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ObjectiveIrritable bowel syndrome with diarrhoea (IBS-D) is a common and challenging condition that significantly reduces quality of life. Enterosgel (polymethylsiloxane polyhydrate) is an intestinal adsorbent which sequesters harmful molecules and is safe and effective in acute infective diarrhoea. This randomised controlled multicentre trial aimed to investigate its safety and efficacy in patients with IBS-D.DesignAfter a 2-week screening phase, participants were randomised into an 8-week double-blind phase, followed by an 8-week open-label and follow-up phase. Participants recorded stool consistency, pain and global symptoms in e-diaries and questionnaires. The primary outcome was the percentage of responders on a composite abdominal pain (≥30% decrease in the weekly score) and stool consistency (50% reduction in days per week with at least one stool of BSFS type 6 or 7) score during at least 4 weeks of the treatment period.Results440 patients with IBS-D were randomised to the double-blind phase with 393 continuing to the open-label phase. The Primary outcome responder rate by intention-to-treat for enterosgel versus placebo was 37.4% vs 24.3% (OR 1.95, NNT 8, p=0.002). Enterosgel also improved stool consistency (48.5% vs 32.5%, pConclusionEnterosgel is safe and effective in IBS-D, providing an alternative to the limited current treatment options.Trial registration numberISRCTN17149988.

Introduction Control status may be a useful tool to assess response to treatment at each clinical visit in COPD. Control status has demonstrated to have long-term predictive value for exacerbations, but there is no information about the short-term predictive value of the lack of control and changes in control status over time. Method Prospective, international, multicenter study aimed at describing the short-term (6 months) prognostic value of control status in patients with COPD. Patients with COPD were classified as controlled/uncontrolled at baseline and at 3,6-month follow-up visits using previously validated criteria of control. Moderate and severe exacerbation rates were compared between controlled and uncontrolled visits and between patients persistently controlled, uncontrolled and those changing control status over follow-up. Results A total of 267 patients were analyzed: 80 (29.8%) were persistently controlled, 43 (16%) persistently uncontrolled and 144 (53.7%) changed control status during follow-up. Persistently controlled patients were more frequently men, with lower (not increased) body mass index and higher FEV1(%). During the 6 months following an uncontrolled patient visit the odds ratio (OR) for presenting a moderate exacerbation was 3.41 (95% confidence interval (CI) 2.47–4.69) and OR = 4.25 (95%CI 2.48–7.27) for hospitalization compared with a controlled patient visit. Conclusions Evaluation of control status at each clinical visit provides relevant prognostic information about the risk of exacerbation in the next 6 months. Lack of control is a warning signal that should prompt investigation and action in order to achieve control status.

Rupert Jones,1– 3 Andrew Davis,1,2 Brooklyn Stanley,1,2 Steven Julious,4 Dermot Ryan,5 David J Jackson,6 David MG Halpin,7 Katherine Hickman,8 Hilary Pinnock,9 Jennifer K Quint,10 Kamlesh Khunti,11 Liam G Heaney,12 Phillip Oliver,4 Salman Siddiqui,13 Ian Pavord,14 David HM Jones,15 Michael Hyland,3,16 Lewis Ritchie,17 Pam Young,18 Tony Megaw,18 Steve Davis,19 Samantha Walker,20 Stephen Holgate,21 Sue Beecroft,22 Anu Kemppinen,1,2 Francis Appiagyei,1,2 Emma-Jane Roberts,1,2 Megan Preston,1,2 Antony Hardjojo,1,2 Victoria Carter,1,2 Marije van Melle,1,2 David Price1,2,17 1Optimum Patient Care, Cambridge, UK; 2Observational and Pragmatic Research Institute, Singapore, Singapore; 3Faculty of Health, University of Plymouth, Plymouth, UK; 4University of Sheffield, South Yorkshire, UK; 5Usher Institute, University of Edinburgh, Edinburgh, UK; 6Guy’s & St Thomas’ NHS Trust, School of Immunology & Microbial Sciences, King’s College London, London, UK; 7University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK; 8Bradford and Leeds Clinical Commissioning Group, Leeds, UK; 9Asthma UK Centre for Applied Research, Usher Institute, The University of Edinburgh, Edinburgh, UK; 10National Heart & Lung Institute, Imperial College London, London, UK; 11Diabetes Research Centre, University of Leicester, Leicester, UK; 12Wellcome-Wolfson Centre for Experimental Medicine, Queen’s University Belfast, Belfast, Northern Ireland; 13Institute for Lung Health, Leicester National Institute for Health Research Biomedical Research Centre, University of Leicester, Leicester, UK; 14Respiratory Medicine Unit and Oxford Respiratory NIHR BRC, Nuffield Department of Medicine, University of Oxford, Oxford, UK; 15Box Surgery, Wiltshire, UK; 16Plymouth Marjon University, Plymouth, UK; 17Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 18Wellbeing Software, Mansfield, UK; 19Interface Clinical Services, Leeds, UK; 20Asthma UK & British Lung Foundation, London, UK; 21Clinical and Experimental Sciences, University of Southampton, Southampton, UK; 22OPEN Health, Buckinghamshire, UKCorrespondence: David PriceAcademic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen, AB25 2ZD, UKTel +65 3105 1489Email dprice@opri.sgIntroduction: Symptoms may persist after the initial phases of COVID-19 infection, a phenomenon termed long COVID. Current knowledge on long COVID has been mostly derived from test-confirmed and hospitalized COVID-19 patients. Data are required on the burden and predictors of long COVID in a broader patient group, which includes both tested and untested COVID-19 patients in primary care.Methods: This is an observational study using data from Platform C19, a quality improvement program-derived research database linking primary care electronic health record data (EHR) with patient-reported questionnaire information. Participating general practices invited consenting patients aged 18– 85 to complete an online questionnaire since 7th August 2020. COVID-19 self-diagnosis, clinician-diagnosis, testing, and the presence and duration of symptoms were assessed via the questionnaire. Patients were considered present with long COVID if they reported symptoms lasting ≥ 4 weeks. EHR and questionnaire data up till 22nd January 2021 were extracted for analysis. Multivariable regression analyses were conducted comparing demographics, clinical characteristics, and presence of symptoms between patients with long COVID and patients with shorter symptom duration.Results: Long COVID was present in 310/3151 (9.8%) patients with self-diagnosed, clinician-diagnosed, or test-confirmed COVID-19. Only 106/310 (34.2%) long COVID patients had test-confirmed COVID-19. Risk predictors of long COVID were age ≥ 40 years (adjusted Odds Ratio [AdjOR]=1.49 [1.05– 2.17]), female sex (adjOR=1.37 [1.02– 1.85]), frailty (adjOR=2.39 [1.29– 4.27]), visit to A&E (adjOR=4.28 [2.31– 7.78]), and hospital admission for COVID-19 symptoms (adjOR=3.22 [1.77– 5.79]). Aches and pain (adjOR=1.70 [1.21– 2.39]), appetite loss (adjOR=3.15 [1.78– 5.92]), confusion and disorientation (adjOR=2.17 [1.57– 2.99]), diarrhea (adjOR=1.4 [1.03– 1.89]), and persistent dry cough (adjOR=2.77 [1.94– 3.98]) were symptom features statistically more common in long COVID.Conclusion: This study reports the factors and symptom features predicting long COVID in a broad primary care population, including both test-confirmed and the previously missed group of COVID-19 patients.Keywords: SARS-CoV-2, questionnaire, observational study, frailty, chronic diseases

David Price,1,2 Rupert Jones,3 Pascal Pfister,4 Hui Cao,5 Victoria Carter,6 Anu Kemppinen,6 Björn Holzhauer,4 Alan Kaplan,7 Allan Clark,8 David MG Halpin,9 Hilary Pinnock,10 James D Chalmers,11 Job FM van Boven,12 Kai M Beeh,13 Konstantinos Kostikas,14 Nicolas Roche,15 Omar Usmani,16 Paul Mastoridis5 1Observational and Pragmatic Research Institute, Singapore, Singapore; 2Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 3Faculty of Health, University of Plymouth, Plymouth, Devon, UK; 4Novartis Pharma AG, Basel, Switzerland; 5Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 6Observational and Pragmatic Research International Ltd, Stubbs House Stubbs Green, London, Norwich, UK; 7Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada; 8Norwich Medical School, University of East Anglia, Norwich, UK; 9University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK; 10Allergy and Respiratory Research Group, Usher Institute, University of Edinburgh, Edinburgh, UK; 11College of Medicine, University of Dundee, Dundee, UK; 12Department of Clinical Pharmacy & Pharmacology, Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 13Clinical Research, Insaf Respiratory Research Institute, Wiesbaden, Germany; 14Respiratory Medicine Department, University of Ioannina School of Medicine, Ioannina, Greece; 15Cochin Hospital and Institute, APHP Centre, University of Paris, Paris, France; 16National Heart & Lung Institute (NHLI), Imperial College London and Royal Brompton Hospital, London, UKCorrespondence: David PriceCentre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen, AB25 2ZD, UKTel +44 65 6962 3627Email dprice@opri.sgBackground: Poor treatment adherence in COPD patients is associated with poor clinical outcomes and increased healthcare burden. Personalized approaches for adherence management, supported with technology-based interventions, may offer benefits to patients and providers but are currently unproven in terms of clinical outcomes as opposed to adherence outcomes.Methods: Maximizing Adherence and Gaining New Information For Your COPD (MAGNIFY COPD study), a pragmatic cluster randomized trial, aims to evaluate the impact of an adherence technology package (interventional package), comprising an adherence review, ongoing provision of a dual bronchodilator but with an add-on inhaler sensor device and a connected mobile application. This will compare time to treatment failure and other clinical outcomes in patients identified at high risk of exacerbations with historic poor treatment adherence as measured by prescription collection to mono/dual therapy over one year (1312 patients) versus usual care. Treatment failure is defined as the first occurrence of one of the following: (1) moderate/severe COPD exacerbation, (2) prescription of triple therapy (inhaled corticosteroid/long-acting β2-agonist/long-acting muscarinic antagonist [ICS/LABA/LAMA]), (3) prescription of additional chronic therapy for COPD, or (4) respiratory-related death. Adherence, moderate/severe exacerbations, respiratory-related healthcare resource utilization and costs, and intervention package acceptance rate will also be assessed. Eligible primary care practices (N=176) participating in the Optimum Patient Care Quality Improvement Program will be randomized (1:1) to either adherence support cluster arm (suitable patients already receiving or initiated Ultibro® Breezhaler® [indacaterol/glycopyrronium] will be offered interventional package) or the control cluster arm (suitable patients continue to receive usual clinical care). Patients will be identified and outcomes collected from anonymized electronic medical records within the Optimum Patient Care Research Database. On study completion, electronic medical record data will be re-extracted to analyze outcomes in both study groups.Registration Number: ISRCTN10567920.Conclusion: MAGNIFY will explore patient benefits of technology-based interventions for electronic adherence monitoring.Keywords: adherence monitoring, applications, chronic obstructive pulmonary disease, medication adherence, pragmatic randomized clinical trial, technology

We aimed to compare clinical characteristics between Asian and Western chronic obstructive pulmonary disease (COPD) patients. This was a sub-analysis of an international, multicenter, prospective cohort study. Asian patients were enrolled in Singapore and South Korea. Western patients were enrolled in Spain, Poland, Ireland, the United Kingdom, and Malta. A total of 349 patients were analyzed. Among them, 110 (32%) patients were Asian and 239 (68%) Western. Male sex was more predominant in Asian than in Western (95% versus 63%, respectively; P

Background and objective The concept of clinical control in COPD has been developed to help in treatment decisions, but it requires validation in prospective studies. Methods This international, multicentre, prospective study aimed to validate the concept of control in COPD. Patients with COPD were classified as controlled/uncontrolled by clinical criteria or CAT scores at baseline and followed up for 18 months. The main outcome was the difference in rate of a composite endpoint of moderate and severe exacerbations or death over the 18-month follow-up period. Results A total of 307 patients were analysed (mean age = 68.6 years and mean FEV1% = 52.5%). Up to 65% and 37.9% of patients were classified as controlled by clinical criteria or CAT, respectively. Controlled patients had significantly less exacerbations during follow-up (by clinical criteria: 1.1 vs 2.6,P< 0.001; by CAT: 1.1 vs 1.9,P= 0.014). Time to first exacerbation was significantly prolonged for patients controlled by clinical criteria only (median: 93 days, IQR: 63; 242 vs 274 days, IQR: 221; 497 days;P< 0.001). Control status by clinical criteria was a better predictor of exacerbations compared to CAT criteria (AUC: 0.67 vs 0.57). Conclusion Control status, defined by easy-to-obtain clinical criteria, is predictive of future exacerbation risk and time to the next exacerbation. The concept of control can be used in clinical practice at each clinical visit as a complement to the current recommendations of initial treatment proposed by guidelines.

Background Irritable bowel syndrome (IBS) with diarrhoea (IBS-D) is a common and chronic condition that can significantly impair quality of life. The emergence of new drugs for IBS-D has been slow and there is a need for new treatments, including drug-free treatments, which are easy to use and suitable for different patient groups. Currently available drug-free treatments include Enterosgel®, an intestinal adsorbent approved for use in IBS-D and acute diarrhoea and available over-the-counter in the UK and 30 countries worldwide. The aim of this randomised, double-blind, placebo-controlled, multi-centre study is to test the efficacy and safety of Enterosgel® compared to placebo in symptomatic treatment in IBS-D. Methods/design We will recruit 430 participants with IBS-D from approximately 30 primary and secondary care sites in England. Participants meeting the required abdominal pain and stool consistency criteria over a 2-week screening period will be randomly allocated to receive blinded treatment (Enterosgel® or placebo) for 8 weeks. This will be followed by an 8-week open-label treatment phase with Enterosgel®. Participants will be allowed to adjust their daily dosage during both phases based on their symptoms. Participants will then return to standard care and those who responded to treatment will receive a follow-up call 8 weeks later. Co-medication with loperamide will be permitted and use recorded. The primary outcome measure is the percentage of participants defined as responders for abdominal pain and stool consistency during at least 4 weeks in the 8-week blinded phase. Secondary outcome measures include stool frequency, stool consistency, abdominal pain, bloating, urgency, adequate relief, questionnaire scores and rescue medication use. Exploratory outcomes will be assessed in subsets of participants including qualitative and quantitative data on faecal microorganisms and biomarkers and gut-related measurements from magnetic resonance imaging data. Discussion This is the first large scale randomised controlled trial investigating Enterosgel® in IBS-D. A study design with blinded phase followed by an open-label phase was chosen to encourage participation and study completion. Demonstrating that Enterosgel® is effective and safe in IBS-D could encourage adoption by patients and healthcare professionals and foster future clinical trials assessing its use in related conditions. Trial registration ISRCTN17149988. Prospectively registered on 14 November 2017.

BackgroundAcute intestinal infections are common conditions causing high morbidity and mortality especially in the young and elderly, resulting in a significant burden on health service resources and the economy. Current National Institute for Health and Care Excellence guidance are fluid and nutritional management; however, this does not reduce the duration of diarrhoea and the challenge of treating diarrhoea itself remains. We investigated the efficacy, tolerability and safety of intestinal adsorbent Enterosgel (polymethylsiloxane polyhydrate) compared with standard care in adults with acute diarrhoea.MethodsThis was a randomised controlled trial enrolling 105 subjects to receive the medical device Enterosgel up to six times daily for up to 8 days with standard care (oral rehydration solution), or standard care alone. The primary endpoint was the duration of diarrhoea (hours) from randomisation to first non-loose stool in the Enterosgel versus control group.ResultsA total of 51 subjects were randomised into the Enterosgel group and 54 into the control group, after excluding missing data, the data from 43 subjects in each group were analysed. Duration of diarrhoea was significantly shorter in the Enterosgel group at 27 hours versus 39 hours in the control group (HR was 1.74 [95% CI 1.06 to 2.87]) (p=0.03). This yielded a number needed to treat value of 5. Enterosgel was well tolerated and safe with no serious adverse events. One serious diarrhoea-related event resulting in hospitalisation was reported in the control group.ConclusionsEnterosgel treatment was associated with a significant reduction in the duration of diarrhoea in adults with patient-reported acute diarrhoea, compared with standard care. These findings support the role of Enterosgel in acute diarrhoea especially in vulnerable groups where rapid resolution of symptoms is required. Reduction in symptom duration could translate to less healthcare costs and socioeconomic burden.Trial registration numberISRCTN20758708

Background Guidelines recommend reducing treatment in patients with well-controlled asthma after 3 months of stability. However, there is inadequate real-life data to guide physicians on therapy change in daily practice. Objective To assess asthma control after change to and step-down of fluticasone propionate/formoterol fumarate dihydrate (FP/FOR) in real-life patients. Methods In a randomized controlled, pragmatic, open-label trial, 225 well-controlled patients with asthma were randomized (1:2) to maintain high-dose fluticasone propionate/salmeterol xinafoate (FP/SAL, 1000/100 μg) or switch to FP/FOR (1000/40 μg) daily for 12 weeks (phase 1). One hundred sixteen patients stable on FP/FOR at week 12 were subsequently randomized (1:1) to maintain this therapy, or stepped down to FP/FOR (500/20 μg) daily for 12 weeks (phase 2). The primary end point was the 7-question Asthma Control Questionnaire (ACQ7) score. Results In phase 1, FP/FOR (1000/40 μg) (n = 126) was noninferior to FP/SAL (1000/100 μg) (n = 73) for ACQ7 (difference in means, −0.12; 95% CI, −0.32 to 0.09). In phase 2, FP/FOR (500/20 μg) (n = 52) was noninferior to FP/FOR (1000/40 μg) (n = 52) for ACQ7 (difference in means, 0.01; 95% CI, −0.20 to 0.22). There was no significant difference in exacerbation rate between the groups in either phase. However, 1 to 2 exacerbations in 12 months before phase 1 were associated with the occurrence of an exacerbation after step-down ( P = .007). Conclusions In patients with well-controlled asthma, a change from FP/SAL to FP/FOR did not compromise asthma control. Step-down of FP/FOR was well tolerated; however, in contrast to current guidelines, our data suggest caution in stepping down patients uncontrolled in the last 12 months. Larger step-down studies are required to confirm these findings.

International audience; Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

The association between common variants in the FTO gene with weight, adiposity and body mass index (BMI) has now been widely replicated. Although the causal variant has yet to be identified, it most likely maps within a 47 kb region of intron 1 of FTO. We performed a genome-wide association study in the Sorbian population and evaluated the relationships between FTO variants and BMI and fat mass in this isolate of Slavonic origin resident in Germany. In a sample of 948 Sorbs, we could replicate the earlier reported associations of intron 1 SNPs with BMI (eg, P-value0.003, Β0.02 for rs8050136). However, using genome-wide association data, we also detected a second independent signal mapping to a region in intron 2/3 about 40-60 kb away from the originally reported SNPs (eg, for rs17818902 association with BMI P-value0.0006, Β0.03 and with fat mass P-value0.0018, Β0.079). Both signals remain independently associated in the conditioned analyses. In conclusion, we extend the evidence that FTO variants are associated with BMI by putatively identifying a second susceptibility allele independent of that described earlier. Although further statistical analysis of these findings is hampered by the finite size of the Sorbian isolate, these findings should encourage other groups to seek alternative susceptibility variants within FTO (and other established susceptibility loci) using the opportunities afforded by analyses in populations with divergent mutational and/or demographic histories. © 2010 Macmillan Publishers Limited All rights reserved.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Multiple sclerosis, the most common cause of progressive neurological disability in young adults, is a chronic inflammatory disease. There is solid evidence for a genetic influence in multiple sclerosis, and deciphering the causative genes could reveal key pathways influencing the disease. A genome region on rat chromosome 9 regulates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Using interval-specific congenic rat lines and association of single-nucleotide polymorphisms with inflammatory phenotypes, we localized the gene of influence to Vav1 , which codes for a signal-transducing protein in leukocytes. Analysis of seven human cohorts (12,735 individuals) demonstrated an association of rs2546133-rs2617822 haplotypes in the first VAV1 intron with multiple sclerosis (CA: odds ratio, 1.18; CG: odds ratio, 0.86; TG: odds ratio, 0.90). The risk CA haplotype also predisposed for higher VAV1 messenger RNA expression. VAV1 expression was increased in individuals with multiple sclerosis and correlated with tumor necrosis factor and interferon-γ expression in peripheral blood and cerebrospinal fluid cells. We conclude that VAV1 plays a central role in controlling central nervous system immune-mediated disease and proinflammatory cytokine production critical for disease pathogenesis.

Background Global Initiative for Asthma (GINA) guidelines recommend a gradual step-down of asthma therapy if asthma has been well-controlled for at least 3 months. In real life, however, many well-controlled patients are prescribed high doses of inhaled corticosteroids (ICS), and are therefore unnecessarily at risk of systemic side effects associated with long-term ICS use. To encourage and facilitate step-down in a clinical setting, further pragmatic studies are required to demonstrate that good control of asthma can be maintained with a lower dose of ICS in stable and controlled patients, and to explore potential predictors for response to step-down.To test if good control of asthma can be maintained in adult patients previously stable on Flutiform® 250 (250 mcg fluticasone/10 mcg formoterol) for 12 weeks, after step-down to Flutiform® 125 (250 mcg fluticasone/5 mcg formoterol).