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Irene Petersen,1,2 Catherine A Welch,3 Irwin Nazareth,1 Kate Walters,1 Louise Marston,1 Richard W Morris,4 James R Carpenter,5,6 Tim P Morris,5 Tra My Pham1 1Department of Primary Care and Population Health, University College London, London NW3 2PF, UK; 2Department of Clinical Epidemiology, Aarhus University, 8200 Aarhus N, Denmark; 3Department of Health Sciences, University of Leicester, Leicester LE1 7RH, UK; 4Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2PS, UK; 5MRC Clinical Trials Unit at UCL, London WC1V 6LJ, UK; 6Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK Background: Clinical databases are increasingly used for health research; many of them capture information on common health indicators including height, weight, blood pressure, cholesterol level, smoking status, and alcohol consumption. However, these are often not recorded on a regular basis; missing data are ubiquitous. We described the recording of health indicators in UK primary care and evaluated key implications for handling missing data.Methods: We examined the recording of health indicators in The Health Improvement Network (THIN) UK primary care database over time, by demographic variables (age and sex) and chronic diseases (diabetes, myocardial infarction, and stroke). Using weight as an example, we fitted linear and logistic regression models to examine the associations of weight measurements and the probability of having weight recorded with individuals’ demographic characteristics and chronic diseases.Results: In total, 6,345,851 individuals aged 18–99 years contributed data to THIN between 2000 and 2015. Women aged 18–65 years were more likely than men of the same age to have health indicators recorded; this gap narrowed after age 65. About 60–80% of individuals had their height, weight, blood pressure, smoking status, and alcohol consumption recorded during the first year of registration. In the years following registration, these proportions fell to 10%–40%. Individuals with chronic diseases were more likely to have health indicators recorded, particularly after the introduction of a General Practitioner incentive scheme. Individuals’ demographic characteristics and chronic diseases were associated with both observed weight measurements and missingness in weight.Conclusion: Missing data in common health indicators will affect statistical analysis in health research studies. A single analysis of primary care data using the available information alone may be misleading. Multiple imputation of missing values accounting for demographic characteristics and disease status is recommended but should be considered and implemented carefully. Sensitivity analysis exploring alternative assumptions for missing data should also be evaluated. Keywords: primary care, EHRs, recording, QOF, multiple imputation, statistics, epidemiology, research methods, data analysis

Manuj Sharma,1 Irwin Nazareth,1 Irene Petersen1,2 1Department of Primary Care and Population Health, University College London, London, UK; 2Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark Abstract: Observational studies which evaluate effectiveness are often viewed with skepticism owing to the fact that patients are not randomized to treatment, meaning that results are more prone to bias. Therefore, randomized controlled trials remain the gold standard for evaluating treatment effectiveness. However, it is not always possible to conduct randomized trials. This may be due to financial constraints, for example, in identifying funding for a randomized trial for medicines that have already gained market authorization. There can also be challenges with recruitment, for example, of people with rare conditions or in hard-to-reach population subgroups. This is why observational studies are still needed. In this manuscript, we discuss how researchers can mitigate the risk of bias in the most common type of observational study design for evaluation of treatment effectiveness, the cohort study. We outline some key issues that warrant careful consideration at the outset when the question is being developed and the cohort study is being designed. We focus our discussion on the importance of deciding when to start follow-up in a study, choosing a comparator, managing confounding and measuring outcomes. We also illustrate the application of these considerations in a more detailed case study based on an examination of comparative effectiveness of two antidiabetic treatments using data collected during routine clinical practice. Keywords: epidemiology, therapeutics, diabetes mellitus, public health, effectiveness

L Fardet,1–3 I Nazareth,1 I Petersen1 1Department of Primary Care and Population Health, University College London, UK; 2Department of Dermatology, Henri Mondor Hospital AP-HP, Créteil, France; 3Equipe d’Accueil 7379 EpiDermE, Université Paris Est Créteil, Créteil, France Background: Hydroxychloroquine and chloroquine may reduce the risk of cancer as they inhibit autophagy, in particular, in people with connective tissue diseases.Methods: The hazard ratios of cancers, metastases, and death were assessed in adults with connective tissue diseases prescribed hydroxychloroquine/chloroquine for at least 1 year in comparison with unexposed individuals with the same underlying conditions. A competing risk survival regression analysis was performed. Data were extracted from the Health Improvement Network UK primary care database.Results: Eight thousand nine hundred and ninety-nine individuals exposed to hydroxychloroquine (98.6%) or chloroquine (1.4%) and 24,118 unexposed individuals were included in the study (median age: 56 [45–66] years, women: 76.8%). When compared to the unexposed group, individuals exposed to hydroxychloroquine/chloroquine were not at lower risk of non-skin cancers (adjusted sub-distribution hazard ratio [sHR]: 1.04 [0.92–1.18], p=0.54), hematological malignancies (adjusted sHR: 1.00 [0.73–1.38], p=0.99), or skin cancers (adjusted sHR: 0.92 [0.78–1.07], p=0.26). The risk of metastasis was not significantly different between the two groups. However, it was significantly lower during the exposure period when compared with the unexposed (adjusted sHR: 0.64 [0.44–0.95] for the overall population and 0.61 [0.38–1.00] for those diagnosed with incident cancers). The risk of death was also significantly lower in those exposed to hydroxychloroquine/chloroquine (adjusted HR: 0.90 [0.81–1.00] in the overall population and 0.78 [0.64–0.96] in those diagnosed with incident cancer).Conclusion: Individuals on long-term exposure to hydroxychloroquine/chloroquine are not at lower risk of cancer. However, hydroxychloroquine/chloroquine may lower the risk of metastatic cancer and death. Keywords: antimalarial drugs, cancer, death, connective tissue diseases

Irene Petersen,1,2 Shuk-Li Collings,1,3 Rachel L McCrea,1 Irwin Nazareth,1 David P Osborn,4 Phil J Cowen,5 Cormac J Sammon1 1Department of Primary Care and Population Health, University College London, London, UK; 2Department of Clinical Epidemiology, Aarhus University, Aarhus N, Denmark; 3OXON Epidemiology, London, UK; 4Division of Psychiatry, University College London, London, UK; 5University Department of Psychiatry, Warneford Hospital, Oxford, UK Objective: The aim of this study was to examine the prevalence of major congenital malformations associated with antiepileptic drug (AED) treatment in pregnancy.Patients and methods: Using data from The Health Improvement Network, we identified women who have given live birth and their offspring. Four subgroups were selected based on the AED treatment in early pregnancy, valproate, carbamazepine, lamotrigine and women not receiving AED treatment. We compared the prevalence of major congenital malformations within children of these four groups and estimated prevalence ratios (PRs) using Poisson regression adjusted for maternal age, sex of child, quintiles of Townsend deprivation score and indication for treatment.Results: In total, 240,071 women were included in the study. A total of 229 women were prescribed valproate in pregnancy, 357 were prescribed lamotrigine and 334 were prescribed carbamazepine and 239,151 women were not prescribed AEDs. Fifteen out of 229 (6.6%) women prescribed valproate gave birth to a child with a major congenital malformation. The figures for lamotrigine, carbamazepine and women not prescribed AEDs were 2.7%, 3.3% and 2.2%, respectively. The prevalence of major congenital malformation was similar for women prescribed lamotrigine or carbamazepine compared to women with no AED treatment in pregnancy. For women prescribed valproate in polytherapy, the prevalence was fourfold higher. After adjustments, the effect of estimates attenuated, but the prevalence remained two- to threefold higher in women prescribed valproate.Conclusion: The results of our study suggest that lamotrigine and carbamazepine are safer treatment options than valproate in pregnancy and should be considered as alternative treatment options for women of childbearing potential and in pregnancy. Keywords: pregnancy, valproate, lamotrigine, carbamazepine, adverse drug effects

Manuj Sharma,1 Irene Petersen,1,2 Irwin Nazareth,1 Sonia J Coton,1 1Department of Primary Care and Population Health, University College London, London, UK; 2Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark Background: Research into diabetes mellitus (DM) often requires a reproducible method for identifying and distinguishing individuals with type 1 DM (T1DM) and type 2 DM (T2DM). Objectives: To develop a method to identify individuals with T1DM and T2DM using UK primary care electronic health records. Methods: Using data from The Health Improvement Network primary care database, we developed a two-step algorithm. The first algorithm step identified individuals with potential T1DM or T2DM based on diagnostic records, treatment, and clinical test results. We excluded individuals with records for rarer DM subtypes only. For individuals to be considered diabetic, they needed to have at least two records indicative of DM; one of which was required to be a diagnostic record. We then classified individuals with T1DM and T2DM using the second algorithm step. A combination of diagnostic codes, medication prescribed, age at diagnosis, and whether the case was incident or prevalent were used in this process. We internally validated this classification algorithm through comparison against an independent clinical examination of The Health Improvement Network electronic health records for a random sample of 500 DM individuals. Results: Out of 9,161,866 individuals aged 0–99 years from 2000 to 2014, we classified 37,693 individuals with T1DM and 418,433 with T2DM, while 1,792 individuals remained unclassified. A small proportion were classified with some uncertainty (1,155 [3.1%] of all individuals with T1DM and 6,139 [1.5%] with T2DM) due to unclear health records. During validation, manual assignment of DM type based on clinical assessment of the entire electronic record and algorithmic assignment led to equivalent classification in all instances. Conclusion: The majority of individuals with T1DM and T2DM can be readily identified from UK primary care electronic health records. Our approach can be adapted for use in other health care settings. Keywords: diabetes and endocrinology, epidemiology, public health, databases, algorithm

Aidan G O’Keeffe,1 Irwin Nazareth,2 Irene Petersen2 1Department of Statistical Science, 2Department of Primary Care and Population Health, University College London, London, UK Background: Statins are widely prescribed for the primary prevention of cardiovascular disease. Guidelines exist for statin prescriptions, but there is little recent analysis concerning prescription trends over time and how these vary with respect to demographic variables.Methods and results: Using The Health Improvement Network primary care database, statin therapy initiation and statin prescription prevalence rates were calculated using data from 7,027,711 individuals across the UK for the years 1995 to 2013, overall and stratified by sex, age group, and socioeconomic deprivation level (Townsend score). Statin therapy initiation rates rose sharply from 1995 (0.51 per 1,000 person-years) up to 2006 (19.83 per 1,000 person-years) and thereafter declined (10.76 per 1,000 person-years in 2013). Males had higher initiation rates than females and individuals aged 60–85 years had higher initiation rates than younger or more elderly age groups. Initiation rates were slightly higher as social deprivation level increased, after accounting for age and sex. Prescription prevalence increased sharply from 1995 (2.36 per 1,000 person-years) to 2013 (128.03 per 1,000 person-years) with males generally having a higher prevalence rate, over time, than females. Prevalence rates over time were generally higher for older age groups but were similar with respect to social deprivation level.Conclusion: The uptake of statins within UK primary care has increased greatly over time with statins being more commonly prescribed to older patients in general and, in recent years, males appear to have been prescribed statins at higher rates than females. After accounting for age and sex, the statin therapy initiation rate increases with the level of social deprivation. Keywords: cardiovascular disease, primary prevention, statin therapy, time trend, United Kingdom

Background: Hydroxychloroquine and chloroquine may reduce the risk of cancer as they inhibit autophagy, in particular, in people with connective tissue diseases. Methods: The hazard ratios of cancers, metastases, and death were assessed in adults with connective tissue diseases prescribed hydroxychloroquine/chloroquine for at least 1 year in comparison with unexposed individuals with the same underlying conditions. A competing risk survival regression analysis was performed. Data were extracted from the Health Improvement Network UK primary care database. Results: Eight thousand nine hundred and ninety-nine individuals exposed to hydroxychloroquine (98.6%) or chloroquine (1.4%) and 24,118 unexposed individuals were included in the study (median age: 56 [45-66] years, women: 76.8%). When compared to the unexposed group, individuals exposed to hydroxychloroquine/chloroquine were not at lower risk of non-skin cancers (adjusted sub-distribution hazard ratio [sHR]: 1.04 [0.92-1.18], p=0.54), hematological malignancies (adjusted sHR: 1.00 [0.73-1.38], p=0.99), or skin cancers (adjusted sHR: 0.92 [0.78-1.07], p=0.26). The risk of metastasis was not significantly different between the two groups. However, it was significantly lower during the exposure period when compared with the unexposed (adjusted sHR: 0.64 [0.44-0.95] for the overall population and 0.61 [0.38-1.00] for those diagnosed with incident cancers). The risk of death was also significantly lower in those exposed to hydroxychloroquine/chloroquine (adjusted HR: 0.90 [0.81-1.00] in the overall population and 0.78 [0.64-0.96] in those diagnosed with incident cancer). Conclusion: Individuals on long-term exposure to hydroxychloroquine/chloroquine are not at lower risk of cancer. However, hydroxychloroquine/chloroquine may lower the risk of metastatic cancer and death. [ABSTRACT FROM AUTHOR]

Background: Early detection could reduce the duration of untreated psychosis. GPs are a vital part of the psychosis care pathway, but find it difficult to detect the early features. An accurate risk prediction tool, P Risk, was developed to detect these., Aim: To externally validate P Risk., Design and Setting: This retrospective cohort study used a validation dataset of 1 647 934 UK Clinical Practice Research Datalink (CPRD) primary care records linked to secondary care records., Method: The same predictors (age; sex; ethnicity; social deprivation; consultations for suicidal behaviour, depression/anxiety, and substance misuse; history of consultations for suicidal behaviour; smoking history; substance misuse; prescribed medications for depression/anxiety/post-traumatic stress disorder/obsessive compulsive disorder; and total number of consultations) were used as for the development of P Risk. Predictive risk, sensitivity, specificity, and likelihood ratios were calculated for various risk thresholds. Discrimination (Harrell's C-index) and calibration were calculated. Results were compared between the development (CPRD GOLD) and validation (CPRD Aurum) datasets., Results: Psychosis risk increased with values of the P Risk prognostic index. Incidence was highest in younger age groups and, in the main, higher in males. Harrell's C was 0.79 (95% confidence interval = 0.78 to 0.79) in the validation dataset and 0.77 in the development dataset. A risk threshold of 1.0% gave sensitivity of 65.9% and specificity of 86.6%., Conclusion: Further testing is required, but P Risk has the potential to be used in primary care to detect future risk of psychosis., (© The Authors.)

Introduction: Smokeless tobacco (SLT) use in low- and middle-income countries has adverse health consequences. We hypothesize that it is feasible to test an intervention of mobile phone messages and face-to-face counseling sessions for SLT cessation in India., Aims and Methods: We conducted an exploratory, individual parallel two group, randomized controlled trial (RCT), with baseline and end-point (3 months from randomization) assessments in urban primary health centers in Odisha, India. A total of 250 current (i.e., users in the last 3 months) SLT users or dual users (ie, smokers and SLT users) were recruited to the trial (125 in each group). Participants were randomized to either routine care, face-to-face counseling, and reminder mobile messages or routine care only. The primary outcomes were to assess the feasibility of running a full RCT including recruitment, compliance, and retention., Results: A total of seven (77.8%) out of nine primary care centers took part in the trial. Out of the 315 SLT users invited to participate, 250 provided consent and were randomized [79.4% (95% CI: 74.5, 83.7)]. Out of the 250 randomized SLT users, 238 [95% (95% CI: 91.8, 97.5)] were followed up at 3 months (117 in the intervention group and 121 in the control group). Of the participants in the intervention group, 74 (63.8%) reported that they received the mobile messages., Conclusions: This exploratory trial demonstrated the feasibility of delivering and evaluating an intervention of mobile phone messages and face-to-face counseling for SLT users in Indian primary care in a full randomized trial., Implications: This study found that combining mobile messages with face-to-face counseling for smokeless tobacco users visiting primary health care settings in India is feasible in terms of recruitment of users, compliance with the intervention, and retention of study participants within the trial. The biochemically verified smokeless tobacco abstinence rate was higher in the intervention group compared with the control group. There was poor agreement between self-reported tobacco cessation and the measured salivary cotinine in smokeless tobacco users. The findings support the feasibility and acceptability of the intervention signaling the need for a larger clinical trial to test the effectiveness of the intervention., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Functional motor disorder-the motor variant of functional neurological disorder-is a disabling condition that is commonly associated with poor health outcomes. Pathophysiological models have inspired new treatment approaches such as specialist physiotherapy, although evidence from large randomised controlled trials is absent. We aimed to assess the clinical effectiveness of a specialist physiotherapy intervention for functional motor disorder compared with treatment as usual., Methods: In this pragmatic, multicentre, phase 3 randomised controlled trial at 11 hospitals in England and Scotland, adults with a clinically definite diagnosis of functional motor disorder, diagnosed by a neurologist, were included. Participants were randomly assigned (1:1, stratified by site) using a remote web-based application to either specialist physiotherapy (a protocolised intervention of nine sessions plus follow-up) or treatment as usual (referral to local community neurological physiotherapy). Individuals working on data collection and analysis were masked to treatment allocation. The primary outcome was the physical functioning domain of the 36-item short form health questionnaire (SF36) at 12 months after randomisation. The primary analysis followed a modified intention-to-treat principle, using a complete case approach; participants who were unable to receive their randomised treatment due to the suspension of health-care services during the COVID-19 pandemic were excluded from the primary analysis. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN56136713, and is completed., Findings: Recruitment occurred between Oct 19, 2018, and March 11, 2020, pausing during the COVID-19 lockdown, and resuming from Aug 3, 2021, to Jan 31, 2022. Of 355 participants who were enrolled, 179 were randomly assigned to specialist physiotherapy and 176 to treatment as usual. 89 participants were excluded from the primary analysis due to COVID-19 interruption to treatment (27 were assigned to specialist physiotherapy and 62 to treatment as usual). After accounting for withdrawals (n=11) and loss to follow-up (n=14), the primary analysis included data from 241 participants (138 [91%] assigned specialist physiotherapy and 103 [90%] assigned treatment as usual). Physical functioning, as assessed by SF36, did not differ significantly between groups (adjusted mean difference 3·5, 95% CI -2·3 to 9·3; p=0·23). There were no serious adverse events related to the trial interventions. 35 serious adverse events were recorded in the specialist physiotherapy group by 24 participants (17·0%), and 24 serious adverse events were recorded in the treatment as usual group by 18 participants (17·0%); one death occurred in the specialist physiotherapy group (cause of death was recorded as suicide). All were considered unrelated to specialist physiotherapy., Interpretation: Although more participants who were assigned specialist physiotherapy self-rated their motor symptoms as improved and had better scores on subjective measures of mental health, the intervention did not result in better self-reported physical functioning at 12 months. Both the specialist and community neurological physiotherapy appeared to be a safe and a valued treatment for selected patients with functional motor disorder. Future research should continue to refine interventions for people with functional motor disorder and develop evidence-based methods to guide treatment triage decisions., Funding: National Institute for Health and Care Research and Health Technology Assessment Programme., Competing Interests: Declaration of interests GN receives research funding from the National Institute for Health and Care Research (NIHR); is a founding member of the Functional Neurological Disorder Society (FNDS); and is on the advisory board for FND patient charities FND Hope UK and FND Action. LM and LHG receive research funding from the NIHR. MJE does medical expert reporting in personal injury and clinical negligence cases, including in cases of functional neurological disorder; has shares in Brain & Mind, which provides neuropsychiatric and neurological rehabilitation in the independent medical sector, including in people with functional neurological disorder; has received financial support for lectures from the International Parkinson's and Movement Disorders Society and the FNDS; receives royalties from Oxford University Press for his book The Oxford Specialist Handbook of Parkinson's Disease and Other Movement Disorder; has received honoraria for medical advice to Teva Pharmaceuticals; receives grant funding, including for studies related to functional neurological disorder, from the National Institute for Health and Care Research and the Medical Research Council; is an associate editor of the European Journal of Neurology; is a member of the international executive committee of the International Parkinson's and Movement Disorders Society and a board member of the FNDS; and is on the medical advisory boards of the charities functional neurological disorder (FND) Hope UK and Dystonia UK. JS reports honoraria from UptoDate, personal fees from Expert Witness Work and grants from National Research Scotland; runs a free self-help website, www.neurosymptoms.org, for patients with Functional Neurological Disorder; and is secretary of FNDS and on the medical advisory boards of the charities FND Hope UK and FND Action. IN has received research funding from NIHR, UK Research and Innovation, and the Wellcome Trust; and was a member of a data safety and monitoring board for a RCT of herbal medication for long COVID. MR has received research funding from Epilepsy Research UK, the NIHR; receives a salary from Elsevier as Editor-in-Chief of Seizure—European Journal of Epilepsy; has received honoraria for talks on unrelated subjects from Angelini Pharma and UCB Pharma; sits on a Lennox Gastaut Syndrome advisory board for UCB Pharma; and received payment from Precisis for chairing a data safety monitoring board of an unrelated commercial study. AC receives research funding from the NIHR, the Medical Research Council, Chief Scientist Office Scotland, and European Union (Etude Program); has received an honorarium from Forum for Indian Neurological Education; personal fees from expert testimony in medicolegal cases relating to FND; is president of the FNDS; and is paid Associate Editor of the Journal of Neurology, Neurosurgery and Psychiatry. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: We aimed to compare differences in suicidality and self-harm between specific lesbian, gay and bisexual (LGB) groups, and investigate whether minority stress factors might contribute to any associations, addressing methodological limitations of previous research., Methods: We analysed data combined from two population-based representative household surveys of English adults (N = 10,443) sampled in 2007 and 2014. Using multivariable logistic regression models adjusted for age, gender, educational attainment, area-level deprivation, and common mental disorder, we tested the association between sexuality and three suicide-related outcomes: past-year suicidal thoughts, past-year suicide attempt, and lifetime non-suicidal self-harm (NSSH). We added bullying and discrimination (separately) to final models to explore whether these variables might mediate the associations. We tested for interactions with gender and survey year., Results: Lesbian/gay people were more likely to report past-year suicidal thoughts [adjusted odds ratio (AOR) = 2.20; 95% CI 1.08-4.50] than heterosexuals. No minority group had an increased probability of suicide attempt. Bisexual (AOR = 3.02; 95% CI = 1.78-5.11) and lesbian/gay (AOR = 3.19; 95% CI = 1.73-5.88) individuals were more likely to report lifetime NSSH than heterosexuals. There was some evidence to support a contribution of bullying in the association between lesbian/gay identity and past-year suicidal thoughts, and of each minority stress variable in the associations with NSSH. There was no interaction with gender or survey year., Conclusion: Specific LGB groups are at elevated risk of suicidal thoughts and NSSH, with a possible contribution of lifetime bullying and homophobic discrimination. These disparities show no temporal shift despite apparent increasing societal tolerance towards sexual minorities., (© 2023. The Author(s).)

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disabling long-term condition of unknown cause. The National Institute for Health and Care Excellence (NICE) published a guideline in 2021 that highlighted the seriousness of the condition, but also recommended that graded exercise therapy (GET) should not be used and cognitive-behavioural therapy should only be used to manage symptoms and reduce distress, not to aid recovery. This U-turn in recommendations from the previous 2007 guideline is controversial.We suggest that the controversy stems from anomalies in both processing and interpretation of the evidence by the NICE committee. The committee: (1) created a new definition of CFS/ME, which 'downgraded' the certainty of trial evidence; (2) omitted data from standard trial end points used to assess efficacy; (3) discounted trial data when assessing treatment harm in favour of lower quality surveys and qualitative studies; (4) minimised the importance of fatigue as an outcome; (5) did not use accepted practices to synthesise trial evidence adequately using GRADE (Grading of Recommendations, Assessment, Development and Evaluations trial evidence); (6) interpreted GET as mandating fixed increments of change when trials defined it as collaborative, negotiated and symptom dependent; (7) deviated from NICE recommendations of rehabilitation for related conditions, such as chronic primary pain and (8) recommended an energy management approach in the absence of supportive research evidence.We conclude that the dissonance between this and the previous guideline was the result of deviating from usual scientific standards of the NICE process. The consequences of this are that patients may be denied helpful treatments and therefore risk persistent ill health and disability., Competing Interests: Competing interests: PW was a coauthor of trials of both graded exercise therapy and cognitive behaviour therapy, including the PACE trial, is a trustee of the Voluntary Hospital of St Bartholomew’s Charity, was a previous member of Independent Medical Experts Group, which advises the UK MoD on its Armed Forces Compensation Scheme, and receives personal consultancy fees from Swiss Re reinsurance company. BA was a centre leader in the PACE trial. AJC reports grants from NIHR (Physio 4 FMD) and CSO (Long Covid Cognitive phenotyping). AJC is a paid associate editor of JNNP and unpaid president elect of the Functional Neurological Disorders Society (FNDS), he gives expert testimony in court on a range of neuropsychiatric topics on a 50% claimant 50%: defender basis. He is the author of a self-help book based on CBT principles for treatment of FND (no royalties taken). DJC declares grants from Pfizer and Aptinyx; consulting fees from AbbVie, Allergan Sales, Heron Therapeutics, Eli Lilly and Company, Aptinyx, H. Lundbeck A/S, Neumentum, Pfizer, Regeneron Pharmaceuticals, Samumed, Swing Therapeutics, Tonix Pharmaceuticals, Virios Therapeutics. Fees from Fasken Martineau DuMoulin, Kellogg, Hansen, Todd, Figel & Frederick, PLLC, Marks & Clerk Law, Nix Patterson, Pfizer, Zuber Lawler & Del Duca. JC reports consulting fees from Bial, and honoraria from Janssen, Bial and Brittania. BAD reports NIH R13 infrastructure grant for 2022 Functional Neurological Disorders Society meeting in Boston. TC was co-investigator of several trials of behavioural interventions for CFS/ME, including the PACE trial, has received royalties for several books and book chapters on CFS/ME and received payments for workshops on CBT for CFS/ME. BAD is on the board of directors of the FNDS and receives royalties from Oxford University Press for 'Psychogenic Nonepileptic Seizures: Towards the Integration of Care'. She does paid consultancy for Bioserenity (EEG interpretations) and Best Doctors (clinical consultations). She received support to attend the American Epilepsy Society Board of Directors meeting in 2021. She chairs the data safety monitoring board of the DSMB NIH-ESETT trial 2015–2019, and received travel expenses to attend the American Epilepsy Society Board of Directors FNDS meeting and Epilepsy Foundation of New England PAB. MJE reports royalties from Oxford University Press for the book 'The Oxford Specialist Handbook of Movement Disorders', consulting fees from UCB (personal) and Merz Pharma (to his institution), honoraria from the International Parkinson’s Disease and Movement Disorder Society, medicolegal fees for personal injury and clinical negligence cases, support to attend meetings from the FNDS, leadership roles in International Parkinson’s Disease and Movement Disorder Society and Dystonia UK, and is a medical board member of FND Action and FND Hope, and board member of the FNDS. JE was the President of the Faculty of Sport and Exercise Medicine at the time of the Royal College of Physicians’ review of this guideline and submitted comments on behalf of the Faculty. He is Medical Director of a company which occasionally manages patients with CFS/ME. AJE has received grant support from the NIH and the Michael J Fox Foundation, personal compensation as a consultant/scientific advisory board member for Neuroderm, Neurocrine, Amneal, Acadia, Acorda, Bexion, Kyowa Kirin, Sunovion, Supernus (formerly, USWorldMeds), Avion Pharmaceuticals, and Herantis Pharma, and publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer. He received an honorarium from Avion. He cofounded REGAIN Therapeutics (a biotech start-up developing nonaggregating peptide analogues as replacement therapies for neurodegenerative diseases) and is co-owner of a patent that covers synthetic soluble nonaggregating peptide analogues as replacement treatments in proteinopathies. PF declares consulting fees from FADL Forlag, Munksgaard, Ny Nordisk Forlag and Arnold Busk, an honorarium from Lundbeck Pharma,and medicolegal fees from Retslægerådet. SF was a co-founding member of the GRADE working group and a member of the GRADE guidance group. She has been engaged in debates related to the evidence regarding CFS/ME for many years from a biopsychosocial perspective. PGlasziou declares an NHMRC Investigator Award: 'Neglected Problems in Health Care' supporting his salary; grants from the National Heart Foundation, Commonwealth Department of Health and WHO for work unconnected to this paper, and is a board member (unpaid) for Therapeutic Guidelines. IH has an NRS Fellowship from CSO, has been paid for medicolegal consultations, receives travel expenses for attending medical conferences and one honorarium from Bristol NHS Neurology Department, and is on the board of Fowler’s syndrome UK Charity. WH was a member of the 2007 NICE Guideline Development Group, and is Chief Medical Officer of LV=, an insurance company. PH was part of the steering committee of the German clinical practice guideline on functional somatic symptoms. MH reports fees for medicolegal expert court reports (none concern CFS/ME). HK reports grants from ZonMw, Stichting NKCV, MS Research, and Dutch Cancer Society, was coauthor of trials of cognitive behaviour therapy, reports royalties for a published treatment manual for CBT for fatigue in CFS/ME, and an honorarium for a lecture from Intercept Pharma Deutschland. A Lehn is an unpaid director of the FNDS. AL reports grants for investigator initiated research grants from Gilead Sciences, AbbVie and Sequiris. AM has been on a trial steering committee for a trial of graded exercise therapy, was formerly the Chair of the British Association for CFS and ME (BACME) and Principal Medical Adviser for Action for ME. IM has been paid honoraria by The@WorkPartnership for lectures on the occupational health management approach to managing long-term conditions (including CFS/ME) in the workplace, is the Academic Dean of the Faculty of Occupational Medicine and commented on the NICE guidelines on the management of CFS/ME on behalf of the Faculty. MM received an honorarium for a lecture in 2020 for ViiV, received financial support to attend the EACS 2021 conference (virtual) and ViiV EACS 2019 conference, and was a centre co-lead for the PACE trial. IN reports research grants received from NIHR and MRC to conduct clinical trials on complex interventions, not specific to CFS/ME, has served on several Data Safety Committee as an independent member for trials on complex interventions, one of which related to CFS/ME, and is Co-Chair of Wellcome Trust/Indian Alliance DBT Team Science Grant and Clinical and Public Health Research Centers Grants Committee. DLP reports grants from the National Institutes of Health and Sidney R. Baer Jr. Foundation for work unrelated to this paper, has received honoraria for continuing medical education lectures at Harvard Medical School and the American Academy of Neurology, royalties from Springer Nature for a textbook on Functional Movement Disorder, is a member of the Board of Directors of the FNDS, senior (paid) editor of Brain and Behavior and is an Editorial Board Member of Epilepsy & Behavior. WP reports occasional paid lectures pertaining to FND (most payments donated to charity), has received fees for expert testimony in court on a range of neurological topics including FND, is a board member of FND Hope and FND Action, and is on the board of directors of the BNPA. MR reports a grant from Elsevier, royalties from Oxford University Press, honoraria from UCB Pharma, LivaNova, Eisai, and Angellini and sits on a data safety monitoring board for IqVia Medtech. WR reports grants from the German Research Foundation, royalties from books and fees for German legal opinions. AS was a member of the 2007 NICE Guideline Development Group for CFS/ME (CG53)]. TS reports being a member of the Board of Directors and Membership and Liaisons Committee of the FNDS and being a member of the Functional Movement Disorders Study Group (Movement Disorders Society). MS was a co-principal investigator for the PACE trial and has led a trial of CBT for CFS/ME. He is current President of the European Association of Psychosomatic Medicine Current (unpaid) and was the previous President of the Academy of Consultation Liaison Psychiatry (unpaid). BS is a Council Member of the Association of British Neurologists and Medical Expert Committee member of FND Hope UK. JS reports grants from Scottish Government and NIHR; royalties from UptoDate, the Donald Baxter Lecture Award, Montreal, titled 'Multiple Sclerosis at the limits', personal fees from expert witness work, Secretary FNDS, Medical Advisor FND Hope, Medical Advisor FND Action, running a self-help website for patients with FND. DTW reports consulting fees for expert opinions on patients in a prolonged disorder of consciousness, fees for occasional medicolegal and personal injury cases, member of NIHR grant Programme Supervisory Committee of a trial of vocational rehabilitation after head injury, Deputy Secretary to British Society of Physical and Rehabilitation Medicine (unpaid) and is employed at a nursing home where he sees 2-3 patients with functional disorders. SCW reports honoraria from two talks on psychological impacts of COVID to Swiss Re during the pandemic, but neither covered CFS nor Long Covid. He is on the Board of the ESRC and am also a member of the Judicial Appointments Commission for which he receives renumeration. None are relevant to this paper. SCW is also on the Board of the South London and Maudsley Foundation NHS Trust for which he receives no renumeration. SCW reports receiving grants to research CFS and has published over 150 papers on this subject, including being an author on several RCTs relevant to this submission, but none within the last 36 months. VW is Head of the Collaborative on Fatigue Following Infection (COFFI) (unpaid). AZ reports fees for expert witness medicolegal reports, but not in cases specifically focused on CFS/ME. No other authors declared any relevant competing interests., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Many infancy-onset epilepsies have poor prognosis for seizure control and neurodevelopmental outcome. Ketogenic diets can improve seizures in children older than 2 years and adults who are unresponsive to antiseizure medicines. We aimed to establish the efficacy of a classic ketogenic diet at reducing seizure frequency compared with further antiseizure medicine in infants with drug-resistant epilepsy., Methods: In this phase 4, open-label, multicentre, randomised clinical trial, infants aged 1-24 months with drug-resistant epilepsy (defined as four or more seizures per week and two or more previous antiseizure medications) were recruited from 19 hospitals in the UK. Following a 1-week or 2-week observation period, participants were randomly assigned using a computer-generated schedule, without stratification, to either a classic ketogenic diet or a further antiseizure medication for 8 weeks. Treatment allocation was masked from research nurses involved in patient care, but not from participants. The primary outcome was the median number of seizures per day, recorded during weeks 6-8. All analyses were by modified intention to treat, which included all participants with available data. Participants were followed for up to 12 months. All serious adverse events were recorded. The trial is registered with the European Union Drug Regulating Authorities Clinical Trials Database (2013-002195-40). The trial was terminated early before all participants had reached 12 months of follow-up because of slow recruitment and end of funding., Findings: Between Jan 1, 2015, and Sept 30, 2021, 155 infants were assessed for eligibility, of whom 136 met inclusion criteria and were randomly assigned; 75 (55%) were male and 61 (45%) were female. 78 infants were assigned to a ketogenic diet and 58 to antiseizure medication, of whom 61 and 47, respectively, had available data and were included in the modifified intention-to-treat analysis at week 8. The median number of seizures per day during weeks 6-8, accounting for baseline rate and randomised group, was similar between the ketogenic diet group (5 [IQR 1-16]) and antiseizure medication group (3 [IQR 2-11]; IRR 1·33, 95% CI 0·84-2·11). A similar number of infants with at least one serious adverse event was reported in both groups (40 [51%] of 78 participants in the ketogenic diet group and 26 [45%] of 58 participants in the antiseizure medication group). The most common serious adverse events were seizures in both groups. Three infants died during the trial, all of whom were randomly assigned a ketogenic diet: one child (who also had dystonic cerebral palsy) was found not breathing at home; one child died suddenly and unexpectedly at home; and one child went into cardiac arrest during routine surgery under anaesthetic. The deaths were judged unrelated to treatment by local principal investigators and confirmed by the data safety monitoring committee., Interpretation: In this phase 4 trial, a ketogenic diet did not differ in efficacy and tolerability to a further antiseizure medication, and it appears to be safe to use in infants with drug-resistant epilepsy. A ketogenic diet could be a treatment option in infants whose seizures continue despite previously trying two antiseizure medications., Funding: National Institute for Health and Care Research., Competing Interests: Declaration of interests NES was supported for a research post by Vitaflo (International) and received grants from Nutricia Advanced Medical Nutrition, Vitaflo (International), and Matthew's Friends charity, and honoraria from Nutricia Advanced Medical Nutrition, Vitaflo (International), and Dr Schaer. SE, SJRH, and JHC report receiving grants from Vitaflo (International) and having a patent nutritional product (WO2013186570) and a patent anticonvulsant compound (WO2016038379A1) issued. JHC reports receiving honoraria from Nutricia and grants from GW Pharmaceuticals, Zogenix, Marinius, and Ovid. SJRH reports receiving consultancy fees and PhD studentship funding from Vitaflo (International). CE reports receiving honorarium from GW Pharmaceuticals/JAZZ Pharmaceuticals. HJT reports receiving honoraria from UCB Pharma, Nutricia, and GW Pharmaceuticals. SA reports receiving honorarium from Nutricia. AP reports receiving honorarium from Biomarin. EN reports receiving honorarium from Vitaflo (International). AD reports receiving consultancy fees from Nutricia and honoraria from Nutricia, GW Pharmaceuticals, and Zogenix. AAM reports receiving honoraria from LivaNova and Danone. NF reports receiving grants from the National Institute for Health and Care Research, the Medical Research Council, Cure Parkinson's Trust, and the European Union, consultancy fees from ALK, Sanofi Aventis, Gedeon Richter, Abbott, Galderma, AstraZeneca, Ipsen, Vertex, Thea, Novo Nordisk, Aimmune, and Ipsen, and honorarium from Abbott Singapore. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: With the growth in use of mobile messages for behaviour change, the need to incorporate personal needs and cultural characteristics of target users has been promoted. The study aimed to describe the findings of content validation of mobile messages designed to promote smokeless tobacco cessation in primary care., Methods: This study used a concurrent mixed-method approach with 13 patients who were tobacco users at urban primary care clinics. The clarity and appeal of 32 messages were rated on a Likert scale from 1 to 10. A mean clarity and appeal score per message was generated. A 5-item discussion guide was used for in-depth interviews and data was analysed using framework analysis., Results: Participants found the content of the messages useful, and preferred shorter and audio formatted messages. The clarity scores for the messages ranged from 7.9 to 9.4 with an average score of 8.7 (SD 0.5). The appeal scores ranged from 7.3 to 9.2, with an average score of 8.5 (SD 0.6)., Conclusions: Twenty-six from a total of 32 messages were found appropriate and finalised for use. This methodology can be used when developing contextually relevant mobile message interventions in other low resource settings.

Background: Cognitive behavioural therapy (CBT) is an effective treatment for depression. Self-directed online CBT interventions have made CBT more accessible at a lower cost. However, adherence is often poor and, in the absence of therapist support, effects are modest and short-term. Delivering CBT online using instant messaging is clinically and cost-effective; however, most existing platforms are limited to instant messaging sessions, without the support of between-session "homework" activities. The INTERACT intervention integrates online CBT materials and 'high-intensity' therapist-led CBT, delivered remotely in real-time. The INTERACT trial will evaluate this novel integration in terms of clinical and cost-effectiveness, and acceptability to therapists and clients., Methods: Pragmatic, two parallel-group multi-centre individually randomised controlled trial, with 434 patients recruited from primary care practices in Bristol, London and York. Participants with depression will be identified via General Practitioner record searches and direct referrals., Inclusion Criteria: aged ≥ 18 years; score ≥ 14 on Beck Depression Inventory (BDI-II); meeting International Classification of Diseases (ICD-10) criteria for depression., Exclusion Criteria: alcohol or substance dependency in the past year; bipolar disorder; schizophrenia; psychosis; dementia; currently under psychiatric care for depression (including those referred but not yet seen); cannot complete questionnaires unaided or requires an interpreter; currently receiving CBT/other psychotherapy; received high-intensity CBT in the past four years; participating in another intervention trial; unwilling/unable to receive CBT via computer/laptop/smartphone. Eligible participants will be randomised to integrated CBT or usual care. Integrated CBT utilises the standard Beckian intervention for depression and comprises nine live therapist-led sessions, with (up to) a further three if clinically appropriate. The first session is 60-90 min via videocall, with subsequent 50-min sessions delivered online, using instant messaging. Participants allocated integrated CBT can access integrated online CBT resources (worksheets/information sheets/videos) within and between sessions. Outcome assessments at 3-, 6-, 9- and 12-month post-randomisation. The primary outcome is the Beck Depression Inventory (BDI-II) score at 6 months (as a continuous variable). A nested qualitative study and health economic evaluation will be conducted., Discussion: If clinically and cost-effective, this model of integrated CBT could be introduced into existing psychological services, increasing access to, and equity of, CBT provision., Trial Registration: ISRCTN, ISRCTN13112900. Registered on 11/11/2020. Currently recruiting participants. Trial registration data are presented in Table 1., (© 2023. The Author(s).)