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Background: It is unclear what impact iron deficiency has on fatigue in people with inflammatory bowel disease (IBD). This systematic review examined the evidence of whether iron deficiency, with or without anaemia, was associated with fatigue in IBD. Fatigue is a common symptom in patients with IBD that can be difficult to manage and treat. A greater understanding of the role and contribution of iron deficiency to fatigue may help improve the management of this condition. Methods: The databases searched were MEDLINE, OVID, CINAHL and Web of Science. Inclusion criteria were studies measuring iron status for iron deficiency (ID) and patient-reported outcome measures (PROMs) for fatigue in patients with IBD of any level of disease activity. Assessment of bias was conducted using the Newcastle Ottawa Scale. Studies were grouped for syntheses according to whether exposure was iron deficiency without anaemia (IDWA) or ID regardless of haemoglobin level. Results: Two hundred and eighty-five individual database results were identified and screened; 32 complete records were reviewed, from which seven studies with 1425 individuals were deemed eligible for inclusion in the results synthesis. Considerable variation in the methods and statistical analysis used to investigate the relationship between ID and fatigue prevented any quantitative synthesis. Studies varied by population disease activity levels, approaches used to define ID and PROMs used to measure fatigue. Three studies directly compared fatigue scores in IDWA to those not iron deficient, two of which showed patients with IDWA had significantly lower fatigue scores. Four studies used ID irrespective of anaemia as the exposure and reported mixed results on fatigue, with only one study reporting a higher prevalence of fatigue in the ID group. Conclusions: There was marked heterogeneity between studies in this review. Two studies found evidence of a slight increase in fatigue levels in patients with IDWA. Though this does not explain all fatigue in patients with IBD, iron replacement should be considered to improve fatigue in iron-deficient patients. [ABSTRACT FROM AUTHOR]

Background The IBD-Control Questionnaire is a simple, generic measure of patient-perceived disease control used increasingly in clinical practice and research. We aimed to address knowledge gaps in its psychometric performance, to ensure that it can be used with confidence in a variety of contexts. Methods We analysed 7341 responses to the IBD Registry COVID-19 survey, sent to 40 911 patients who completed an online self-assessment tool during the pandemic. Questions covered demographics, comorbidities, inflammatory bowel disease [IBD] sub-type, and IBD-Control Questionnaire and symptom scores [CD-PRO2 or UC-PRO2]. Psychometric properties of IBD-Control-8 were tested overall and within subgroups (Crohn's disease [CD], ulcerative colitis [UC] and IBD unclassified; male and female; ≤65 and >65 years; number of co-morbidities; deprivation status). Results Internal consistency was very strong overall [α: 0.84, ω: 0.89] and for each subgroup [α range: 0.81–0.85; ω: 0.86–0.90]. Construct validity was demonstrated by moderate correlation of each item with global rating [VAS] [ r s range: 0.47–0.65], strong correlation between IBD-Control-8 score and VAS [ r s = 0.74], moderate-to-strong with PRO2 scores [CD: r s = −0.718; UC: r s = −0.602] and significantly higher IBD-Control-8 scores for PRO2-remission vs PRO2-active, consistent across subgroups. Exploratory and confirmatory factor analyses demonstrated a two-factor model (items loading onto 'Health-related Quality of Life' [HRQoL] or 'Treatment' domains). Extensive tests for factorial invariance confirmed consistency. Conclusions IBD-Control-8 is a psychometrically robust scale which can be used across a range of populations. It offers a quick, reliable, and valid method of assessing patient-perceived control. The construct of 'control' includes traditional HRQoL and a novel domain relating to treatment perception. [ABSTRACT FROM AUTHOR]

Adults with Crohn's disease (CD) may be at risk of micronutrient insufficiency in clinical remission through restrictive eating, malabsorption, abnormal losses or inflammation. This systematic review synthesises the literature on micronutrient insufficiency in CD in clinical remission in terms of the prevalence of low circulating micronutrient concentrations and as a comparison against a healthy control (HC). Studies were included if the population was predominantly in remission. A total of 42 studies met the inclusion criteria; 12 were rated as low quality, leaving 30 studies covering 21 micronutrients of medium/high quality that were included in the synthesis. Vitamins D and B12 were the most frequently reported nutrients (8 and 11); there were few eligible studies for the remaining micronutrients. The prevalence studies were consistent in reporting individuals with low Vitamins A, B6, B12 and C, β-carotene, D, Magnesium, Selenium and Zinc. The comparator studies were inconsistent in finding differences with CD populations; Vitamin D, the most reported nutrient, was only lower than the HC in one-quarter of the studies. Adult CD populations are likely to contain individuals with low levels of one or more micronutrients, with the most substantial evidence for Vitamins D and B12. The studies on other micronutrients are of insufficient number, standardisation and quality to inform practice. [ABSTRACT FROM AUTHOR]

Author(s): N. Gehrels (corresponding author) [1]; C. L. Sarazin [2]; P. T. O'Brien [3]; B. Zhang [4]; L. Barbier [1]; S. D. Barthelmy [1]; A. Blustin [5]; D. N. Burrows [...]

Author(s): C. H. Blake [1]; J. S. Bloom (corresponding author) [1, 2]; D. L. Starr [13]; E. E. Falco [3]; M. Skrutskie [9]; E. E. Fenimore [7]; G. Duchêne [12]; [...]

Background and Aims Subcutaneous [SC] vedolizumab presents the opportunity for inflammatory bowel disease [IBD] patients to manage their treatment at home. There are currently no data on the process of transitioning patients established on intravenous [IV] to SC vedolizumab as part of routine clinical care. The aim of this programme is to evaluate the clinical and biochemical outcomes of switching a cohort of IBD patients established on IV vedolizumab to SC, at 12 weeks following the transition. Methods In all, 178 adult patients were offered the opportunity to transition to SC vedolizumab. Patients who agreed were reviewed prior to switching and at Week 12 [W12] after their first SC dose. Evaluation outcomes included disease activity scores, the IBD-Control Patient-Reported Outcome Measures [PROMs], and faecal calprotectin [FCP]. Reasons for patients declining or accepting transitioning, pharmacokinetics, adverse drug reactions, and risk factors for a poor outcome in SARS-CoV-2 infection were also assessed. Results A total of 124 patients agreed to transition, of whom 106 patients had been on IV vedolizumab for at least 4 months. There were no statistically significant differences in disease activity scores or IBD-Control PROMs between baseline and W12. A statistically significant increase in FCP was observed [31 µg/g vs. 47 µg/g; p = 0.008], although this was unlikely to be clinically relevant. The most common adverse drug reaction reported was injection site reactions [15%]. Based on this cohort of patients, an expected reduction of £572,000 per annum is likely to be achieved. Conclusions Transitioning patients established on IV vedolizumab to SC appears to be safe and effective, with high patient satisfaction and multiple benefits for the health service. [ABSTRACT FROM AUTHOR]

Primary non-response and secondary loss of response remain a significant issue with the currently available treatment options for a significant proportion of patients with inflammatory bowel disease (IBD). There are multiple unmet needs in the IBD treatment algorithm and new treatment options are required. As our understanding of the pathogenesis of IBD evolves, new therapeutic targets are being identified. The JAK-STAT pathway has been extensively studied. Tofacitinib, a JAK1 inhibitor, is now licensed for use in the induction and maintenance of ulcerative colitis and there are a large number of molecules currently under investigation. These new small molecule drugs (SMDs) will challenge current treatment pathways at a time when clinical therapeutic outcomes are rapidly evolving and becoming more ambitious. This is a review of the current JAK1 inhibitors in IBD including the current evidence from clinical trials. [ABSTRACT FROM AUTHOR]

Background Anti-TNF exposure has been linked to demyelination events. We sought to describe the clinical features of demyelination events following anti-TNF treatment and to test whether affected patients were genetically predisposed to multiple sclerosis [MS]. Methods We conducted a case-control study to describe the clinical features of demyelination events following anti-TNF exposure. We compared genetic risk scores [GRS], calculated using carriage of 43 susceptibility loci for MS, in 48 cases with 1219 patients exposed to anti-TNF who did not develop demyelination. Results Overall, 39 [74%] cases were female. The median age [range] of patients at time of demyelination was 41.5 years [20.7–63.2]. The median duration of anti-TNF treatment was 21.3 months [0.5-99.4] and 19 [36%] patients were receiving concomitant immunomodulators. Most patients had central demyelination affecting the brain, spinal cord, or both. Complete recovery was reported in 12 [23%] patients after a median time of 6.8 months [0.1–28.7]. After 33.0 months of follow-up, partial recovery was observed in 29 [55%] patients, relapsing and remitting episodes in nine [17%], progressive symptoms in three [6%]: two [4%] patients were diagnosed with MS. There was no significant difference between MS GRS scores in cases (mean -3.5 × 10–4, standard deviation [SD] 0.0039) and controls [mean -1.1 × 10–3, SD 0.0042] [ p = 0.23]. Conclusions Patients who experienced demyelination events following anti-TNF exposure were more likely female, less frequently treated with an immunomodulator, and had a similar genetic risk to anti-TNF exposed controls who did not experience demyelination events. Large prospective studies with pre-treatment neuroimaging are required to identify genetic susceptibility loci. [ABSTRACT FROM AUTHOR]

Background and Aims Mucosal healing is important in Crohn's disease therapies. Epithelial homeostasis becomes dysregulated in Crohn's, with increased permeability, inflammation, and diarrhoea. MicroRNAs are small non-coding RNAs that regulate gene expression and show changes in inflammatory bowel disease. Tumour necrosis factor alpha [TNFα] inhibitor protein 3 is raised in Crohn's and regulates TNFα-mediated activation of NFκB. We investigated TNFα regulation by microRNA in Crohn's disease [CD], and studied effects on epithelial permeability and inflammation. Methods Colonic epithelium from CD and healthy donor biopsies was isolated using laser capture microdissection, and microRNA was quantified. Tumour necrosis factor alpha inhibitor protein 3 was characterised immunohistochemically on serial sections. Expression effect of microRNA was confirmed with luciferase reporter assays. Functional barrier permeability studies and innate cytokine release were investigated with cell and explant culture studies. Results MicroRNA23a levels significantly increased in colonic Crohn's epithelium compared with healthy epithelium. Luciferase reporter assays in transfected epithelial cells confirmed that microRNA23a repressed expression via the 3' untranslated region of tumour necrosis factor alpha inhibitor protein 3 mRNA, coinciding with increased NFκB-mediated transcription. Immunohistochemical staining of TNFAIP3 protein in colonic biopsies was reduced or absent in adjacent Crohn's sections, correlating inversely with microRNA23a levels and encompassing some intercohort variation. Overexpression of microRNA23a increased epithelial barrier permeability in a colonic epithelial model and increased inflammatory cytokine release in cultured explant biopsies, mimicking Crohn's disease characteristics. Conclusions MicroRNA23a overexpression in colonic Crohn's epithelium represses tumour necrosis factor alpha inhibitor protein 3, enhancing sensitivity to TNFα, with increased intestinal permeability and cytokine release. [ABSTRACT FROM AUTHOR]

Symptomatic ulcerative colitis (UC) can be a chronic, disabling condition. Flares in disease activity are associated with many of the negative impacts of mild-to-moderate UC. Rapid resolution of flares can provide benefits to patients and healthcare systems. i Support Therapy-Access to Rapid Treatment (iSTART) introduces patient-centered care for mild-to-moderate UC. iSTART provides patients with the ability to self-assess symptomology and self-start a short course of second-line treatment when necessary. An international panel of experts produced consensus statements and recommendations. These were informed by evidence from systematic reviews on the epidemiology, mesalazine (5-ASA) treatment, and patient use criteria for second-line therapy in UC. Optimized 5-ASA is the first-line treatment in all clinical guidelines, but may not be sufficient to induce remission in all patients. Corticosteroids should be prescribed as second-line therapy when needed, with budesonide MMX® being a preferred steroid option. Active involvement of suitable patients in management of UC flares has the potential to improve therapy, with patients able to show good accuracy for flare self-assessment using validated tools. There is a place in the UC treatment pathway for an approach such as iSTART, which has the potential to provide patient, clinical and economic benefits. [ABSTRACT FROM AUTHOR]

Summary: Background: Iron deficiency has a high prevalence in inflammatory bowel disease (IBD) patients, with negative impact on quality of life and work capacity. Aim: To propose an innovative approach based on early intervention, treating to target and tight monitoring in the management of iron deficiency in IBD patients. Methods: We conducted a literature review on PubMed and Medline using pre‐defined keywords and terms to identify relevant studies on iron deficiency in IBD. Results: Many physicians are focused on treating anaemia; however, anaemia is one of the consequences of iron deficiency. Hence, our therapeutic goal for these patients should evolve towards prevention of anaemia by screening and treating iron deficiency. Early diagnosis of iron deficiency is based on a combination of ferritin concentration and transferrin saturation. We consider that normalisation of these biomarkers reflects iron stores replenishment and should be considered as a major therapeutic goal. Treating iron deficiency regardless of the presence of anaemia seems to improve quality of life in several chronic conditions and should be considered as an innovative approach in IBD although strong evidence is still lacking. Tight monitoring is required to allow early detection of iron deficiency recurrence and to consider prompt additional iron supplementation. Conclusion: We propose to extrapolate a three‐step strategy (early detection and intervention, treating‐to‐target and tight monitoring) to the management of iron deficiency in IBD patients. Universally applied, this proactive approach is expected to result in better outcomes in IBD patients. [ABSTRACT FROM AUTHOR]

Interleukin-13 (IL-13) is an important Type 2 T helper (Th2) cytokine, controlling biological functions in epithelium and has been linked to asthma, atopic dermatitis and ulcerative colitis (UC). Interleukin-13 signals through IL-13 receptor α-1 (IL13RA1 (gene) and IL13Rα1 (protein)), a receptor that can be regulated by microRNAs (miRs). MicroRNAs are small non-coding single-stranded RNAs with a role in several pathologies. However, their relevance in the pathophysiology of UC, a chronic inflammatory condition of the colonic mucosa, is poorly characterised. Here, we determined the expression of IL13Rα1 in UC, its potential regulation by miRs and the subsequent effect on IL-13 signalling. Inflamed mucosa of UC patients showed decreased mRNA and protein expression of IL13RA1 when compared to healthy controls. We show that miR-31 and miR-155 are upregulated in inflamed UC mucosa and that both directly target the 3' untranslated region of IL13RA1 mRNA. Transfection of miR-31 and miR-155 mimics reduced the expression of IL13RA1 mRNA and protein, and blocked IL-13-dependent phosphorylation of signal transducer and activator of transcription 6 (STAT6) in HT-29 cells, a gut epithelium cell line. Interleukin-13 activation of suppressor of cytokine signaling 1 (SOCS1) and eotaxin-3 (CCL26) expression was also diminished. MicroRNA-31/microRNA-155 mimics also downregulated IL13RA1 in ex vivo human inflamed UC biopsies. We propose that miR-31 and miR-155 have an important role in limiting IL-13 signalling in UC disease. [ABSTRACT FROM AUTHOR]

Introduction: Southampton General Hospital provides inflammatory bowel disease (IBD) services for a population of 650 000. Biological agents have impacted hugely on IBD but are costly drugs requiring careful supervision. These challenges led us to develop a specialist nurseled biologics service to improve patient care. Method: A 2010 case note audit highlighted areas for improvement in monitoring biologics and follow-up. A business case was developed to establish an IBD nurse to ensure identification and appropriate screening, education and review of biologics patients. A gain share was agreed with the local Care Commissioning Group (CCG) and £60 000 invested. Outcomes were reaudited in 2014. Results: Biologic use has grown rapidly from 90 patients in 2011 to 330 in 2014. All records are now kept in a centralised database. Infection screening improved from 79% to 100%. In 2014, 96% of patients had follow-up =4 months post-induction to assess response, but two patients were seen at 7 months. 80% were followed up again at 9-12 months (100% at 9-14 months), all with treatment decisions. The initial investment was recouped via commissioners funding 368 additional outpatient appointments and 35 colonoscopies. Savings represented 15% total yearly biologic costs. Conclusions: The introduction of the IBD biologics nurse-led service resulted in significant gains in care quality and costs. The need for improved follow-up of patients on biologics reflects increased pressures on clinic resources across the country. With continued biologics expansion, the introduction of a biologics nurse has provided invaluable support to patients and the IBD team at Southampton General Hospital. [ABSTRACT FROM AUTHOR]

The mechanism that causes the prompt-emission episode of gamma-ray bursts (GRBs) is still widely debated despite there being thousands of prompt detections. The favoured internal shock model relates this emission to synchrotron radiation. However, it does not always explain the spectral indices of the shape of the spectrum, which is often fit with empirical functions, such as the Band function. Multi-wavelength observations are therefore required to help investigate the possible underlying mechanisms that causes the prompt emission. We present GRB 121217A, for which we were able to observe its near-infrared (NIR) emission during a secondary prompt-emission episode with the Gamma-Ray burst Optical Near-infrared Detector (GROND) in combination with the Swift and Fermi satellites, which cover an energy range of 5 orders of magnitude (10-3 keV to 100 keV). We determine a photometric redshift of z = 3:1 ± 0:1 with a line-of-sight with little or no extinction (AV ∼ 0 mag) utilising the optical/NIR SED. From the afterglow, we determine a bulk Lorentz factor of Γ0 ∼ 250 and an emission radius of R < 1018 cm. The prompt-emission broadband spectral energy distribution is well fit with a broken power law with β1 = -0:3 ± 0:1 and β2 = 0:6 ± 0:1 that has a break at E = 6:6 ± 0:9 keV, which can be interpreted as the maximum injection frequency. Self-absorption by the electron population below energies of Ea < 6 keV suggest a magnetic field strength of B ∼ 105 G. However, all the best fit models underpredict the flux observed in the NIR wavelengths, which also only rebrightens by a factor of ∼2 during the second prompt emission episode, in stark contrast to the X-ray emission, which rebrightens by a factor of ∼100. This suggests an afterglow component is dominating the emission. We present GRB 121217A, one of the few GRBs that has multi-wavelength observations of the prompt-emission period and shows that it can be understood with a synchrotron radiation model. However, due to the complexity of the GRB's emission, other mechanisms that result in Band-like spectra cannot be ruled out. [ABSTRACT FROM AUTHOR]

The first Crohn's disease (CD) susceptibility gene identified was CARD15, which is a member of the emerging NOD-like receptor (NLR) family. These function as intracellular cystosolic pattern recognition receptors (PRRs) and play a central role in the innate immune response. We studied other members of the NLR family using a gene-wide haplotype tagging approach in a well-characterised collection of 547 CD patients and 465 controls. Four single nucleotide polymorphisms (SNPs) in NLRP3 had P values < 0.05 and are in high linkage disequilibrium (LD) with each other ( r2 > 0.90 for all four SNPs). rs4925648 and rs10925019 were the most strongly associated with CD susceptibility ( P = 0.001, odds ratio (OR) 1.62, 95% CI 1.2–2.18; and P = 6.5 × 10−4, OR 1.65, 95% CI 1.23–2.19, respectively). rs1363758 located in NLRP11 was associated with CD susceptibility [ P = 0.002 (1.64, 1.19–2.25)], which was weakly confirmed in an independent case–cohort collection on joint analysis [ P = 0.05, (1.28, 1–1.64)]. On sub-phenotype analysis, an interesting association between NLRP1 and skin extra-intestinal manifestations and colonic, inflammatory CD was identified. None of these results was replicated in the Wellcome Trust Case Control Consortium study and therefore need replication in a further large cohort. [ABSTRACT FROM AUTHOR]

We report here the development of a three-dimensional (3D) magnetic force microscope for applying forces to and measuring responses of biological systems and materials. This instrument combines a conventional optical microscope with a free-floating or specifically bound magnetic bead used as a mechanical probe. Forces can be applied by the bead to microscopic structures of interest (specimens), while the reaction displacement of the bead is measured. This enables 3D mechanical manipulations and measurements to be performed on specimens in fluids. Force is generated by the magnetically permeable bead in reaction to fields produced by external electromagnets. The displacement is measured by interferometry using forward light scattered by the bead from a focused laser beam. The far-field interference pattern is imaged on a quadrant photodetector from which the 3D displacement can be computed over a limited range about the focal point. The bead and specimen are mounted on a 3D translation stage and feedback techniques are used to keep the bead within this limited range. We demonstrate the system with application to beads attached to cilia in human lung cell cultures. [ABSTRACT FROM AUTHOR]