Acceptance and Commitment Therapy plus usual care for improving quality of life in people with motor neuron disease (COMMEND): a multicentre, parallel, randomised controlled trial in the UK.

BACKGROUND: Motor neuron disease is a progressive, fatal neurodegenerative disease for which there is no cure. Acceptance and Commitment Therapy (ACT) is a psychological therapy incorporating acceptance, mindfulness, and behaviour change techniques. We aimed to evaluate the effectiveness of ACT plus usual care, compared with usual care alone, for improving quality of life in people with motor neuron disease. METHODS: We conducted a parallel, multicentre, two-arm randomised controlled trial in 16 UK motor neuron disease care centres or clinics. Eligible participants were aged 18 years or older with a diagnosis of definite or laboratory-supported probable, clinically probable, or possible familial or sporadic amyotrophic lateral sclerosis; progressive muscular atrophy; or primary lateral sclerosis; which met the World Federation of Neurology's El Escorial diagnostic criteria. Participants were randomly assigned (1:1) to receive up to eight sessions of ACT adapted for people with motor neuron disease plus usual care or usual care alone by a web-based system, stratified by site. Participants were followed up at 6 months and 9 months post-randomisation. Outcome assessors and trial statisticians were masked to treatment allocation. The primary outcome was quality of life using the McGill Quality of Life Questionnaire-Revised (MQOL-R) at 6 months post-randomisation. Primary analyses were multi-level modelling and modified intention to treat among participants with available data. This trial was pre-registered with the ISRCTN Registry (ISRCTN12655391). FINDINGS: Between Sept 18, 2019, and Aug 31, 2022, 435 people with motor neuron disease were approached for the study, of whom 206 (47%) were assessed for eligibility, and 191 were recruited. 97 (51%) participants were randomly assigned to ACT plus usual care and 94 (49%) were assigned to usual care alone. 80 (42%) of 191 participants were female and 111 (58%) were male, and the mean age was 63·1 years (SD 11·0). 155 (81%) participants had primary outcome data at 6 months post-randomisation. After controlling for baseline scores, age, sex, and therapist clustering, ACT plus usual care was superior to usual care alone for quality of life at 6 months (adjusted mean difference on the MQOL-R of 0·66 [95% CI 0·22-1·10]; d=0·46 [0·16-0·77]; p=0·0031). Moderate effect sizes were clinically meaningful. 75 adverse events were reported, 38 of which were serious, but no adverse events were deemed to be associated with the intervention. INTERPRETATION: ACT plus usual care is clinically effective for maintaining or improving quality of life in people with motor neuron disease. As further evidence emerges confirming these findings, health-care providers should consider how access to ACT, adapted for the specific needs of people with motor neuron disease, could be provided within motor neuron disease clinical services. FUNDING: National Institute for Health and Care Research Health Technology Assessment and Motor Neurone Disease Association.

Classification and stratification in pilonidal sinus disease: findings from the PITSTOP cohort.

AIM: Research in pilonidal disease faces several challenges, one of which is consistent and useful disease classification. The International Pilonidal Society (IPS) proposed a four-part classification in 2017. The aim of this work was to assess the validity and reliability of this tool using data from the PITSTOP cohort study. METHOD: Face validity was assessed by mapping the items/domains in the IPS tool against tools identified through a systematic review. Key concepts were defined as those appearing in more than two-thirds of published tools. Concurrent and predictive validity were assessed by comparing key patient-reported outcome measures between groups at baseline and at clinic visit. The outcomes of interest were health utility, Cardiff Wound Impact Questionnaire (CWIQ) and pain score between groups. Significance was set at p = 0.05 a priori. Interrater reliability was assessed using images captured during the PITSTOP cohort. Ninety images were assessed by six raters (two experts, two general surgeons and two trainees), and classified into IPS type. Interrater reliability was assessed using the unweighted kappa and unweighted Gwet's AC1 statistics. RESULTS: For face validity items represented in the IPS were common to other classification systems. Concurrent and predictive validity assessment showed differences in health utility and pain between groups at baseline, and for some treatment groups at follow-up. Assessors agreed the same classification in 38% of participants [chance-corrected kappa 0.52 (95% CI 0.42-0.61), Gwet's AC1 0.63 (95% CI 0.56-0.69)]. CONCLUSION: The IPS classification demonstrates key aspects of reliability and validity that would support its implementation.

Cost-effectiveness of acceptance and commitment therapy for people living with motor neuron disease, and their health-related quality of life.

BACKGROUND: Given the degenerative nature of the condition, people living with motor neuron disease (MND) experience high levels of psychological distress. The purpose of this research was to investigate the cost-effectiveness of acceptance and commitment therapy (ACT), adapted for the specific needs of this population, for improving quality of life. METHODS: A trial-based cost-utility analysis over a 9-month period was conducted comparing ACT plus usual care (n = 97) versus usual care alone (n = 94) from the perspective of the National Health Service. In the primary analysis, quality-adjusted life years (QALYs) were computed using health utilities generated from the EQ-5D-5L questionnaire. Sensitivity analyses and subgroup analyses were also carried out. RESULTS: Difference in costs was statistically significant between the two arms, driven mainly by the intervention costs. Effects measured by EQ-5D-5L were not statistically significantly different between the two arms. The incremental cost-effectiveness was above the £20,000 to £30,000 per QALY gained threshold used in the UK. However, the difference in effects was statistically significant when measured by the McGill Quality of Life-Revised (MQOL-R) questionnaire. The intervention was cost-effective in a subgroup experiencing medium deterioration in motor neuron symptoms. CONCLUSIONS: Despite the intervention being cost-ineffective in the primary analysis, the significant difference in the effects measured by MQOL-R, the low costs of the intervention, the results in the subgroup analysis, and the fact that ACT was shown to improve the quality of life for people living with MND, suggest that ACT could be incorporated into MND clinical services.

Research and practice priorities in pilonidal sinus disease: a consensus from the PITSTOP study.

AIM: Pilonidal sinus disease is a common condition treated by colorectal surgeons. There is a lack of literature in the field to guide optimal management of this condition. As part of the PITSTOP study, we aimed to identify policy and research priorities to provide direction to the field. METHOD: Patients and surgeons were invited to participate. A 'So what, now what' exercise was conducted, informed by data from PITSTOP. This generated statements for research and practice priorities. A three-round online Delphi study was conducted, ranking statements based on policy and research separately. Statements were rated 1 (not important) to 9 (important). Statements that were rated 7-9 by more than 70% of participants were entered into the consensus meeting. Personalized voting feedback was shown between rounds. A face-to-face meeting was held to discuss statements, and participants were asked to rank statements using a weighted choice vote. RESULTS: Twenty-two people participated in the focus group, generating 14 research and 19 policy statements. Statements were voted on by 56 participants in round 1, 53 in round 2 and 51 in round 3. A total of 15 policy statements and 19 research statements were discussed in the consensus round. Key policy statements addressed treatment strategies and intensity, surgeon training opportunities, need for classification and the impact of treatment on return to work. Research recommendations included design of future trials, methodology considerations and research questions. CONCLUSION: This study has identified research and policy priorities in pilonidal sinus disease which are relevant to patients and clinicians. These should inform practice and future research.

Real-world practice and outcomes in pilonidal surgery: Pilonidal Sinus Treatment Studying The Options (PITSTOP) cohort.

BACKGROUND: Numerous surgical approaches exist for the treatment of pilonidal disease. Current literature on treatment is of poor quality, limiting the ability to define optimal intervention. The aim of this study was to provide real-world data on current surgical practice and report patient and risk-adjusted outcomes, informing future trial design. METHODS: This UK-wide multicentre prospective cohort study, including patients (aged over 16 years) who had definitive treatment for symptomatic pilonidal disease, was conducted between May 2019 and March 2022. Patient and disease characteristics, and intervention details were analysed. Data on patient-reported outcomes, including pain, complications, treatment failure, wound issues, and quality of life, were gathered at various time points up to 6 months after surgery. Strategies were implemented to adjust for risk influencing different treatment choices and outcomes. RESULTS: Of the 667 participants consenting, 574 (86.1%) were followed up to the study end. Twelve interventions were observed. Broadly, 59.5% underwent major excisional surgery and 40.5% minimally invasive surgery. Complications occurred in 45.1% of the cohort. Those who had minimally invasive procedures had better quality of life and, after risk adjustment, less pain (score on day 1: mean difference 1.58, 95% c.i. 1.14 to 2.01), fewer complications (difference 17.5 (95% c.i. 9.1 to 25.9)%), more rapid return to normal activities (mean difference 25.9 (18.4 to 33.4) days) but a rate of higher treatment failure (difference 9.6 (95% c.i. 17.3 to 1.9)%). At study end, 25% reported an unhealed wound and 10% had not returned to normal activities. CONCLUSION: The burden after surgery for pilonidal disease is high and treatment failure is common. Minimally invasive techniques may improve outcomes at the expense of a 10% higher risk of treatment failure.

Prehospital early warning scores for adults with suspected sepsis: the PHEWS observational cohort and decision-analytic modelling study.

Background: Guidelines for sepsis recommend treating those at highest risk within 1 hour. The emergency care system can only achieve this if sepsis is recognised and prioritised. Ambulance services can use prehospital early warning scores alongside paramedic diagnostic impression to prioritise patients for treatment or early assessment in the emergency department. Objectives: To determine the accuracy, impact and cost-effectiveness of using early warning scores alongside paramedic diagnostic impression to identify sepsis requiring urgent treatment. Design: Retrospective diagnostic cohort study and decision-analytic modelling of operational consequences and cost-effectiveness. Setting: Two ambulance services and four acute hospitals in England. Participants: Adults transported to hospital by emergency ambulance, excluding episodes with injury, mental health problems, cardiac arrest, direct transfer to specialist services, or no vital signs recorded. Interventions: Twenty-one early warning scores used alongside paramedic diagnostic impression, categorised as sepsis, infection, non-specific presentation, or other specific presentation. Main outcome measures: Proportion of cases prioritised at the four hospitals; diagnostic accuracy for the sepsis-3 definition of sepsis and receiving urgent treatment (primary reference standard); daily number of cases with and without sepsis prioritised at a large and a small hospital; the minimum treatment effect associated with prioritisation at which each strategy would be cost-effective, compared to no prioritisation, assuming willingness to pay £20,000 per quality-adjusted life-year gained. Results: Data from 95,022 episodes involving 71,204 patients across four hospitals showed that most early warning scores operating at their pre-specified thresholds would prioritise more than 10% of cases when applied to non-specific attendances or all attendances. Data from 12,870 episodes at one hospital identified 348 (2.7%) with the primary reference standard. The National Early Warning Score, version 2 (NEWS2), had the highest area under the receiver operating characteristic curve when applied only to patients with a paramedic diagnostic impression of sepsis or infection (0.756, 95% confidence interval 0.729 to 0.783) or sepsis alone (0.655, 95% confidence interval 0.63 to 0.68). None of the strategies provided high sensitivity (> 0.8) with acceptable positive predictive value (> 0.15). NEWS2 provided combinations of sensitivity and specificity that were similar or superior to all other early warning scores. Applying NEWS2 to paramedic diagnostic impression of sepsis or infection with thresholds of > 4, > 6 and > 8 respectively provided sensitivities and positive predictive values (95% confidence interval) of 0.522 (0.469 to 0.574) and 0.216 (0.189 to 0.245), 0.447 (0.395 to 0.499) and 0.274 (0.239 to 0.313), and 0.314 (0.268 to 0.365) and 0.333 (confidence interval 0.284 to 0.386). The mortality relative risk reduction from prioritisation at which each strategy would be cost-effective exceeded 0.975 for all strategies analysed. Limitations: We estimated accuracy using a sample of older patients at one hospital. Reliable evidence was not available to estimate the effectiveness of prioritisation in the decision-analytic modelling. Conclusions: No strategy is ideal but using NEWS2, in patients with a paramedic diagnostic impression of infection or sepsis could identify one-third to half of sepsis cases without prioritising unmanageable numbers. No other score provided clearly superior accuracy to NEWS2. Research is needed to develop better definition, diagnosis and treatments for sepsis. Study registration: This study is registered as Research Registry (reference: researchregistry5268). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/136/10) and is published in full in Health Technology Assessment; Vol. 28, No. 16. See the NIHR Funding and Awards website for further award information.

Sepsis is a life-threatening condition in which an abnormal response to infection causes heart, lung or kidney failure. People with sepsis need urgent treatment. They need to be prioritised at the emergency department rather than waiting in the queue. Paramedics attempt to identify people with possible sepsis using an early warning score (based on simple measurements, such as blood pressure and heart rate) alongside their impression of the patient's diagnosis. They can then alert the hospital to assess the patient quickly. However, an inaccurate early warning score might miss cases of sepsis or unnecessarily prioritise people without sepsis. We aimed to measure how accurately early warning scores identified people with sepsis when used alongside paramedic diagnostic impression. We collected data from 71,204 people that two ambulance services transported to four different hospitals in 2019. We recorded paramedic diagnostic impressions and calculated early warning scores for each patient. At one hospital, we linked ambulance records to hospital records and identified who had sepsis. We then calculated the accuracy of using the scores alongside diagnostic impression to diagnose sepsis. Finally, we used modelling to predict how many patients (with and without sepsis) paramedics would prioritise using different strategies based on early warning scores and diagnostic impression. We found that none of the currently available early warning scores were ideal. When they were applied to all patients, they prioritised too many people. When they were only applied to patients whom the paramedics thought had infection, they missed many cases of sepsis. The NEWS2, score, which ambulance services already use, was as good as or better than all the other scores we studied. We found that using the NEWS2, score in people with a paramedic impression of infection could achieve a reasonable balance between prioritising too many patients and avoiding missing patients with sepsis.

Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial.

BACKGROUND: A previous controlled trial of autologous haematopoietic stem-cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune-ablative regimen of reduced intensity versus standard of care in this patient population. METHODS: This open-label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18-60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub-score of ≥2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem-cell mobilisation (cyclophosphamide 1 g/m2 with granulocyte colony-stimulating factor (G-CSF) 5 µg/kg) and stem-cell harvest (minimum 2·0 × 106 CD34+ cells per kg), before conditioning (fludarabine 125 mg/m2, cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7·5 mg/kg in total) and subsequent stem-cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub-score of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading. This trial is registered with the ISRCTN registry, 17160440. FINDINGS: Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48-week follow-up; in the control group, nine (90%) reached 48-week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure. INTERPRETATION: Although HSCT with an immune-ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease. FUNDING: Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.

Determining a risk-proportionate approach to the validation of statistical programming for clinical trials.

BACKGROUND: The contribution of the statistician to the design and analysis of a clinical trial is acknowledged as essential. Ability to reconstruct the statistical contribution to a trial requires rigorous and transparent documentation as evidenced by the reproducibility of results. The process of validating statistical programmes is a key requirement. While guidance relating to software development and life cycle methodologies details steps for validation by information systems developers, there is no guidance applicable to programmes written by statisticians. We aimed to develop a risk-based approach to the validation of statistical programming that would support scientific integrity and efficient resource use within clinical trials units. METHODS: The project was embedded within the Information Systems Operational Group and the Statistics Operational Group of the UK Clinical Research Collaboration Registered Clinical Trials Unit network. Members were asked to share materials relevant to validation of statistical programming. A review of the published literature, regulatory guidance and knowledge of relevant working groups was undertaken. Surveys targeting the Information Systems Operational Group and Statistics Operational Group were developed to determine current practices across the Registered Clinical Trials Unit network. A risk-based approach was drafted and used as a basis for a workshop with representation from statisticians, information systems developers and quality assurance managers (n = 15). The approach was subsequently modified and presented at a second, larger scale workshop (n = 47) to gain a wider perspective, with discussion of content and implications for delivery. The approach was revised based on the discussions and suggestions made. The workshop was attended by a member of the Medicines for Healthcare products Regulatory Agency Inspectorate who also provided comments on the revised draft. RESULTS: Types of statistical programming were identified and categorised into six areas: generation of randomisation lists; programmes to explore/understand the data; data cleaning, including complex checks; derivations including data transformations; data monitoring; or interim and final analysis. The risk-based approach considers each category of statistical programme against the impact of an error and its likelihood, whether the programming can be fully prespecified, the need for repeated use and the need for reproducibility. Approaches to the validation of programming within each category are proposed. CONCLUSION: We have developed a risk-based approach to the validation of statistical programming. It endeavours to facilitate the implementation of targeted quality assurance measures while making efficient use of limited resources.

Development and validation of a multivariable model for prediction of malignant transformation and recurrence of oral epithelial dysplasia.

BACKGROUND: Oral epithelial dysplasia (OED) is the precursor to oral squamous cell carcinoma which is amongst the top ten cancers worldwide. Prognostic significance of conventional histological features in OED is not well established. Many additional histological abnormalities are seen in OED, but are insufficiently investigated, and have not been correlated to clinical outcomes. METHODS: A digital quantitative analysis of epithelial cellularity, nuclear geometry, cytoplasm staining intensity and epithelial architecture/thickness is conducted on 75 OED whole-slide images (252 regions of interest) with feature-specific comparisons between grades and against non-dysplastic/control cases. Multivariable models were developed to evaluate prediction of OED recurrence and malignant transformation. The best performing models were externally validated on unseen cases pooled from four different centres (n = 121), of which 32% progressed to cancer, with an average transformation time of 45 months. RESULTS: Grade-based differences were seen for cytoplasmic eosin, nuclear eccentricity, and circularity in basal epithelial cells of OED (p < 0.05). Nucleus circularity was associated with OED recurrence (p = 0.018) and epithelial perimeter associated with malignant transformation (p = 0.03). The developed model demonstrated superior predictive potential for malignant transformation (AUROC 0.77) and OED recurrence (AUROC 0.74) as compared with conventional WHO grading (AUROC 0.68 and 0.71, respectively). External validation supported the prognostic strength of this model. CONCLUSIONS: This study supports a novel prognostic model which outperforms existing grading systems. Further studies are warranted to evaluate its significance for OED prognostication.

Prehospital early warning scores for adults with suspected sepsis: retrospective diagnostic cohort study.

BACKGROUND: Ambulance services need to identify and prioritise patients with sepsis for early hospital assessment. We aimed to determine the accuracy of early warning scores alongside paramedic diagnostic impression to identify sepsis that required urgent treatment. METHODS: We undertook a retrospective diagnostic cohort study involving adult emergency medical cases transported to Sheffield Teaching Hospitals ED by Yorkshire Ambulance Service in 2019. We used routine ambulance service data to calculate 21 early warning scores and categorise paramedic diagnostic impressions as sepsis, infection, non-specific presentation or other presentation. We linked cases to hospital records and identified those meeting the sepsis-3 definition who received urgent hospital treatment for sepsis (reference standard). Analysis determined the accuracy of strategies that combined early warning scores at varying thresholds for positivity with paramedic diagnostic impression. RESULTS: We linked 12 870/24 955 (51.6%) cases and identified 348/12 870 (2.7%) with a positive reference standard. None of the strategies provided sensitivity greater than 0.80 with positive predictive value greater than 0.15. The area under the receiver operating characteristic curve for the National Early Warning Score, version 2 (NEWS2) applied to patients with a diagnostic impression of sepsis or infection was 0.756 (95% CI 0.729, 0.783). No other early warning score provided clearly superior accuracy to NEWS2. Paramedic impression of sepsis or infection had sensitivity of 0.572 (0.519, 0.623) and positive predictive value of 0.156 (0.137, 0.176). NEWS2 thresholds of >4, >6 and >8 applied to patients with a diagnostic impression of sepsis or infection, respectively, provided sensitivities and positive predictive values of 0.522 (0.469, 0.574) and 0.216 (0.189, 0.245), 0.447 (0.395, 0.499) and 0.274 (0.239, 0.313), and 0.314 (0.268, 0.365) and 0.333 (0.284, 0.386). CONCLUSION: No strategy is ideal but using NEWS2 alongside paramedic diagnostic impression of infection or sepsis could identify one-third to half of sepsis cases without prioritising unmanageable numbers. No other score provided clearly superior accuracy to NEWS2. TRIAL REGISTRATION NUMBER: researchregistry5268, https://www.researchregistry.com/browse-the-registry%23home/registrationdetails/5de7bbd97ca5b50015041c33/.

Acceptance and Commitment Therapy for people living with motor neuron disease: an uncontrolled feasibility study.

BACKGROUND: Motor neuron disease (MND) is a fatal, progressive neurodegenerative disease that causes progressive weakening and wasting of limb, bulbar, thoracic and abdominal muscles. Clear evidence-based guidance on how psychological distress should be managed in people living with MND (plwMND) is lacking. Acceptance and Commitment Therapy (ACT) is a form of psychological therapy that may be particularly suitable for this population. However, to the authors' knowledge, no study to date has evaluated ACT for plwMND. Consequently, the primary aim of this uncontrolled feasibility study was to examine the feasibility and acceptability of ACT for improving the psychological health of plwMND. METHODS: PlwMND aged ≥ 18 years were recruited from 10 UK MND Care Centres/Clinics. Participants received up to 8 one-to-one ACT sessions, developed specifically for plwMND, plus usual care. Co-primary feasibility and acceptability outcomes were uptake (≥ 80% of the target sample [N = 28] recruited) and initial engagement with the intervention (≥ 70% completing ≥ 2 sessions). Secondary outcomes included measures of quality of life, anxiety, depression, disease-related functioning, health status and psychological flexibility in plwMND and quality of life and burden in caregivers. Outcomes were assessed at baseline and 6 months. RESULTS: Both a priori indicators of success were met: 29 plwMND (104%) were recruited and 76% (22/29) attended ≥ 2 sessions. Attrition at 6-months was higher than anticipated (8/29, 28%), but only two dropouts were due to lack of acceptability of the intervention. Acceptability was further supported by good satisfaction with therapy and session attendance. Data were possibly suggestive of small improvements in anxiety and psychological quality of life from baseline to 6 months in plwMND, despite a small but expected deterioration in disease-related functioning and health status. CONCLUSIONS: There was good evidence of acceptability and feasibility. Limitations included the lack of a control group and small sample size, which complicate interpretation of findings. A fully powered RCT to evaluate the clinical and cost-effectiveness of ACT for plwMND is underway. TRIAL REGISTRATION: The study was pre-registered with the ISRCTN Registry (ISRCTN12655391).

Accuracy of efficient data methods to determine the incidence of hospital-acquired thrombosis and major bleeding in medical and surgical inpatients: a multicentre observational cohort study in four UK hospitals.

OBJECTIVES: We evaluated the accuracy of using routine health service data to identify hospital-acquired thrombosis (HAT) and major bleeding events (MBE) compared with a reference standard of case note review. DESIGN: A multicentre observational cohort study. SETTING: Four acute hospitals in the UK. PARTICIPANTS: A consecutive unselective cohort of general medical and surgical patients requiring hospitalisation for a period of >24 hours during the calendar year 2021. We excluded paediatric, obstetric and critical care patients due to differential risk profiles. INTERVENTIONS: We compared preidentified sources of routinely collected information (using hospital coding data and local contractually mandated thrombosis datasets) to data extracted from case notes using a predesigned workflow methodology. PRIMARY AND SECONDARY OUTCOME MEASURES: We defined HAT as objectively confirmed venous thromboembolism occurring during hospital stay or within 90 days of discharge and MBE as per international consensus. RESULTS: We were able to source all necessary routinely collected outcome data for 87% of 2008 case episodes reviewed. The sensitivity of hospital coding data (International Classification of Diseases 10th Revision, ICD-10) for the diagnosis of HAT and MBE was 62% (95% CI, 54 to 69) and 38% (95% CI, 27 to 50), respectively. Sensitivity improved to 81% (95% CI, 75 to 87) when using local thrombosis data sets. CONCLUSIONS: Using routinely collected data appeared to miss a substantial proportion of outcome events, when compared with case note review. Our study suggests that currently available routine data collection methods in the UK are inadequate to support efficient study designs in venous thromboembolism research. TRIAL REGISTRATION NUMBER: NIHR127454.

Temporal association between invasive procedures and infective endocarditis.

OBJECTIVE: Antibiotic prophylaxis has been recommended for patients at increased risk of infective endocarditis (IE) undergoing specific invasive procedures (IPs) despite a lack of data supporting its use. Therefore, antibiotic prophylaxis recommendations ceased in the mid-2000s for all but those at high IE risk undergoing invasive dental procedures. We aimed to quantify any association between IPs and IE. METHODS: All 14 731 IE hospital admissions in England between April 2010 and March 2016 were identified from national admissions data, and medical records were searched for IP performed during the 15-month period before IE admission. We compared the incidence of IP during the 3 months immediately before IE admission (case period) with the incidence during the preceding 12 months (control period) to determine whether the odds of developing IE were increased in the 3 months after certain IP. RESULTS: The odds of IE were increased following permanent pacemaker and defibrillator implantation (OR 1.54, 95% CI 1.27 to 1.85, p<0.001), extractions/surgical tooth removal (OR 2.14, 95% CI 1.22 to 3.76, p=0.047), upper (OR 1.58, 95% CI 1.34 to 1.85, p<0.001) and lower gastrointestinal endoscopy (OR 1.66, 95% CI 1.35 to 2.04, p<0.001) and bone marrow biopsy (OR 1.76, 95% CI 1.16 to 2.69, p=0.039). Using an alternative analysis, bronchoscopy (OR 1.33, 95% CI 1.06 to 1.68, p=0.049) and blood transfusions/red cell/plasma exchange (OR 1.2, 95% CI 1.07 to 1.35, p=0.012) were also associated with IE. CONCLUSIONS: This study identifies a significant association between specific IPs (permanent pacemaker and defibrillator implantation, dental extraction, gastrointestinal endoscopy and bronchoscopy) and subsequent IE that warrants re-evaluation of current antibiotic prophylaxis recommendations to prevent IE in high IE risk individuals.

A randomised controlled trial of acceptance and commitment therapy plus usual care compared to usual care alone for improving psychological health in people with motor neuron disease (COMMEND): study protocol.

BACKGROUND: Motor neuron disease (MND) is a rapidly progressive, fatal neurodegenerative disease that predominantly affects motor neurons from the motor cortex to the spinal cord and causes progressive wasting and weakening of bulbar, limb, abdominal and thoracic muscles. Prognosis is poor and median survival is 2-3 years following symptom onset. Psychological distress is relatively common in people living with MND. However, formal psychotherapy is not routinely part of standard care within MND Care Centres/clinics in the UK, and clear evidence-based guidance on improving the psychological health of people living with MND is lacking. Previous research suggests that Acceptance and Commitment Therapy (ACT) may be particularly suitable for people living with MND and may help improve their psychological health. AIMS: To assess the clinical and cost-effectiveness of ACT modified for MND plus usual multidisciplinary care (UC) in comparison to UC alone for improving psychological health in people living with MND. METHODS: The COMMEND trial is a multi-centre, assessor-blind, parallel, two-arm RCT with a 10-month internal pilot phase. 188 individuals aged ≥ 18 years with a diagnosis of definite, laboratory-supported probable, clinically probable, or possible familial or sporadic amyotrophic lateral sclerosis, and additionally the progressive muscular atrophy and primary lateral sclerosis variants, will be recruited from approximately 14 UK-based MND Care Centres/clinics and via self-referral. Participants will be randomly allocated to receive up to eight 1:1 sessions of ACT plus UC or UC alone by an online randomisation system. Participants will complete outcome measures at baseline and at 6- and 9-months post-randomisation. The primary outcome will be quality of life at six months. Secondary outcomes will include depression, anxiety, psychological flexibility, health-related quality of life, adverse events, ALS functioning, survival at nine months, satisfaction with therapy, resource use and quality-adjusted life years. Primary analyses will be by intention to treat and data will be analysed using multi-level modelling. DISCUSSION: This trial will provide definitive evidence on the clinical and cost-effectiveness of ACT plus UC in comparison to UC alone for improving psychological health in people living with MND. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN12655391. Registered 17 July 2017, https://www.isrctn.com/ISRCTN12655391 . PROTOCOL VERSION: 3.1 (10/06/2020).

Optimal pharmacotherapy pathway in adults with diabetic peripheral neuropathic pain: the OPTION-DM RCT.

BACKGROUND: The mainstay of treatment for diabetic peripheral neuropathic pain is pharmacotherapy, but the current National Institute for Health and Care Excellence guideline is not based on robust evidence, as the treatments and their combinations have not been directly compared. OBJECTIVES: To determine the most clinically beneficial, cost-effective and tolerated treatment pathway for diabetic peripheral neuropathic pain. DESIGN: A randomised crossover trial with health economic analysis. SETTING: Twenty-one secondary care centres in the UK. PARTICIPANTS: Adults with diabetic peripheral neuropathic pain with a 7-day average self-rated pain score of ≥ 4 points (Numeric Rating Scale 0-10). INTERVENTIONS: Participants were randomised to three commonly used treatment pathways: (1) amitriptyline supplemented with pregabalin, (2) duloxetine supplemented with pregabalin and (3) pregabalin supplemented with amitriptyline. Participants and research teams were blinded to treatment allocation, using over-encapsulated capsules and matching placebos. Site pharmacists were unblinded. OUTCOMES: The primary outcome was the difference in 7-day average 24-hour Numeric Rating Scale score between pathways, measured during the final week of each pathway. Secondary end points included 7-day average daily Numeric Rating Scale pain score at week 6 between monotherapies, quality of life (Short Form questionnaire-36 items), Hospital Anxiety and Depression Scale score, the proportion of patients achieving 30% and 50% pain reduction, Brief Pain Inventory - Modified Short Form items scores, Insomnia Severity Index score, Neuropathic Pain Symptom Inventory score, tolerability (scale 0-10), Patient Global Impression of Change score at week 16 and patients' preferred treatment pathway at week 50. Adverse events and serious adverse events were recorded. A within-trial cost-utility analysis was carried out to compare treatment pathways using incremental costs per quality-adjusted life-years from an NHS and social care perspective. RESULTS: A total of 140 participants were randomised from 13 UK centres, 130 of whom were included in the analyses. Pain score at week 16 was similar between the arms, with a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for duloxetine supplemented with pregabalin compared with amitriptyline supplemented with pregabalin, a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for pregabalin supplemented with amitriptyline compared with amitriptyline supplemented with pregabalin and a mean difference of 0.0 points (98.3% confidence interval -0.4 to 0.4 points) for pregabalin supplemented with amitriptyline compared with duloxetine supplemented with pregabalin. Results for tolerability, discontinuation and quality of life were similar. The adverse events were predictable for each drug. Combination therapy (weeks 6-16) was associated with a further reduction in Numeric Rating Scale pain score (mean 1.0 points, 98.3% confidence interval 0.6 to 1.3 points) compared with those who remained on monotherapy (mean 0.2 points, 98.3% confidence interval -0.1 to 0.5 points). The pregabalin supplemented with amitriptyline pathway had the fewest monotherapy discontinuations due to treatment-emergent adverse events and was most commonly preferred (most commonly preferred by participants: amitriptyline supplemented with pregabalin, 24%; duloxetine supplemented with pregabalin, 33%; pregabalin supplemented with amitriptyline, 43%; p = 0.26). No single pathway was superior in cost-effectiveness. The incremental gains in quality-adjusted life-years were small for each pathway comparison [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -0.002 (95% confidence interval -0.011 to 0.007) quality-adjusted life-years, amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline -0.006 (95% confidence interval -0.002 to 0.014) quality-adjusted life-years and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline 0.007 (95% confidence interval 0.0002 to 0.015) quality-adjusted life-years] and incremental costs over 16 weeks were similar [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -£113 (95% confidence interval -£381 to £90), amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £155 (95% confidence interval -£37 to £625) and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £141 (95% confidence interval -£13 to £398)]. LIMITATIONS: Although there was no placebo arm, there is strong evidence for the use of each study medication from randomised placebo-controlled trials. The addition of a placebo arm would have increased the duration of this already long and demanding trial and it was not felt to be ethically justifiable. FUTURE WORK: Future research should explore (1) variations in diabetic peripheral neuropathic pain management at the practice level, (2) how OPTION-DM (Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus) trial findings can be best implemented, (3) why some patients respond to a particular drug and others do not and (4) what options there are for further treatments for those patients on combination treatment with inadequate pain relief. CONCLUSIONS: The three treatment pathways appear to give comparable patient outcomes at similar costs, suggesting that the optimal treatment may depend on patients' preference in terms of side effects. TRIAL REGISTRATION: The trial is registered as ISRCTN17545443 and EudraCT 2016-003146-89. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme, and will be published in full in Health Technology Assessment; Vol. 26, No. 39. See the NIHR Journals Library website for further project information.

The number of people with diabetes is growing rapidly in the UK and is predicted to rise to over 5 million by 2025. Diabetes causes nerve damage that can lead to severe painful symptoms in the feet, legs and hands. One-quarter of all people with diabetes experience these symptoms, known as 'painful diabetic neuropathy'. Current individual medications provide only partial benefit, and in only around half of patients. The individual drugs, and their combinations, have not been compared directly against each other to see which is best. We conducted a study to see which treatment pathway would be best for patients with painful diabetic neuropathy. The study included three treatment pathways using combinations of amitriptyline, duloxetine and pregabalin. Patients received all three treatment pathways (i.e. amitriptyline treatment for 6 weeks and pregabalin added if needed for a further 10 weeks, duloxetine treatment for 6 weeks and pregabalin added if needed for a further 10 weeks and pregabalin treatment for 6 weeks and amitriptyline added if needed for a further 10 weeks); however, the order of the treatment pathways was decided at random. We compared the level of pain that participants experienced in each treatment pathway to see which worked best. On average, people said that their pain was similar after each of the three treatments and their combinations. However, two treatments in combination helped some patients with additional pain relief if they only partially responded to one. People also reported improved quality of life and sleep with the treatments, but these were similar for all the treatments. In the health economic analysis, the value for money and quality of life were similar for each pathway, and this resulted in uncertainty in the cost-effectiveness conclusions, with no one pathway being more cost-effective than the others. The treatments had different side effects, however; pregabalin appeared to make more people feel dizzy, duloxetine made more people nauseous and amitriptyline resulted in more people having a dry mouth. The pregabalin supplemented by amitriptyline pathway had the smallest number of treatment discontinuations due to side effects and may be the safest for patients.

Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.

BACKGROUND: Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP. METHODS: OPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0-10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443. FINDINGS: Between Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was -0·1 (98·3% CI -0·5 to 0·3) for D-P versus A-P, -0·1 (-0·5 to 0·3) for P-A versus A-P, and 0·0 (-0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway. INTERPRETATION: To our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy. FUNDING: National Institute for Health Research (NIHR) Health Technology Assessment programme.

Interventions for the prevention or treatment of epidural-related maternal fever: a systematic review and meta-analysis.

BACKGROUND: Epidural-related maternal fever in women in labour has consequences for the mother and neonate. There has been no systematic review of preventive strategies. METHODS: RCTs evaluating methods of preventing or treating epidural-related maternal fever in women in active labour were eligible. We searched MEDLINE, EMBASE, CINAHL, Web of Science, CENTRAL, and grey literature sources were searched from inception to April 2021. Two review authors independently undertook study selection. Data extraction and quality assessment was performed by a single author and checked by a second. The Cochrane Risk of Bias 2 tool was used. Meta-analyses for the primary outcome, incidence of intrapartum fever, were performed using the DerSimonian and Laird random effects model to produce summary risk ratios (RRs) with 95% confidence intervals (95% CIs). RESULTS: Forty-two records, representing 34 studies, were included. Methods of reduced dose epidural reduced the incidence of intrapartum fever, but this was not statistically significant when six trials at high risk of bias were removed (seven trials; 857 participants; RR=0.83; 95% CI, 0.41-1.67). Alternative methods of analgesia and high-dose prophylactic systemic steroids reduced the risk of intrapartum fever compared with epidural analgesia. Prophylactic paracetamol was not effective. CONCLUSIONS: There is no clear evidence to support the use of any individual preventative or therapeutic intervention for epidural-related maternal fever. Further research should focus on understanding the mechanism of fever development to enable RCTs of potential interventions to reduce the incidence of intrapartum fever development and the subsequent disease burden felt by the neonate. CLINICAL TRIAL REGISTRATION: CRD42021246929.

Infective endocarditis following invasive dental procedures: IDEA case-crossover study.

BACKGROUND: Infective endocarditis is a heart infection with a first-year mortality rate of ≈ 30%. It has long been thought that infective endocarditis is causally associated with bloodstream seeding with oral bacteria in ≈ 40-45% of cases. This theorem led guideline committees to recommend that individuals at increased risk of infective endocarditis should receive antibiotic prophylaxis before undergoing invasive dental procedures. However, to the best of our knowledge, there has never been a clinical trial to prove the efficacy of antibiotic prophylaxis and there is no good-quality evidence to link invasive dental procedures with infective endocarditis. Many contend that oral bacteria-related infective endocarditis is more likely to result from daily activities (e.g. tooth brushing, flossing and chewing), particularly in those with poor oral hygiene. OBJECTIVE: The aim of this study was to determine if there is a temporal association between invasive dental procedures and subsequent infective endocarditis, particularly in those at high risk of infective endocarditis. DESIGN: This was a self-controlled, case-crossover design study comparing the number of invasive dental procedures in the 3 months immediately before an infective endocarditis-related hospital admission with that in the preceding 12-month control period. SETTING: The study took place in the English NHS. PARTICIPANTS: All individuals admitted to hospital with infective endocarditis between 1 April 2010 and 31 March 2016 were eligible to participate. INTERVENTIONS: This was an observational study; therefore, there was no intervention. MAIN OUTCOME MEASURE: The outcome measure was the number of invasive and non-invasive dental procedures in the months before infective endocarditis-related hospital admission. DATA SOURCES: NHS Digital provided infective endocarditis-related hospital admissions data and dental procedure data were obtained from the NHS Business Services Authority. RESULTS: The incidence rate of invasive dental procedures decreased in the 3 months before infective endocarditis-related hospital admission (incidence rate ratio 1.34, 95% confidence interval 1.13 to 1.58). Further analysis showed that this was due to loss of dental procedure data in the 2-3 weeks before any infective endocarditis-related hospital admission. LIMITATIONS: We found that urgent hospital admissions were a common cause of incomplete courses of dental treatment and, because there is no requirement to record dental procedure data for incomplete courses, this resulted in a significant loss of dental procedure data in the 2-3 weeks before infective endocarditis-related hospital admissions. The data set was also reduced because of the NHS Business Services Authority's 10-year data destruction policy, reducing the power of the study. The main consequence was a loss of dental procedure data in the critical 3-month case period of the case-crossover analysis (immediately before infective endocarditis-related hospital admission), which did not occur in earlier control periods. Part of the decline in the rate of invasive dental procedures may also be the result of the onset of illness prior to infective endocarditis-related hospital admission, and part may be due to other undefined causes. CONCLUSIONS: The loss of dental procedure data in the critical case period immediately before infective endocarditis-related hospital admission makes interpretation of the data difficult and raises uncertainty over any conclusions that can be drawn from this study. FUTURE WORK: We suggest repeating this study elsewhere using data that are unafflicted by loss of dental procedure data in the critical case period. TRIAL REGISTRATION: This trial is registered as ISRCTN11684416. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 28. See the NIHR Journals Library website for further project information.

Infective endocarditis is a life-threatening infection of the heart valves. Most people are at low risk of infective endocarditis. However, those with certain cardiac conditions are at moderate risk of infective endocarditis, and those with artificial or repaired heart valves, a history of infective endocarditis and certain congenital heart conditions are at high risk of infective endocarditis. In around 40­45% of cases, oral bacteria are the cause of infective endocarditis. For many years, those people at moderate or high risk of infective endocarditis were given antibiotics (antibiotic prophylaxis) before invasive dental procedures such as extractions to reduce the risk of infective endocarditis. There is no good-quality evidence, however, to support the effectiveness of antibiotic prophylaxis, or the link between invasive dental procedures and infective endocarditis. Many believe that the oral bacteria that cause infective endocarditis are more likely to enter the blood during daily activities (e.g. toothbrushing, flossing or chewing), particularly in those with poor oral hygiene, than on the rare occasions when invasive dental procedures are performed. The aim of this study was to link English NHS data on infective endocarditis-related hospital admissions and dental treatments to determine if infective endocarditis is more likely in the weeks immediately after an invasive dental procedure than at any other time. When we linked the data sets and plotted the occurrence of different dental treatments over the year before infective endocarditis-related hospital admission, we detected a problem in the way that dental data were recorded. Unfortunately, there was a failure to collect dental procedure data when courses of treatment were incomplete. As one of the most common reasons for not completing a course of treatment was emergency admission to hospital, this meant that the number of dental procedures recorded decreased in the weeks before any emergency hospital admission. We have attempted to correct for this, but the data loss has affected the data quality. Although the data suggest an association between invasive dental procedures and infective endocarditis in individuals at high risk of infective endocarditis, the certainty of this association has been weakened.

Prediction of malignant transformation and recurrence of oral epithelial dysplasia using architectural and cytological feature specific prognostic models.

Oral epithelial dysplasia (OED) is a precursor state usually preceding oral squamous cell carcinoma (OSCC). Histological grading is the current gold standard for OED prognostication but is subjective and variable with unreliable outcome prediction. We explore if individual OED histological features can be used to develop and evaluate prognostic models for malignant transformation and recurrence prediction. Digitised tissue slides for a cohort of 109 OED cases were reviewed by three expert pathologists, where the prevalence and agreement of architectural and cytological histological features was assessed and association with clinical outcomes analysed using Cox proportional hazards regression and Kaplan-Meier curves. Within the cohort, the most prevalent features were basal cell hyperplasia (72%) and irregular surface keratin (60%), and least common were verrucous surface (26%), loss of epithelial cohesion (30%), lymphocytic band and dyskeratosis (34%). Several features were significant for transformation (p < 0.036) and recurrence (p < 0.015) including bulbous rete pegs, hyperchromatism, loss of epithelial cohesion, loss of stratification, suprabasal mitoses and nuclear pleomorphism. This led us to propose two prognostic scoring systems including a '6-point model' using the six features showing a greater statistical association with transformation and recurrence (bulbous rete pegs, hyperchromatism, loss of epithelial cohesion, loss of stratification, suprabasal mitoses, nuclear pleomorphism) and a 'two-point model' using the two features with highest inter-pathologist agreement (loss of epithelial cohesion and bulbous rete pegs). Both the 'six point' and 'two point' models showed good predictive ability (AUROC ≥ 0.774 for transformation and 0.726 for recurrence) with further improvement when age, gender and histological grade were added. These results demonstrate a correlation between individual OED histological features and prognosis for the first time. The proposed models have the potential to simplify OED grading and aid patient management. Validation on larger multicentre cohorts with prospective analysis is needed to establish their usefulness in clinical practice.