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Intravenous immunoglobulin treatment for encephalitis in children aged 6 months to 16 years: the IgNiTE RCT
Background There are data suggesting that intravenous immunoglobulin treatment has some benefit for certain forms of encephalitis but robust evidence from large randomised controlled trials in children with all-cause encephalitis is lacking. Objective To evaluate whether intravenous immunoglobulin treatment improves neurological outcomes in childhood encephalitis when given early in the illness. Design Phase 3b, investigator-initiated, randomised, double-blind, placebo-controlled trial of intravenous immunoglobulin for the treatment of encephalitis in children. Setting Twenty-one NHS Hospitals in the UK. Participants Children aged 6 months to 16 years with a diagnosis of acute or sub-acute encephalitis. Intervention Two doses (1 g/kg/dose) of either intravenous immunoglobulin or matching placebo, given 24–36 hours apart, in addition to standard treatment. Main outcome measure Participants were followed up for 12 months (+/– 4 weeks) after randomisation. The primary outcome measure was a ‘good recovery’ defined as a score of ≤ 2 on the Paediatric Glasgow Outcome Score Extended at 12 months after randomisation. Secondary outcomes The secondary outcomes were clinical, neurological, neuroimaging and neuropsychological results, identification of the proportion of children with immune-mediated encephalitis, and intravenous immunoglobulin safety data. Results We planned to recruit 308 children over a 42-month period. After enrolment of 18 participants (8 male; 44%) over 21 months (from December 2015 to September 2017), funding was withdrawn due to slow recruitment and the study was terminated. Ten participants were randomised to the intravenous immunoglobulin group, and eight to the placebo group, and all 18 participants were included in the analysis. At 12 months after randomisation, 9 participants [50%; intravenous immunoglobulin n = 5 (50%), placebo n = 4 (50%)] made good recovery and 5 participants [28%; intravenous immunoglobulin n = 3 (30%), placebo n = 2 (25%)] made a poor recovery. Three participants in the placebo group (43%) experienced a total of 10 serious adverse events compared with none in the intravenous immunoglobulin group but none of the adverse events were judged to be related to the study treatment. No deaths occurred during the study period. Conclusion ImmunoglobuliN in the Treatment of Encephalitis (IgNiTE) was halted prematurely due to slow recruitment. Given the small sample size, the study was underpowered to evaluate the effect of intravenous immunoglobulin when compared with placebo in childhood encephalitis. The study findings, albeit from a small sample size, support existing evidence that encephalitis results in poor neurological outcomes for many children. Lessons learned from the ImmunoglobuliN in the Treatment of Encephalitis trial would be valuable for the success of future trials set up to address the efficacy of early treatment with intravenous immunoglobulin in all-cause encephalitis in children. Study limitations and future work The study was underpowered to evaluate the efficacy of intravenous immunoglobulin in the treatment of childhood encephalitis due to the small sample size achieved. Future trials should seek to address this important question. Trial registration This trial is registered as Clinical Trials.gov (NCT02308982) and ISRCTN15791925. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/212/15) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 6. See the NIHR Funding and Awards website for further award information.
Evaluating the efficacy and mechanisms of a ketogenic diet as adjunctive treatment for people with treatment-resistant depression: A protocol for a randomised controlled trial
Background: One-third of people with depression do not respond to antidepressants, and, after two adequate courses of antidepressants, are classified as having treatment-resistant depression (TRD). Some case reports suggest that ketogenic diets (KDs) may improve some mental illnesses, and preclinical data indicate that KDs can influence brain reward signalling, anhedonia, cortisol, and gut microbiome which are associated with depression. To date, no trials have examined the clinical effect of a KD on TRD. Methods: This is a proof-of-concept randomised controlled trial to investigate the efficacy of a six-week programme of weekly dietitian counselling plus provision of KD meals, compared with an intervention involving similar dietetic contact time and promoting a healthy diet with increased vegetable consumption and reduction in saturated fat, plus food vouchers to purchase healthier items. At 12 weeks we will assess whether participants have continued to follow the assigned diet. The primary outcome is the difference between groups in the change in Patient Health Questionnaire-9 (PHQ-9) score from baseline to 6 weeks. PHQ-9 will be measured at weeks 2, 4, 6 and 12. The secondary outcomes are the differences between groups in the change in remission of depression, change in anxiety score, functioning ability, quality of life, cognitive performance, reward sensitivity, and anhedonia from baseline to 6 and 12 weeks. We will also assess whether changes in reward sensitivity, anhedonia, cortisol awakening response and gut microbiome may explain any changes in depression severity. Discussion: This study will test whether a ketogenic diet is an effective intervention to reduce the severity of depression, anxiety and improve quality of life and functioning ability for people with treatment-resistant depression.
Identification of patients undergoing chronic kidney replacement therapy in primary and secondary care data: validation study based on OpenSAFELY and UK Renal Registry.
OBJECTIVE: To validate primary and secondary care codes in electronic health records to identify people receiving chronic kidney replacement therapy based on gold standard registry data. DESIGN: Validation study using data from OpenSAFELY and the UK Renal Registry, with the approval of NHS England. SETTING: Primary and secondary care electronic health records from people registered at 45% of general practices in England on 1 January 2020, linked to data from the UK Renal Registry (UKRR) within the OpenSAFELY-TPP platform, part of the NHS England OpenSAFELY covid-19 service. PARTICIPANTS: 38 745 prevalent patients (recorded as receiving kidney replacement therapy on 1 January 2020 in UKRR data, or primary or secondary care data) and 10 730 incident patients (starting kidney replacement therapy during 2020), from a population of 19 million people alive and registered with a general practice in England on 1 January 2020. MAIN OUTCOME MEASURES: Sensitivity and positive predictive values of primary and secondary care code lists for identifying prevalent and incident kidney replacement therapy cohorts compared with the gold standard UKRR data on chronic kidney replacement therapy. Agreement across the data sources overall, and by treatment modality (transplantation or dialysis) and personal characteristics. RESULTS: Primary and secondary care code lists were sensitive for identifying the UKRR prevalent cohort (91.2% (95% confidence interval (CI) 90.8% to 91.6%) and 92.0% (91.6% to 92.4%), respectively), but not the incident cohort (52.3% (50.3% to 54.3%) and 67.9% (66.1% to 69.7%)). Positive predictive values were low (77.7% (77.2% to 78.2%) for primary care data and 64.7% (64.1% to 65.3%) for secondary care data), particularly for chronic dialysis (53.7% (52.9% to 54.5%) for primary care data and 49.1% (48.0% to 50.2%) for secondary care data). Sensitivity decreased with age and index of multiple deprivation in primary care data, but the opposite was true in secondary care data. Agreement was lower in children, with 30% (295/980) featuring in all three datasets. Half (1165/2315) of the incident patients receiving dialysis in UKRR data had a kidney replacement therapy code in the primary care data within three months of the start date of the kidney replacement therapy. No codes existed whose exclusion would substantially improve the positive predictive value without a decrease in sensitivity. CONCLUSIONS: Codes used in primary and secondary care data failed to identify a small proportion of prevalent patients receiving kidney replacement therapy. Codes also identified many patients who were not recipients of chronic kidney replacement therapy in UKRR data, particularly dialysis codes. Linkage with UKRR kidney replacement therapy data facilitated more accurate identification of incident and prevalent kidney replacement therapy cohorts for research into this vulnerable population. Poor coding has implications for any patient care (including eligibility for vaccination, resourcing, and health policy responses in future pandemics) that relies on accurate reporting of kidney replacement therapy in primary and secondary care data.
General practitioners’ risk literacy and real-world prescribing of potentially hazardous drugs: a cross-sectional study
BackgroundOveruse of medical care is a pervasive problem. Studies using hypothetical scenarios suggest that physicians’ risk literacy influences medical decisions; real-world correlations, however, are lacking. We sought to determine the association between physicians’ risk literacy and their real-world prescriptions of potentially hazardous drugs, accounting for conflicts of interest and perceptions of benefit–harm ratios in low-value prescribing scenarios.Setting and sampleCross-sectional study—conducted online between June and October 2023 via field panels of Sermo (Hamburg, Germany)—with a convenience sample of 304 English general practitioners (GPs).MethodsGPs’ survey responses on their treatment-related risk literacy, conflicts of interest and perceptions of the benefit–harm ratio in low-value prescribing scenarios were matched to their UK National Health Service records of prescribing volumes for antibiotics, opioids, gabapentin and benzodiazepines and analysed for differences.Results204 GPs (67.1%) worked in practices with ≥6 practising GPs and 226 (76.0%) reported 10–39 years of experience. Compared with GPs demonstrating low risk literacy, GPs with high literacy prescribed fewer opioids (mean (M): 60.60 vs 43.88 prescribed volumes/1000 patients/6 months, p=0.016), less gabapentin (M: 23.84 vs 18.34 prescribed volumes/1000 patients/6 months, p=0.023), and fewer benzodiazepines (M: 17.23 vs 13.58 prescribed volumes/1000 patients/6 months, p=0.037), but comparable volumes of antibiotics (M: 48.84 vs 40.61 prescribed volumes/1000 patients/6 months, p=0.076). High-risk literacy was associated with lower conflicts of interest (ϕ = 0.12, p=0.031) and higher perception of harms outweighing benefits in low-value prescribing scenarios (p=0.007). Conflicts of interest and benefit–harm perceptions were not independently associated with prescribing behaviour (all ps >0.05).Conclusions and relevanceThe observed association between GPs with higher risk literacy and the prescription of fewer hazardous drugs suggests the importance of risk literacy in enhancing patient safety and quality of care.
The long-term impact of vaginal surgical mesh devices on pain clinic and psychological service referrals, anti-inflammatory testing and pelvic scans in UK primary care: A cohort study with the Clinical Practice Research Datalink.
OBJECTIVE: To examine long-term complications in women with stress urinary incontinence (SUI) and pelvic organ prolapse (POP), with and without surgical mesh implants. DESIGN: Longitudinal open cohort study from 1 April 2006 (or 1 April 2012) to 30 November 2018. SETTING: The Clinical Practice Research Datalink (CPRD) Gold database, which is linked to Hospital Episodes Statistics (HES) inpatient data, the HES Diagnostic Imaging Dataset (DID), Office for National Statistics mortality data and Index of Multiple Deprivation socio-economic status data. SAMPLE: Women aged ≥18 years with a diagnostic SUI/POP Read code. METHODS: Rates are estimated using negative binomial regression. MAIN OUTCOME MEASURES: Rates of referrals for: psychological and pain services; urinalysis, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) testing; and pelvic ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) scans. RESULTS: A cohort of 220 544 women were eligible for inclusion; 74% (n = 162 687) had SUI, 37% (n = 82 123) had POP and 11% (n = 24 266) had both. Rates of psychological referrals and CT scans were lower in women with SUI mesh surgery, but this was offset by higher rates of CRP testing in women with SUI or POP mesh, MRI scans in women with SUI mesh, and urinalysis testing and referrals to pain clinics for women with POP mesh. CONCLUSIONS: Our results suggest a higher burden of morbidity in women with SUI/POP mesh surgery, and that these women may require ongoing follow-up in the primary care setting.
Preventable suicides involving medicines: A systematic case series of coroners’ reports in England and Wales
Background: In England and Wales coroners have a duty to write a report, called a Prevention of Future Deaths report or PFD, when they believe that actions should be taken to prevent future deaths. Coroners send PFDs to individuals and organisations who are required to respond within 56 days. Despite the increase in mental health concerns and growing use of medicines, deaths reported by coroners that have involved medicine-related suicides had not yet been explored. Therefore, this study aimed to systematically assess coroners’ PFD reports involving suicides in which a medicine caused or contributed to the death to identify lessons for suicide prevention. Methods: Using the Preventable Deaths Tracker database (https://preventabledeathstracker.net/), 3037 coroners' PFD reports in England and Wales were screened for eligibility between July 2013 and December 2019. Reports were included if they involved suicide or intentional self-harm and prescribed or over-the-counter medication; illicit drugs were excluded. Following data extraction, descriptive statistics, document and content analysis were performed to assess coroners’ concerns and the recipients of reports. Results: There were 734 suicide-related coroner reports, with 100 (14%) reporting a medicine. Opioids (40%) were the most common class involved, followed by antidepressants (30%). There was wide geographical variation in the writing of reports; coroners in Manchester wrote the most (18%). Coroners expressed 237 concerns; the most common were procedural inadequacies (14%, n = 32), inadequate documentation and communication (10%, n = 22), and inappropriate prescription access (9%, n = 21). 203 recipients received the PFDs, with most sent to NHS trusts (31%), clinical commissioning groups (10%), and general practices (10%), of which only 58% responded to the coroner. Conclusions: One in four coroner reports in England and Wales involved suicides, with one in seven suicide-related deaths involving a medicine. Concerns raised by coroners highlighted gaps in care that require action from the Government, health services, and prescribers to aid suicide prevention. Coroner reports should be routinely used and monitored to inform public health policy, disseminated nationally, and responses to coroners should be transparently enforced so that actions are taken to prevent future suicides.
A realist evaluation of how, why and when objective structured clinical exams (OSCEs) are experienced as an authentic assessment of clinical preparedness.
INTRODUCTION: Whilst rarely researched, the authenticity with which Objective Structured Clinical Exams (OSCEs) simulate practice is arguably critical to making valid judgements about candidates' preparedness to progress in their training. We studied how and why an OSCE gave rise to different experiences of authenticity for different participants under different circumstances. METHODS: We used Realist evaluation, collecting data through interviews/focus groups from participants across four UK medical schools who participated in an OSCE which aimed to enhance authenticity. RESULTS: Several features of OSCE stations (realistic, complex, complete cases, sufficient time, autonomy, props, guidelines, limited examiner interaction etc) combined to enable students to project into their future roles, judge and integrate information, consider their actions and act naturally. When this occurred, their performances felt like an authentic representation of their clinical practice. This didn't work all the time: focusing on unavoidable differences with practice, incongruous features, anxiety and preoccupation with examiners' expectations sometimes disrupted immersion, producing inauthenticity. CONCLUSIONS: The perception of authenticity in OSCEs appears to originate from an interaction of station design with individual preferences and contextual expectations. Whilst tentatively suggesting ways to promote authenticity, more understanding is needed of candidates' interaction with simulation and scenario immersion in summative assessment.
Infections diagnosed in children and young people screened for malaria in UK emergency departments: a retrospective multi-centre study
Background: Data on imported infections in children and young people (CYP) are sparse. Aims: To describe imported infections in CYP arriving from malaria-endemic areas and presenting to UK emergency departments (ED) who were screened for malaria. Methods: This is a retrospective, multi-centre, observational study nested in a diagnostic accuracy study for malaria rapid diagnostic tests. Any CYP < 16 years presenting to a participating ED with a history of fever and travel to a malaria-endemic area between 1 January 2016 and 31 December 2017 and who had a malaria screen as a part of standard care were included. Geographical risk was calculated for the most common tropical infections. Results: Of the 1414 CYP screened for malaria, 44.0% (n = 622) arrived from South Asia and 33.3% (n = 471) from sub-Saharan Africa. Half (50.0%) had infections common in both tropical and non-tropical settings such as viral upper respiratory tract infection (URTI); 21.0% of infections were coded as tropical if gastro-enteritis is included, with a total of 4.2% (60) cases of malaria. CYP diagnosed with malaria were 7.44 times more likely to have arrived from sub-Saharan Africa than from South Asia (OR 7.44, 3.78–16.41). Conclusion: A fifth of CYP presenting to participating UK EDs with fever and a history of travel to a malaria-endemic area and who were screened for malaria had a tropical infection if diarrhoea is included. A third of CYP had no diagnosis. CYP arriving from sub-Saharan Africa had the greatest risk of malaria. Abbreviations: CYP: children and young people; ED: emergency department; PERUKI: Paediatric Emergency Research in the UK and Ireland; RDT: rapid diagnostic test; VFR: visiting friends and relatives.
Motivational interviewing for smoking cessation.
BACKGROUND: Motivational Interviewing (MI) is a directive patient-centred style of counselling, designed to help people to explore and resolve ambivalence about behaviour change. It was developed as a treatment for alcohol abuse, but may help smokers to a make a successful attempt to quit. OBJECTIVES: To determine the effects of motivational interviewing in promoting smoking cessation. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group Specialized Register for studies with terms (motivational OR motivation OR motivating OR motivate OR behavi* OR motivat*) and (interview* OR session* OR counsel* OR practi*) in the title or abstract, or as keywords. Date of the most recent search: April 2009. SELECTION CRITERIA: Randomized controlled trials in which motivational interviewing or its variants were offered to smokers to assist smoking cessation. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate. The main outcome measure was abstinence from smoking after at least six months follow up. We used the most rigorous definition of abstinence in each trial, and biochemically validated rates where available. Subjects lost to follow up were treated as continuing smokers. We performed meta-analysis using a fixed-effect Mantel-Haenszel model. MAIN RESULTS: We identified 14 studies published between 1997 and 2008, involving over 10,000 smokers. Trials were conducted in one to four sessions, with the duration of each session ranging from 15 to 45 minutes. All but two of the trials used supportive telephone contacts, and supplemented the counselling with self-help materials. MI was generally compared with brief advice or usual care in the trials. Interventions were delivered by primary care physicians, hospital clinicians, nurses or counsellors. Our meta-analysis of MI versus brief advice or usual care yielded a modest but significant increase in quitting (RR 1.27; 95% CI 1.14 to 1.42). Subgroup analyses suggested that MI was effective when delivered by primary care physicians (RR 3.49; 95% CI 1.53 to 7.94) and by counsellors (RR 1.27; 95% CI 1.12 to 1.43), and when it was conducted in longer sessions (more than 20 minutes per session) (RR 1.31; 95% CI 1.16 to 1.49). Multiple session treatments may be slightly more effective than single sessions, but both regimens produced positive outcomes. Evidence is unclear at present on the optimal number of follow-up calls.There was variation across the trials in treatment fidelity. All trials used some variant of motivational interviewing.Critical details in how it was modified for the particular study population, the training of therapists and the content of the counselling were sometimes lacking from trial reports. AUTHORS' CONCLUSIONS: Motivational interviewing may assist smokers to quit. However, the results should be interpreted with caution due to variations in study quality, treatment fidelity and the possibility of publication or selective reporting bias.
Brief opportunistic interventions by general practitioners to promote smoking cessation: A conversation analytic study
Very brief opportunistic interventions for smoking cessation are effective, cost-saving for health systems, and universally recommended in guidelines. However, evidence suggests that clinicians are reluctant to intervene, citing interactional difficulties. Only one UK study has specifically examined smoking discussions, within naturally occurring primary care consultations. However smoking cessation treatment was not available at the time. We examined existing datasets amounting to 519 video-recordings of GP consultations in England for instances of talk about smoking. We used conversation analytic methods to assess patients' responses to doctors asking about smoking, giving advice on smoking, and offering cessation treatment. In 31 recordings it was apparent that the patient smoked, and, in 25/31 consultations, doctors initiated the topic of smoking. They did so by asking about smoking status, commonly during the history-taking phase of the consultation. In many instances, these questions led to active resistance from patients against being placed in a discreditable category, for example by minimising their smoking. This was more pronounced when GPs pursued efforts to quantify the amount smoked. Thereafter, where doctors returned to the topic of smoking, they did so typically by linking smoking to the patient's medical condition, which likewise led to resistance. Guidance recommends that GPs advise on how best to quit smoking where patients are interested in doing so, but this was only evident in a minority of consultations. Where GPs offered support for cessation, they did so using interactional practices that minimised the need for the patient to respond and thereby accept. Interactional difficulties were found to be common in consultations between GPs and people who smoke when GPs actions aligned with some VBA guidelines. Future research should examine when and how advice on how best to quit, and offers of support, should be delivered within primary care consultations.
The old and familiar meets the new and unknown: patient and clinician perceptions on e-cigarettes for smoking reduction in UK general practice, a qualitative interview study
Background and Aims: Clinicians could promote e-cigarettes for harm reduction to people who smoke but cannot stop, but many clinicians feel uneasy doing so. In a randomized controlled trial (RCT), primary care clinicians offered free e-cigarettes and encouraged people with chronic diseases who were unwilling to stop smoking to switch to vaping. We interviewed clinicians and patients to understand how to adopt harm reduction in routine practice. Design: Qualitative analysis nested within an RCT, comprising thematic analysis of semi-structured interviews with primary care clinicians who delivered the trial intervention, and patients who took part. Setting: Primary care clinics in England. Participants/Cases: Twenty-one patients and 11 clinicians, purposively sampled from an RCT. Measurements: We qualitatively explored patients’ and clinicians’ experiences of: being offered/offering an e-cigarette, past and current perceptions about e-cigarettes and applying a harm reduction approach. Findings: Four themes captured clinicians’ and patients’ reported perspectives. These were: (1) concepts of safety/risk, with clinicians concerned about recommending a product with unknown long-term risks and patients preferring the known risks of cigarettes; (2) clinicians felt they were going out on a limb by offering these as though they were prescribing them, whereas patients did not share this view; (3) equating quitting with success, as both patients and clinicians conceptualized e-cigarettes as quitting aids; and (4) unchanged views, as clinicians reported that training did not change their existing views about e-cigarettes. These themes were united by the higher-order concept: ‘The old and familiar meets the new and unknown’, as a contradiction between this new approach and long-established methods underpinned these concerns. Conclusions: A qualitative analysis found barriers obstructing clinicians and patients from easily accepting e-cigarettes for harm reduction, rather than as aids to support smoking cessation: clinicians had difficulty reconciling harm reduction with their existing ethical models of practice, even following targeted training, and patients saw e-cigarettes as quitting aids.
General practitioner views on addressing weight opportunistically in primary care: An embedded sequential mixed-methods study
Objective: To assess GPs’ thoughts, feelings, and practices on providing opportunistic weight loss interventions before and after educational training and application in practice. Methods: In an embedded sequential mixed-methods design, 137 GPs delivered a 30-second brief opportunistic intervention to a mean of 14 patients with obesity. To assess GPs’ experiences and views on the intervention, all were invited to complete pre- and post-trial questionnaires and 18 were purposively interviewed. Data were transcribed verbatim and analysed using inductive framework analysis. Results: GPs’ attitudes (importance, feasibility, appropriateness, helpfulness, and effectiveness), capacities (comfort, confidence, and knowledge), perceived subjective norms (role expectations), willingness, and intentions on providing weight loss interventions were predominantly improved post-trial. The research setting allowed GPs to depersonalise intervening on obesity and feel more comfortable discussing the topic. Beyond the trial, GPs reverted largely to not intervening, citing barriers that had reportedly been overcome during the trial. Conclusion: GPs who delivered the intervention had positive experiences doing so, shifting their beliefs modestly that this intervention is important, feasible, and acceptable. Practice implications: Given that outside of the trial GPs were apprehensive about intervening without a prompt, developing systems to prompt patients may support implementation.