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Tham T Le,1 David B Price,2– 4 Clement Erhard,5 Bill Cook,6 Anna Quinton,7 Rohit Katial,8 George C Christoff,9 Luis Perez-de-Llano,10 Alan Altraja,11,12 Celine Bergeron,13 Arnaud Bourdin,14 Mariko Siyue Koh,15,16 Lauri Lehtimäki,17,18 Bassam Mahboub,19 Nikolaos G Papadopoulos,20,21 Paul Pfeffer,22,23 Chin Kook Rhee,24 Victoria Carter,2,3 Neil Martin,25,26 Trung N Tran1 On behalf of the EVEREST Study Working Group1BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD, USA; 2Observational and Pragmatic Research Institute, Singapore; 3Optimum Patient Care Global, Cambridge, UK; 4Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 5BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK; 6Respiratory and Immunology, BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD, USA; 7BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK; 8Global Medical Respiratory, BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD, USA; 9Faculty of Public Health, Medical University Sofia, Sofia, Bulgaria; 10Department of Respiratory Medicine, University Hospital Lucus Augusti, Lugo, Spain; 11Department of Pulmonology, University of Tartu, Tartu, Estonia; 12Lung Clinic, Tartu University Hospital, Tartu, Estonia; 13Centre for Lung Health, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada; 14PhyMedExp, University of Montpellier, CNRS, INSERM, University Hospital of Montpellier, Montpellier, France; 15Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore; 16Duke-NUS Medical School, Singapore; 17Allergy Centre, Tampere University Hospital, Tampere, Finland; 18Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; 19Rashid Hospital, Dubai Health Authority, Dubai, United Arab Emirates; 20Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK; 21Allergy Department, 2nd Pediatric Clinic, University of Athens, Athens, Greece; 22Department of Respiratory Medicine, Barts Health NHS Trust, London, UK; 23Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 24Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul, South Korea; 25Respiratory and Immunology, BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK; 26University of Leicester, Leicester, UKCorrespondence: Trung N Tran, BioPharmaceuticals Medical, Respiratory and Immunology, AstraZeneca, Gaithersburg, MD, USA, Email trung.tran1@astrazeneca.comIntroduction: Patients with severe asthma may be prescribed biologic therapies to improve disease control. The EVEREST study aimed to characterize the global disease burden of patients with severe asthma without access to biologics and those who have access but do not receive biologics, as well as the remaining unmet need despite use of these therapies.Methods: This was a historical cohort study of patients with severe asthma (aged ≥ 18 years) in the International Severe Asthma Registry receiving Global Initiative for Asthma (GINA) 2018 step 5 treatment, or with uncontrolled disease at GINA step 4. Prospective data on patient clinical characteristics, healthcare resource utilization, and medication use over a 12-month period between December 2017 and May 2022 were assessed for the following five groups: biologics accessible (omalizumab, mepolizumab, reslizumab, benralizumab, or dupilumab); biologics inaccessible; biologics accessible but not received; biologics accessible and received; and biologic recipients whose asthma remained suboptimally controlled.Results: Overall, 9587 patients from 21 countries were included. Among patients in the biologics accessible (n=5073), biologics inaccessible (n=3041), and biologics accessible but not received (n=382) groups, 41.4%, 18.7%, and 49.6% experienced at least two exacerbations, 11.5%, 10.5%, and 6.2% required at least one hospitalization, 47.9%, 54.6%, and 71.2% had uncontrolled asthma, and 23.9%, 8.6%, and 11.0% received long-term oral corticosteroids (LTOCS), respectively. Following biologic therapy, among patients who received biologics overall (n=2666) and among those whose asthma remained suboptimally controlled (n=1780), 19.1% and 23.0% experienced at least two exacerbations, 2.7% and 2.9% required at least one hospitalization, and 16.7% and 22.0% received LTOCS, respectively.Conclusion: There is a substantial disease burden in both patients without access to biologics and those with access who do not receive these therapies, although specific outcomes may vary between these groups. There also remains a high unmet need among biologic recipients, many of whom have a suboptimal response to treatment.Keywords: biologic, disease burden, healthcare resource utilization, severe asthma

The objective of this study was to create a North American e-cigarette, or electronic nicotine delivery system (ENDS), market map representative of the 2020 and 2021 commercial market for analysis of harmful and potentially harmful constituents (HPHCs) and other chemicals in aerosol. The study consisted of 14 brands (seven closed pod-based, four open (refillable) pod-based, two cigalike, one disposable) and analyzed multiple e-liquid formulations per brand with varying labelled nicotine concentrations and flavors, equating to 35 unique tested ENDS. Aerosol was generated using two puffing regimes (ISO 27068 and intense) and analyzed for primary constituents, metals, carbonyls, and glycidol in a head-to-head comparison in the same testing laboratory. Nicotine yields per puff ranged from 0.045 mg/puff for the lowest yielding ENDS under the ISO 27068 puffing regime to 1.11 mg/puff for the highest yielding ENDS under intense puffing conditions. For carbonyls, all ENDS generated quantifiable amounts of acetaldehyde, acrolein, and formaldehyde in collected aerosol, irrespective of puffing regime, with an increase in yields observed under intense puffing compared to ISO 27068 puffing for the majority of tested ENDS. For metals, the ENDS aerosol yielded nickel (Ni) ranging from below limits of detection (BLOD) to >30 ng/puff, while quantifiable levels of chromium (Cr), copper (Cu), and lead (Pb) were only associated with select ENDS. All tested ENDS aerosol contained quantifiable glycidol ranging from 0.003 to >1.00 µg/puff for ISO 20768 and 0.005 to 1.10 µg/puff for intense puffing regimes. As a category, ENDS aerosol showed significantly reduced levels of HPHCs compared to 1R6F combustible cigarette (CC) smoke on a per nicotine basis. However, there was variability among ENDS and the aerosol of some ENDS products produced increased levels of specific HPHCs (e.g., formaldehyde and nickel) compared to 1R6F CC smoke. The observed HPHC variations appear to be primarily dependent on device design. In summary, this work is one of the most comprehensive analyses of HPHCs for North American ENDS using validated analytical methods in the same test facility for a head-to-head comparison.

Michael J Cook,1 Basant K Puri2– 4 1Vis À Vis Symposiums, Bury St Edmunds, UK; 2CAR, Cambridge, UK; 3Department of Psychology, Neapolis University, Pafos, 8042, Cyprus; 4Faculty of Health and Wellbeing, University of Winchester, Winchester, UKCorrespondence: Michael J Cook, Email mcook98@msn.comAbstract: Human babesiosis is caused when erythrocytes are invaded by Babesia. Infection can occur from the bite of an infected tick, blood transfusion or congenitally. Issues related to the infecting species, symptomology and testing technology are discussed and the implications of accurate incidence and prevalence of the disease discussed. Human babesiosis is considered to be relatively rare in the UK. With a considerable number of non-specific symptoms and diagnostic testing limitations, it is probable that true positives are being missed. Based on co-infection data for Borrelia and Babesia from Rhode Island and Connecticut, and on Borrelia seropositivity data from northeastern France, the prevalence of babesiosis in those aged under 35 years, 35 to 44 years, 45 to 54 years and 55 years and over would be expected to be 0.6%, 1.8%, 2.8% and 3.5%, respectively. Based on the prevalence of infections in ticks and canines and a disease model previously published, it is estimated that the UK incidence of human babesiosis is likely to be approximately 18,500 cases per year.Keywords: Babesia, Babesia venatorum, lyme disease, coinfection, blood transfusion, serology testing

Sarah Cook,1 David Osborn,2,3 Arti Maini,1 Ravi Parekh,1 Shamini Gnani,1 Thomas Beaney,1 Ana Luisa Neves,1 Sonia Saxena,1 Jennifer K Quint1 1School of Public Health, Imperial College London, London, UK; 2Division of Psychiatry, University College London, London, UK; 3Camden and Islington NHS Foundation Trust, London, UKCorrespondence: Sarah Cook, White City Campus, Imperial College London, 9th Floor Michael Uren Building, London, W12 0BZ, UK, Email sarah.cook@imperial.ac.ukPurpose: Electronic health records (EHR) are valuable resources for health research; however, their use is challenging. A validated alcohol use disorder (AUD) codelist for UK primary care is needed to improve population-based research in this patient group. We aimed to develop an AUD codelist for use in the Clinical Practice Research Datalink (CPRD) Aurum database, a UK EHR primary-care database.Methods: The CPRD code browser was searched using keywords related to alcohol use using a previously developed search strategy. The resulting codes were categorised as AUD if they were: a) diagnostic of AUD, b) indicated alcohol withdrawal, or c) indicated chronic alcohol-related harm (physical or mental). Codes related to alcohol use but not used to define AUD were also classified into relevant categories (alcohol status, acute harm, and alcohol screening). All codes were categorised independently by at least two reviewers (one person reviewed all codes and five reviewers (all practising GPs) each reviewed a subset of codes (100– 200 codes each). Disagreements in categorisation were discussed by at least three coders and a consensus was reached. The reliability of categorisation was assessed using kappa statistics.Results: In total, 556 potential codes related to alcohol use were identified. The Kappa for reliability between coders was moderate for both AUD (0.72) and across all categories (0.62), with substantial variability between coders (AUD: 0.33– 0.97; all categories 0.36– 0.74). In the final codelist, 138 codes were included as indicating AUD: 38 codes identified which indicated diagnosis of AUD, 14 indicating withdrawal plus 85 codes indicating chronic alcohol-related harm (41 physical health and 44 mental health).Conclusion: Many codes are used in primary care to record alcohol use and associated harms, and there is substantial variability in how clinicians categorise them. While future work formally validating the codelist against gold standard clinical reviews and qualitative work with General Practitioners is needed for a deeper understanding of coding processes, we have documented here the process used for the development of an AUD codelist within primary care which can be used as a reference for future research.Keywords: alcohol use disorder, electronic health records, primary care, clinical practice research datalink

Eno Osode,1 Erica Cook,2 Ali Tomlin2 1Institute for Health Research, University of Bedfordshire, Luto, UK; 2School of Psychology, University of Bedfordshire, Luton, UKCorrespondence: Eno Osode, Institute for Health Research, University of Bedfordshire, Putteridge Bury, Hitchin Road, Luton, LU2 8LE, UK, Email Enoosode@yahoo.co.uk; Eno.osode@study.beds.ac.ukBackground: Evidence suggests that child maltreatment (CM) is associated with an elevated risk of adult diseases in later life. Emerging evidence shows that CM in childhood is associated with metabolic syndrome (MetS) in adulthood. However, no study has systematically examined the evidence. Hence, this review aims to synthesise the evidence on the association between forms of CM and MetS in adulthood.Methods: Electronic databases of CINAHL, Medline, PsychInfo, SOCINDEX, and Scopus were systematically searched using predefined key terms to identify relevant published studies on the association between CM and MetS from the beginning of indexing to 1st January 2024. Studies were included if they met the selection criteria. The quality of studies was appraised using suitable criteria for cross-sectional and prospective studies.Results: The search revealed a total of 2411 studies. Five studies met the inclusion criteria and were included in the review. The findings revealed that there was an association between physical abuse and MetS in women across two studies and one study in men. In addition, one study reported an association between emotional abuse and the risk of MetS in men, while two studies revealed increased odds with CM. However, no significant associations were reported between MetS and childhood sexual abuse and neglect, respectively.Conclusion: These findings suggest that some forms of CM may increase a person’s risk of having MetS. However, there is a need for methodological improvements due to heterogeneity in studies, mainly on the assessment and definition of CM. Further research is needed on forms of CM and MetS to understand the underlying mechanisms of the associations found and to identify targeted strategies to prevent the impact of CM on MetS and subsequent future health.Keywords: child maltreatment, metabolic syndrome, systematic review

Donna D Carstens,1 Diego J Maselli,2 Erin E Cook,3 Fan Mu,3 Jingyi Chen,3 Danni Yang,3 Jessica Karacz DeMartino,1 Yen Chung1 1Respiratory & Immunology, AstraZeneca, Wilmington, DE, USA; 2Division of Pulmonary Diseases & Critical Care, University of Texas Health, San Antonio, TX, USA; 3Health Economic and Outcomes Research, Analysis Group, Boston, MA, USACorrespondence: Jessica Karacz DeMartino, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE, 19897, USA, Tel +1 302-897-0843, Email jessica.demartino@astrazeneca.com

David Baldwin,1 Jonathan Carmichael,2 Gordon Cook,3 Neal Navani,4,5 James Peach,6 Ruth Slater,7 Pete Wheatstone,8 Julia Wilkins,7 Nicola Allen-Delingpole,9 Cicely EP Kerr,10 Khalid Siddiqui11 1Department of Respiratory Medicine, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; 2Department of Oncology, The National Institute for Health Research Leeds In Vitro Diagnostics Co-Operative (NIHR Leeds MIC), Leeds, UK; 3Cancer Research UK Trials Unit, LICTR, University of Leeds & NIHR (Leeds) IVD MIC, Leeds, UK; 4Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK; 5Department of Thoracic Medicine, University College London Hospital, London, UK; 6Human Centric Drug Discovery, Wood Centre for Innovation, Oxford, UK; 7Health Economics Unit, London, UK; 8Patient and Public Involvement and Engagement Group, DATA-CAN, London, UK; 9The Association of the British Pharmaceutical Industry, London, UK; 10Research Data Scotland, Bayes Centre, Edinburgh, UK; 11Janssen-Cilag Ltd, High Wycombe, UKCorrespondence: James Peach, Human Centric Drug Discovery, Wood Centre for Innovation, Quarry Road, Oxford, OX3 8SB, UK, Email james@humancentricdd.comAbstract: Duration of overall survival in patients with cancer has lengthened due to earlier detection and improved treatments. However, these improvements have created challenges in assessing the impact of newer treatments, particularly those used early in the treatment pathway. As overall survival remains most decision-makers’ preferred primary endpoint, therapeutic innovations may take a long time to be introduced into clinical practice. Moreover, it is difficult to extrapolate findings to heterogeneous populations and address the concerns of patients wishing to evaluate everyday quality and extension of life. There is growing interest in the use of surrogate or interim endpoints to demonstrate robust treatment effects sooner than is possible with measurement of overall survival. It is hoped that they could speed up patients’ access to new drugs, combinations, and sequences, and inform treatment decision-making. However, while surrogate endpoints have been used by regulators for drug approvals, this has occurred on a case-by-case basis. Evidence standards are yet to be clearly defined for acceptability in health technology appraisals or to shape clinical practice. This article considers the relevance of the use of surrogate endpoints in cancer in the UK context, and explores whether collection and analysis of real-world UK data and evidence might contribute to validation.Keywords: cancer, surrogate endpoints, real-world data, multiple myeloma, lung cancer, quality of life

Large language models (LLM) (e.g., ChatGPT) have garnered massive attention due to their potential to serve as interactive partners for a wide range of teaching and learning activities. In instructed second language acquisition, one potential use of LLMs is for pragmatics instruction. The current study sought to assess ChatGPT’s suitability for this task by analyzing its output in response to 144 DCTs (discourse completion tasks), which test a language learner’s ability to create apologies, requests, and refusals over differential levels of social and power distance, and degrees of imposition. Quantitatively, ChatGPT produced significantly shorter apologies than the other two speech acts (p < .001, R2 = .49), utilizing fewer pragmatic strategies (p < .001, R2 = .38). Closer social distance and greater imposition also resulted in longer responses, with higher imposition also eliciting ChatGPT to use more pragmatic strategies. Qualitatively, human raters scored ChatGPT’s apologies significantly lower in terms of their appropriateness, politeness, and language use, despite there being no statistical differences in ratings for requests and refusals. The main pedagogical implications are that, while ChatGPT offers an attractive option for students looking for more language exposure and interaction outside of the classroom, some degree of skepticism is still required due to its quantitative and qualitative inconsistencies.

Georgie M Massen,1 Hannah R Whittaker,1 Sarah Cook,1 Gisli Jenkins,2 Richard J Allen,3,4 Louise V Wain,3,4 Iain Stewart,2 Jennifer K Quint,1 On behalf of DEMISTIFI consortiumAndrew Thorley, Anna Duckworth, Ali-Reza Mohammadi-Nejad, Aloysious Aravinthan, Anthony Harbottle, Armando Mendez Villalon, Chris Scotton, Christopher Denton, Daniel Lea, Dorothee Auer, Ebrima Joof, Eleanor Cox, Elizabeth Eves, Elizabeth Robertson, Emma Blamont, Fasihul Khan, Georgie Massen, Gina Parcesepe, Gisli Jenkins, Gordon Moran, Guruprasad Aithal, Hilary Longhurst, Iain Stewart, Jane Paxton, Jennifer Quint, Karen Piper Hanley, Kate Frost, Leo Casmino, Lisa Chakrabarti, Louise Wain, Margot Roeth, Maria Kaisar, Martin Craig, Michael Nation, Mohammad Alireza Kisomi, Mujdat Zeybel, Neil Guha, Nicholas Selby, Nick Oliver, Nick Selby, Olivia C Leavy, Penny Gowland, Philip Quinlan, Rachel Chambers, Richard Allen, Richard Hubbard, Rob Slack, Rutger Ploeg, Sam Moss, Sara Fawaz, Scott Turner, Shauntelle Quammie, Simon Johnson, Stamatios N Sotiropoulos, Stuart Astbury, Susan Francis, Tom Giles, Valerie Quinn, Wendy Adams, Xin Chen, Zhendi Gong 1School of Public Health, Imperial College London, London, UK; 2National Heart and Lung Institute, Imperial College London, London, UK; 3Department of Population Health Sciences, University of Leicester, Leicester, UK; 4NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK; National Heart and Lung Institute, Imperial College London, London, United Kingdom; University of Exeter, Exeter, United Kingdom; Sir Peter Mansfield Imaging Centre, Mental Health and Clinical Neurosciences, School of Medicine, University of Nottingham, Nottingham NG7 2UH, United Kingdom; Institute for Health Research (NIHR) Nottingham Biomedical Research Ctr, Queens Medical Ctr, Nottingham, United Kingdom; Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK; Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; Patient and Public Involvement and Engagement, Nottingham University Hospitals, Nottingham, United Kingdom; Digital Research Service, University of Nottingham, Nottingham, United Kingdom; Department of Clinical and Biomedical Sciences, University of Exeter,Exeter, United Kingdom; Centre for Rheumatology, Royal Free Hospital and University College London, London, UK; Digital Research Service, University of Nottingham, Nottingham, United Kingdom; Mental Health & Clinical Neurosciences,School of Medicine, University ofNottingham, Nottingham, UK; Sir Peter Mansfield Imaging Centre,School of Medicine, University ofNottingham, Nottingham, UK; NIHR Nottingham Biomedical ResearchCentre, Queen’s Medical Centre,University of Nottingham, Nottingham,UK; School of Life Sciences, University of Nottingham, Nottingham, United Kingdom, 2National Public Health Laboratories; Ministry of Health and Social Welfare, Banjul, The Gambia; Sir Peter Mansfield Imaging Centre, School of Physics & Astronomy, University of Nottingham, Nottingham, UK; NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; Diabetes UK, UK; Diabetes UK, UK; Scleroderma and Raynaud’s UK, UK; Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester, UK; Imperial College London, London, United Kingdom; Department of Population Health Sciences, University of Leicester, Leicester, UK; NIHR Leicester Biomedical Research Centre, Leicester, UK; Gisli Jenkins, Margaret Turner Warwick Centre for Fibrosing Lung Disease, National Heart and Lung Institute, Imperial College London, United Kingdom; Gordon W. Moran, NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; Guruprasad P. Aithal, NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; Dyskeratosis Congenita (DC) Action, UK; National Heart and Lung Institute, Imperial College London, London, UK; Dyskeratosis Congenita (DC) Action, UK; National Heart and Lung Institute, Imperial College London, London, UK; Division of Gastroenterology and Hepatology, Manchester University NHS Foundation Trust, Manchester, UK; Patient and Public Involvement and Engagement, Nottingham University Hospitals, Nottingham, United Kingdom; Sarcoidosis UK, UK; School of Veterinary Medicine and Science, Sutton Bonington Campus, University of Nottingham, Nottingham, UK; Medical Research Council Versus Arthritis Centre for Musculoskeletal Ageing Research, Nottingham, UK; Department of Population Health Sciences, University of Leicester, Leicester, UK; NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK; University of Nottingham, Nottingham, UK; Nuffield Department of Surgical Sciences, University of Oxford; Sir Peter Mansfield Imaging Center, School of Medicine, University of Nottingham, Nottingham, UK ; Wellcome Centre for Integrative Neuroimaging, Nuffield Department of Clinical Neurosciences, University of Oxford, UK; Quantified Imaging, London, UK; Kidney Research UK, UK; Sir Peter Mansfield Imaging Centre, Mental Health and Clinical Neurosciences, School of Medicine, University of Nottingham, Nottingham NG7 2UH, United Kingdom; NationalInstitute for Health Research (NIHR) Nottingham Biomedical Research Ctr, Queens Medical Ctr, Nottingham, United Kingdom; NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, Nottingham, UK; NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; Centre for Kidney Research and Innovation, University of Nottingham, Royal Derby Hospital Campus,Derby, UK; Department of Medicine, Imperial College London, London, UK; Centre for Kidney Research and Innovation, School of Medicine, University of Nottingham; Department of Non-communicable Disease Epidemiology, The London School of Hygiene and Tropical Medicine, London, UK; Department of Health Sciences, University of Leicester,Leicester, UK; Universiy of Nottingham, Sir Peter Mansfield Imaging Centre, Nottingham, United Kingdom; The Digital Research Service, University of Nottingham, UK; Centre for Inflammation and Tissue Repair, University College London, London, UK; Department of Population Health Sciences, University of Leicester, Leicester, UK, 2NIHR Leicester Biomedical Research Centre, Leicester, UK; University of Nottingham, Nottingham, UK; Galecto, Stevenage, Hertfordshire, UK; Nuffield Department of Surgical Sciences, University of Oxford, and Biomedical Research Centre Oxford; Imperial College London, London, United Kingdom; University of Nottingham, Nottingham, UK; NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; University of Norringham, Nottingham, United Kingdom; Centre for Respiratory Research, NIHRRespiratory Biomedical Research Centre,School of Medicine, Biodiscovery Institute,University Park, University of Nottingham,Nottingham, UK; Sir Peter Mansfield Imaging Centre, School of Medicine, University of Nottingham, Nottingham, UK; Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford, UK; National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Queens Medical Centre, Nottingham, UK; Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK; NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; Sir Peter Mansfield Imaging Centre, School of Physics, University of Nottingham, UK; The Digital Research Service & The Advanced Data Analysis Centre, University of Nottingham, UK; Margaret Turner Warwick Centre for Fibrosing Lung Disease, National Heart and Lung Institute, Imperial College London, United Kingdom; Action for Pulmonary Fibrosis, United Kingdom; School of Computer Science, University of Nottingham, UK; School of Computer Science, University of Nottingham, UKCorrespondence: Georgie M Massen, Email g.massen21@imperial.ac.ukBackground: Electronic healthcare records (EHRs) are used to document diagnoses, symptoms, tests, and prescriptions. Though not primarily collected for research purposes, owing to the size of the data as well as the depth of information collected, they have been used extensively to conduct epidemiological research. The Clinical Practice Research Datalink (CPRD) is an EHR database containing representative data of the UK population with regard to age, sex, race, and social deprivation measures. Fibrotic conditions are characterised by excessive scarring, contributing towards organ dysfunction and eventual organ failure. Fibrosis is associated with ageing as well as many other factors, it is hypothesised that fibrotic conditions are caused by the same underlying pathological mechanism. We calculated the prevalence of fibrotic conditions (as defined in a previous Delphi survey of clinicians) as well as the prevalence of fibrotic multimorbidity (the proportion of people with multiple fibrotic conditions).Methods: We included a random sample of 993,370 UK adults, alive, and enrolled at a UK general practice, providing data to the CPRD Aurum database as of 1st of January 2015. Individuals had to be eligible for linkage to hospital episode statistics (HES) and ONS death registration. We calculated the point prevalence of fibrotic conditions and multi-morbid fibrosis on the 1st of January 2015. Using death records of those who died in 2015, we investigated the prevalence of fibrosis associated death. We explored the most commonly co-occurring fibrotic conditions and determined the settings in which diagnoses were commonly made (primary care, secondary care or after death).Results: The point prevalence of any fibrotic condition was 21.46%. In total, 6.00% of people had fibrotic multimorbidity. Of the people who died in 2015, 34.82% had a recording of a fibrotic condition listed on their death certificate.Conclusion: The key finding was that fibrotic multimorbidity affects approximately 1 in 16 people.Plain Language Summary: Fibrotic conditions are scarring conditions which impact the way an organ functions and eventually lead to organ failure. We studied routinely collected health data from GPs, hospitals, and death certificates to estimate the percentage of UK adults who had fibrotic diseases. We found that 1 in 5 people had at least one fibrotic disease, and we also found that 1 in 16 people had more than one fibrotic disease.Keywords: fibrosis, CPRD, electronic health records, multimorbidity, fibrotic multimorbidity, ONS

George M Anderson,1,2 Edwin H Cook,3 Randy D Blakely,4 James S Sutcliffe,5,6 Jeremy Veenstra-VanderWeele7,8 1Yale Child Study Center, Yale University School of Medicine, New Haven, CT, USA; 2Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA; 3Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA; 4FAU Stiles-Nicholson Brain Institute, Department of Biomedical Science, Florida Atlantic University, Jupiter, FL, USA; 5Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA; 6Department of Psychiatry & Behavioral Sciences, Vanderbilt University, Nashville, TN, USA; 7Department of Psychiatry, College of Medicine, Columbia University, New York, NY, USA; 8New York State Psychiatric Institute, Columbia University, New York, NY, USACorrespondence: George M Anderson, Yale Child Study Center, 230 S. Frontage Road, New Haven, CT, USA, Email george.anderson@yale.eduAbstract: We believe there are serious problems with a recently published and highly publicized paper entitled “Serotonin reduction in post-acute sequelae of viral infection.” The blood centrifugation procedure reportedly used by Wong et al would produce plasma that is substantially (over 95%) depleted of platelets. Given this, their published mean plasma serotonin values of 1.2 uM and 2.4 uM for the control/contrast groups appear to be at least 30 to 60 times too high and should be disregarded. The plasma serotonin values reported for the long COVID and viremia patients also should be disregarded, as should any comparisons to the control/contrast groups. We also note that the plasma serotonin means for the two control/contrast groups are not in good agreement. In the “Discussion” section, Wong et al state that their results tend to support the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of COVID-19, and they encourage further clinical trials of SSRIs. While they state that, “Our animal models demonstrate that serotonin levels can be restored and memory impairment reversed by precursor supplementation or SSRI treatment”, it should be noted that no data are presented showing an increase or restoration in circulating serotonin with SSRI administration. In fact, one would expect a marked decline in platelet serotonin due to SSRIs’ effective inhibition of the platelet serotonin transporter. Wong et al hypothesize that problems of long COVID arise from too little peripheral serotonin. However, given the frequent presence of a hyperaggregation state in long COVID, and the known augmenting effects of platelet serotonin on platelet aggregation, it is plausible to suggest that reductions in platelet serotonin might be associated with a lessening of the cardiovascular sequelae of COVID-19.Keywords: serotonin, COVID-19, plasma, platelets, long COVID, viral infection

Sara Hatam,1,&ast; Sean Timothy Scully,2,&ast; Sarah Cook,3,&ast; Hywel T Evans,2,&ast; Alastair Hume,4 Constantinos Kallis,3 Ian Farr,2 Chris Orton,2 Aziz Sheikh,1 Jennifer K Quint3 1Usher Institute, The University of Edinburgh, Edinburgh, UK; 2Population Data Science, Swansea University Medical School, Swansea, UK; 3School of Public Health, Imperial College London, London, UK; 4EPCC, The University of Edinburgh, Edinburgh, UK&ast;These authors contributed equally to this workCorrespondence: Jennifer K Quint, Email j.quint@imperial.ac.ukBackground: Electronic healthcare records (EHRs) are an important resource for health research that can be used to improve patient outcomes in chronic respiratory diseases. However, consistent approaches in the analysis of these datasets are needed for coherent messaging, and when undertaking comparative studies across different populations.Methods and Results: We developed a harmonised curation approach to generate comparable patient cohorts for asthma, chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) using datasets from within Clinical Practice Research Datalink (CPRD; for England), Secure Anonymised Information Linkage (SAIL; for Wales) and DataLoch (for Scotland) by defining commonly derived variables consistently between the datasets. By working in parallel on the curation methodology used for CPRD, SAIL and DataLoch for asthma, COPD and ILD, we were able to highlight key differences in coding and recording between the databases and identify solutions to enable valid comparisons.Conclusion: Codelists and metadata generated have been made available to help re-create the asthma, COPD and ILD cohorts in CPRD, SAIL and DataLoch for different time periods, and provide a starting point for the curation of respiratory datasets in other EHR databases, expediting further comparable respiratory research.Keywords: COPD, asthma, ILD, HER, harmonisation, data curation