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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.

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).

Case–control studies are frequently employed as a means of testing for association between a disease of interest and candidate etiological risk factors. However, despite the apparent simplicity of this approach, spurious results are not uncommon1 and may easily arise if study design fails to avoid bias in the selection of study subjects.2 Because practical considerations mean that it is rarely possible to recruit cases and controls in an identical manner, it is usual to select study subjects from within a well-defined population, where exposure to the risk factor of interest is assumed to be distributed homogenously. However, bias may arise if the assumption of homogeneity is invalid, and subgroups that differ in the frequency of the candidate risk factor are concealed within the population from which cases and controls are drawn. In this situation, differences in ascertainment may result in biased representation of the relevant subgroups among the samples of cases and controls, thereby creating an apparent difference in exposure and a false-positive association. Furthermore, even if cases and controls are randomly selected from the whole population, false-positive associations may still occur if the frequency of the disease and of the candidate risk factor correlate across these subgroups (see the example from genetics below).3,4 Counterintuitively, such false-positive associations become increasingly more likely as sample size increases5; but do not occur (irrespective of sample size) if the study population is homogeneous with respect either to the frequency of the disease or to the candidate risk factor.4 In the analysis of month of birth, researchers have invariably assumed homogeneity within individual countries and have therefore felt justified in using averaged population statistics as controls. Here, we review the evidence that month of birth varies significantly with geographical location6–8 and over time8–11 in the normal population and consider the implication of this variation for case–control studies considering month of birth as a risk factor for the development of multiple sclerosis.

Background Although recent genome-wide association studies have identified several genetic variants contributing to the complex aetiology of multiple sclerosis (MS), expression and functional studies are required to further understand its molecular basis. Objectives To identify genes and pathways with differential expression in MS. Design The authors conducted a systematic review of seven microarray studies, in which expression in immune cells was compared between MS patients and controls. These studies include a previously unpublished study, which is described here in detail. Results and conclusion Although in general the overlap between studies was poor, 229 genes were found to be differentially expressed in MS in at least two studies, of which 11 were in three studies and HSPA1A in four studies. After excluding the authors' unpublished experiment which may have been affected by certain confounding factors and inclusion of treated subjects, 135 genes were identified in at least two studies. The differentially expressed genes were significantly associated with several immunological pathways, including interleukin (IL)-4, IL-6, IL-17 and glucocorticoid receptor signalling pathways. 15 of the 229 loci have shown some association with MS in published genome-wide association studies (p, Article summary Article focus To identify genes showing differential expression in multiple sclerosis through genome-wide expression profiling in peripheral blood mononuclear cells. To conduct a systematic review of genome-wide expression studies in multiple sclerosis in order to identify the most frequently reported genes. To identify pathways associated with genes most frequently reported as differentially expressed in multiple sclerosis. Key messages The vast majority of all genes reported as differentially expressed were only identified in a single study. However, 229 genes were reported as differentially expressed in MS to the same direction in at least two of the seven studies reviewed, 12 genes of which were in at least three studies. After excluding our unpublished experiment. which may have been affected by confounding factors and inclusion of treated subjects, 135 genes were identified in at least two studies. The differentially expressed genes were significantly associated with several immunological pathways, including the IL-4, IL-6, IL-17 and glucocorticoid receptor signalling pathways. Strengths and limitations of this study This is the first systematic review of genome-wide expression studies conducted in peripheral immune cells in multiple sclerosis. Strict criteria were applied for inclusion of studies, and clearly underpowered studies with fewer than 10 cases or controls were excluded. Many of the genes we found to be reported by at least two studies have interesting immunological functions and can be considered promising candidates for further studies. However, the studies included should not be considered directly comparable owing to differences in samples, platforms and analyses methods used. In addition, the majority of these studies are small and should be viewed with some caution. All studies were conducted in relatively heterogeneous cell populations, and some of the findings could therefore be explained by differences in numbers of different cell populations rather than differential transcriptional activity in MS. Finally, our previously unpublished microarray study may have been affected by differences between the labs where the patient and controls samples were prepared for arrays, as well as by the higher mean age of controls. Our study also included four patients who had received immunomodulatory treatment at the time of sample collection.

Background: The concept of clinical control in COPD has been developed to help in treatment decisions, but it requires validation in prospective studies. Method: This international, multicenter, prospective study aimed to validate the concept of control in COPD [ control = stability ( no exacerbations or impairment in CAT scores) + low impact ( low level of symptoms)]. Data from the screening visit was used to: investigate the level of control, compare characteristics of patients according to the control status, and perform a sensitivity analysis of the levels of control using either clinical criteria or questionnaires ( COPD Assessment Test -CAT- or Clinical COPD Questionnaire -CCQ-). Results: A total of 314 patients were analysed, mean age was 68.5 years and mean FEV1 was 52.6% of predicted. According to the prespecified criteria 21% of patients were classified as controlled, all of them with mild/moderate COPD ( Body mass index, Obstruction, Dyspnea and Exacerbations, -BODEx- index