Janssen, G. Salvadore Employee of: Janssen, J. Singh Employee of: Janssen, M. Curran Employee of: Janssen, I. Caers Employee of: Janssen, W. Drevets Employee of: Janssen, G. Wittenberg Employee of: Janssen, G. Chen Employee of: Janssen

Background Genome wide association studies (GWAS) have yielded over 100 genetic loci associated with rheumatoid arthritis (RA). However, the utility of GWAS studies for drug discovery is limited because most GWAS hits do not reside in coding regions and have no known function. Elucidating potential transcriptional regulatory roles of GWAS hits will allow functional annotation of disease-related GWAS loci and lead to better understanding of RA etiology. Objectives To identify potential molecular drivers of RA by mapping expression quantitative trait loci (eQTLs) from gene expression and genotype data from a cohort of RA patients. Methods eQTLs were mapped using whole blood transcriptome data (Affymetrix microarray) from 377 RA patients with inadequate response to methotrexate enrolled in a clinical trial at baseline. Genotypes were generated from whole genome sequencing of DNA from the same subjects. eQTL mapping was performed by linear regression on adjusted data and FDR was estimated with a permutation method separately for local and distant associations. Results We report over 6,000 unique genes with significant eQTLs that represent potential molecular drivers. These eQTLs are enriched for genetic variants associated with RA. Additionally, the genes associated with these RA GWAS loci represent several disease-relevant biological pathways, including antigen presentation and B cell signaling. While there are multiple published eQTL datasets from non-RA cohorts, our analysis suggests that there is utility in detecting eQTLs from disease-relevant cohorts. Indeed, we identified several eQTLs overlapping with RA GWAS loci that have not been reported previously. We also demonstrate that integration with publicly available epigenomics datasets enables elucidation of cell-type-specific relationships. In particular, genes with expression driven by active enhancers in specific immune cell types (e.g., B cells and T helper cells) were identified, generating hypotheses that can be validated experimentally. Conclusions As one of the first studies to detect eQTLs from RA patients, this work provides a valuable resource to better understand the genetic basis for RA and aid in translating genetics research into therapeutic interventions. Overall, this analysis highlights the value of studying peripheral blood given the challenge of obtaining large numbers of synovial tissue biopsies from RA patients. Disclosure of Interest A. Walsh Employee of: Johnson & Johnson, J. Whitaker Employee of: Johnson & Johnson, C. Huang Employee of: Johnson & Johnson, Y. Cherkas Employee of: Johnson & Johnson, S. Lamberth Employee of: Johnson & Johnson, C. Brodmerkel Employee of: Johnson & Johnson, M. Curran Employee of: Johnson & Johnson, R. Dobrin Shareholder of: Johnson & Johnson, Employee of: Johnson & Johnson

Background Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disease resulting in joint inflammation and damage. Despite the current therapies available, only a small percentage of RA pts achieve remission. To improve care and treatment for RA pts, a deeper understanding of the mechanisms that drive disease and response to therapy are desirable. The molecular understanding of disease and treatment mechanisms of RA continues to evolve. Objectives To explore the utility of peripheral blood expression profiling for informing disease and treatment mechanisms, samples derived from the GO-FURTHER golimumab study in RA were evaluated. This study examines if whole blood (WB) gene expression profiles can be utilized to: identify a baseline disease profile (DP) for pts with moderate-to-severe RA elucidate the pharmacodynamic (PD) and response profile of golimumab IV treatment, and delineate the peripheral biological processes dysregulated in RA and modulated by golimumab IV. Methods mRNA from 487 WB samples collected in a Phase III study of golimumab IV (GO-FURTHER) in pts with active RA despite methotrexate (MTX) therapy was isolated and profiled using the Affymetrix HT HG-U133+ PM Array (Santa Clara, CA). Samples were collected at Wks 0 and 14 from pts treated with IV placebo + MTX (PBO; n=161) or IV golimumab 2mg/kg + MTX (GLM; n=326) administered at Wks 0, 4, and every 8 wks thereafter. Non-RA WB samples (healthy controls; n=22) were obtained from Bioreclamation (Hicksville, NY). Results A disease profile comparing baseline gene expression profiles of RA to healthy controls yielded about 2000 differentially expressed genes (DEGs), while comparison of post-treatment to pre-treatment samples generated a PD profile of about 3000 DEGs. Over 70% of genes in the DP are downregulated as well as humoral immune response and B and T cell receptor signaling pathways. Pathways upregulated in the DP include innate immune response, Toll-like receptor (TLR), and cell activation. Treatment with golimumab modulates more than 30% of the disease profile, while just over 25% of PD effect is shared with the DP. The above mentioned pathways are common between the DP and PD profiles and are reversed, in part, through changes in peripheral cell populations post-golimumab treatment. A significant decrease in neutrophils and increase in lymphocytes was observed in the periphery at Wk 12 and in gene expression profiles representative of these cells at Wk 14 post-treatment. In addition, response to golimumab at Wk 14 was associated with more gene changes in B and T cell receptor signaling pathways in comparison to nonresponders. Conclusions Gene expression from the periphery of RA pts can be used for identification of a DP as well as the PD effect and response profile to golimumab IV. The most significant biological pathways and functions associated with the DP or PD effect are related to immune response and function. At baseline, RA pts had an increased innate and decreased adaptive immune profile in the periphery and majority of these processes were reversed by treatment with golimumab IV. Defining the pathways dysregulated in RA and modified by effective treatment as well as those that remain dysregulated aids in defining novel areas for potential therapeutic intervention. Disclosure of Interest Y. Cherkas Employee of: Janssen Research & Development, LLC., C. Brodmerkel Employee of: Janssen Research & Development, LLC., M. Curran Employee of: Janssen Research & Development, LLC., S. Lamberth Employee of: Janssen Research & Development, LLC. DOI 10.1136/annrheumdis-2014-eular.2032

Background The use of whole blood gene expression to predict and follow the response to TNF inhibition therapy in RA has been challenging due to the complex nature of the data. Objectives Here we employ an approach to gene expression analysis that is based on gene expression “modules” previously reported by Chaussabel, et al. (1) Methods Whole blood RNA (PAXgene) was obtained at baseline and 12 weeks on two cohorts of rheumatoid arthritis patients beginning anti-TNF therapy. The initial cohort was enrolled by the Autoimmune Biomarkers Collaborative Network (ABCoN) and contains 50 subjects stratified by EULAR Good Responders (N=14), Moderate Responders (N=21) and Non Responders (N=15) at 12 weeks after starting therapy. Results Good and Moderate Responders exhibited highly significant changes in multiple modules using a hypergeometric analysis. These included dramatic decreases in modules related to the myeloid lineage and inflammation, along with increases in B cell and plasma cell modules as well as in a number of modules related to the MHC and ribosomal proteins and other “undefined” module groups. Strikingly, Non Responders exhibited very little change in any modules. We have replicated these data in patients enrolled in a clinical trial of Simponi®, with full expression data available on 29 Good Responders, and 37 Moderate Responders. We observed nearly identical modular changes to those identified in the ABCoN Responders after 14 weeks of treatment. Only 6 Non Responders were available for study in this dataset, making convincing replication difficult for this subgroup. Several other replication datasets are currently being analyzed. Conclusions These data suggest that using gene expression modules related to inflammatory disease may provide a valuable method of characterizing the responder status of RA patients treated with TNF inhibitors. References Chaussabel D, Quinn C, Shen J, Patel P, Glaser C, Baldwin N, Stichweh D, Blankenship D, Li L, Munagala I, Bennett L, Allantaz F, Mejias A, Ardura M, Kaizer E, Monnet L, Allman W, Randall H, Johnson D, Lanier A, Punaro M, Wittkowski KM, White P, Fay J, Klintmalm G, Ramilo O, Palucka AK, Banchereau J, Pascual V. A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus. Immunity. 2008 Jul 18;29(1):150-64. doi: 10.1016/j.immuni.2008.05.012. Disclosure of Interest M. Curran Employee of: Janssen Research & Development, LLC., M. Oswald Grant/research support: Janssen Research & Development, LLC., A. Lee Grant/research support: Janssen Research & Development, LLC., Y. Cherkas Employee of: Janssen Research & Development, LLC., C. Brodmerkel Employee of: Janssen Research & Development, LLC., S. Lamberth Employee of: Janssen Research & Development, LLC., P. Gregersen Grant/research support: Janssen Research & Development, LLC. DOI 10.1136/annrheumdis-2014-eular.3724

Background Currently, disease activity in Rheumatoid Arthritis (RA) is measured using scoring systems that rely primarily on a collection of subjective measures from patients and clinicians. To improve care and treatment for RA patients, objective measurements of disease activity and response to treatment are desirable. Using a small cohort derived from an ongoing study of intravenously administered golimumab (GO-FURTHER), we evaluated the performance of Vectra-DA™ (Crescendo Biosciences), a multi-biomarker serum-based test designed to measure RA disease activity through correlation with DAS28-CRP and is sensitive to anti-TNF therapy 1 . Objectives This analysis examines if Vectra-DA™ correlates with disease activity and golimumab response in a clinical trial setting. Methods 137 serum samples collected in a Phase III study of intravenously administered golimumab in pts with active RA despite methotrexate (MTX) therapy were analyzed using Vectra-DA™ (Crescendo Bioscience © ; San Francisco, CA, USA). Samples were collected at wks 0, 2, 4, and 14 from patients (pts) treated with IV placebo + MTX (PBO; n= 42) or IV golimumab 2mg/kg + MTX (GLM; n=95) who received study medications at wks 0, 4, and every 8 weeks thereafter. Healthy control serum samples (n=21) were obtained from Bioreclamation (Hicksville, NY). Results A subset of pts from the GO-FURTHER study was chosen for analysis with Vectra-DA™. Among pts in the GO-FURTHER subset, the ACR50 response rates were 35.8% for GLM and 7.1% for PBO at week 14 and 48.4% for GLM and 16.7% for PBO at wk 24. Correlation of Vectra-DA™ and DAS28-CRP scores was r=0.51 (95% CI=0.45-0.57) using all four timepoints tested. Study pts had statistically higher mean Vectra-DA™ scores (64.2 at wk 0; 45.5 at wk 2; 50.2 at wk4; 44.9 at wk14) compared to healthy controls (35.2). At baseline, there were no significant differences in GLM and PBO-treated pts by Vectra-DA™ or DAS28-CRP scores. As early as week 2, GLM-treated subjects had a significant drop in Vectra-DA™ score of ∆= -18.7 (p= 16 ). The decrease in Vectra-DA™ score was maintained through wk 14, whereas PBO-treated subjects did not have a significant change in Vectra-DA™ scores from baseline to weeks 2, 4 and 14. Vectra-DA™ scores were statistically different between GLM-treated pts who achieved ACR50 at wk 14 versus nonresponders at wks 0 (p=0.024), 4 (p=0.013), and 14 (p=0.009). Vectra-DA™ scores were not statistically different between GLM-treated pts who achieved an ACR50 response at wk 24 versus nonresponders at all timepoints tested, although a trend was seen at wk 14 (p= 0.054). Conclusions Vectra-DA™ offers a molecular measurement of RA disease activity that can discriminate between normal subjects and RA pts, and also PBO and GLM-treated pts as early as wk 2 post-treatment. GLM treated wk14 responders had significantly lower Vectra-DA™ scores compared with nonresponders. The Vectra-DA™ score reflects a patient’s disease activity before and after the treatment with intravenous golimumab. References Weinblatt ME, Shadick NA, Manning W, et al. Use of a Multi-Biomarker Score for Rheumatoid Arthritis Disease Activity (Vectra™ DA) to Assess Response to Therapy.(Poster Session I: May 26, 2011, 11:45 BST). EULAR Congress 2011. Disclosure of Interest S. Lamberth Employee of: Janssen R & D, LLC, Y. Cherkas Employee of: Janssen R & D, LLC, C. Brodmerkel Employee of: Janssen R & D, LLC, M. Curran Employee of: Janssen R & D, LLC

Background Anemia of chronic inflammation is found in patients with rheumatoid arthritis (RA). Studies have found that RA patients with anemia are more likely to have more severe joint damage. 1 Hepcidin is a peptide hormone that regulates iron homeostasis, is elevated in anemic conditions, and is up-regulated by interleukin-6 (IL-6). IL-6 is also elevated in RA. Sirukumab (CNTO136), a human anti-IL-6 monoclonal antibody, was investigated for efficacy in a Phase 2b dose ranging study of patients with active RA despite concurrent methotrexate treatment. Objectives This analysis examines if sirukumab treatment had positive effects in RA patients anemic at baseline (week 0) by reducing hepcidin and increasing hemoglobin through week 12 of treatment. Methods Serum samples collected in the Ph2b study at week 0, day 5, week 2, and the pre-specified week 12 primary endpoint were analyzed for hepcidin, hemoglobin, and anemia-related markers (ferritin, iron, total iron biding capacity, unsaturated iron bind capacity). Patients were treated with SC placebo (PBO; n=30) or SC sirukumab 100 mg 2QW, 100 mg 4QW, 50 mg 4QW (n=30 for each arm), or 25 mg 4QW (n=31). Results The overall ACR 50 response at week 12 to sirukumab was 24.0% (PBO 3.3%). At week 0, 5/30 (16.7%) of PBO and 37/121 (30.6%) of sirukumab-treated patients were anemic. In the anemic patients, the mean week 0 hepcidin concentrations were 25.1 ng/mL in the PBO group, and 87.4 ng/mL in the sirukumab-treated patients. At week 12, the sirukumab-treated patients mean hepcidin concentration was significantly reduced to 38.1 ng/mL (p=0.0029), while the PBO mean hepcidin concentration was unchanged (31.4 ng/mL; p=0.6250). No dose-response of sirukumab on serum hepcidin concentration was seen. Hemoglobin levels in the anemic patients increased in the sirukumab-treated patients (10.6 g/dL at week 0; 11.8 g/dL at week 12; p Conclusions Sirukumab was effective in reducing serum concentrations of hepcidin through week 12 of treatment. Serum hemoglobin levels in anemic patients increased significantly following sirukumab treatment, with half of the patients normalizing hemoglobin levels. This indicates that in addition to demonstrating efficacy, treatment of RA patients with sirukumab may be effective in reversing inflammation-related anemia. References Peeters HR, et al. Ann Rheum Dis. 1996;55:162-168 Disclosure of Interest G. Toedter Employee of: Janssen Research & Development, LLC, S. Sague Employee of: Janssen Research & Development, LLC, X. Wu Employee of: Janssen Research & Development, LLC, M. Curran Employee of: Janssen Research & Development, LLC, B. Hsu Employee of: Janssen Research & Development, LLC

Bladder stones are a rare complication of pregnancy, with only 10 cases reported this century. This patient required a cesarean section for obstructed labor resulting from a 7 cm stone. Cystotomy with removal of the stone was performed with subsequent development of a vesicocutaneous fistula.

Background Asthma is a heterogeneous disease and development of novel therapeutics requires an understanding of pathophysiologic phenotypes. The purpose of the ADEPT study was to correlate clinical features and biomarkers with molecular characteristics, by profiling asthma (NCT01274507). This report presents for the first time the study design, and characteristics of the recruited subjects. Methods Patients with a range of asthma severity and healthy non-atopic controls were enrolled. The asthmatic subjects were followed for 12 months. Assessments included history, patient questionnaires, spirometry, airway hyper-responsiveness to methacholine, fractional exhaled nitric oxide (FENO), and biomarkers measured in induced sputum, blood, and bronchoscopy samples. All subjects underwent sputum induction and 30 subjects/cohort had bronchoscopy. Results Mild (n = 52), moderate (n = 55), severe (n = 51) asthma cohorts and 30 healthy controls were enrolled from North America and Western Europe. Airflow obstruction, bronchodilator response and airways hyperresponsiveness increased with asthma severity, and severe asthma subjects had reduced forced vital capacity. Asthma control questionnaire-7 (ACQ7) scores worsened with asthma severity. In the asthmatics, mean values for all clinical and biomarker characteristics were stable over 12 months although individual variability was evident. FENO and blood eosinophils did not differ by asthma severity. Induced sputum eosinophils but not neutrophils were lower in mild compared to the moderate and severe asthma cohorts. Conclusions The ADEPT study successfully enrolled asthmatics across a spectrum of severity and non-atopic controls. Clinical characteristics were related to asthma severity and in general asthma characteristics e.g. lung function, were stable over 12 months. Use of the ADEPT data should prove useful in defining biological phenotypes to facilitate personalized therapeutic approaches. Electronic supplementary material The online version of this article (doi:10.1186/s12931-015-0299-y) contains supplementary material, which is available to authorized users.