Reprint of: 'A new framework for developing and evaluating complex interventions: update of Medical Research Council guidance'.

The UK Medical Research Council's widely used guidance for developing and evaluating complex interventions has been replaced by a new framework, commissioned jointly by the Medical Research Council and the National Institute for Health Research, which takes account of recent developments in theory and methods and the need to maximise the efficiency, use, and impact of research.

Almanac - Retrieval-Augmented Language Models for Clinical Medicine.

BACKGROUND: Large language models (LLMs) have recently shown impressive zero-shot capabilities, whereby they can use auxiliary data, without the availability of task-specific training examples, to complete a variety of natural language tasks, such as summarization, dialogue generation, and question answering. However, despite many promising applications of LLMs in clinical medicine, adoption of these models has been limited by their tendency to generate incorrect and sometimes even harmful statements. METHODS: We tasked a panel of eight board-certified clinicians and two health care practitioners with evaluating Almanac, an LLM framework augmented with retrieval capabilities from curated medical resources for medical guideline and treatment recommendations. The panel compared responses from Almanac and standard LLMs (ChatGPT-4, Bing, and Bard) versus a novel data set of 314 clinical questions spanning nine medical specialties. RESULTS: Almanac showed a significant improvement in performance compared with the standard LLMs across axes of factuality, completeness, user preference, and adversarial safety. CONCLUSIONS: Our results show the potential for LLMs with access to domain-specific corpora to be effective in clinical decision-making. The findings also underscore the importance of carefully testing LLMs before deployment to mitigate their shortcomings. (Funded by the National Institutes of Health, National Heart, Lung, and Blood Institute.).

Randomised placebo-controlled trial of antenatal corticosteroids for planned birth in twins (STOPPIT-3): study protocol.

INTRODUCTION: The aim of the STOPPIT-3 study is to determine the clinical and cost effectiveness of antenatal corticosteroids (ACS) prior to planned birth of twins in a multicentre placebo-controlled trial with internal pilot. METHODS AND ANALYSIS: This study will comprise a multicentre, double-blinded, randomised, placebo-controlled trial in at least 50 UK obstetric units. The target population is 1552 women with a twin pregnancy and a planned birth between 35 and 38+6 weeks' gestation recruited from antenatal clinics. Women will be randomised to Dexamethasone Phosphate (24 mg) or saline administered via two intramuscular injections 24 hours apart, 24-120 hours prior to scheduled birth. OUTCOMES: The primary outcome is need for respiratory support within 72 hours of birth. Secondary and safety outcomes will be included. Cognitive and language development at age 2 years will be assessed in a subset of participants using the Parent report of Children's Abilities-Revised questionnaire. We will also determine the cost effectiveness of the treatment with ACS compared with placebo. ETHICS AND DISSEMINATION: STOPPIT-3 has been funded and approved by the National Institute of Healthcare Research. It has been approved by the West Midlands Research Ethics Committee (22/WM/0018). The results will be disseminated via publication in peer-reviewed journals and conference presentation and will also be communicated to the public via links with charity partners and social media. TRIAL SPONSOR: The University of Edinburgh and Lothian Health Board ACCORD, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ. TRIAL REGISTRATION NUMBER: ISRCTN59959611.

Central Venous Access Devices for the Delivery of Systemic Anticancer Therapy: An Economic Evaluation.

OBJECTIVES: Patients undergoing long-term anticancer therapy typically require one of 3 venous access devices: Hickman-type device (HICK), peripherally inserted central catheter (PICC), or implantable chest wall port (PORT). Recent evidence has shown PORT is safer and improves patient satisfaction. However, PORT did not show improvement in quality-adjusted life-years and was more expensive. Decisions regarding cost-effectiveness in the United Kingdom are typically informed by a cost-per-quality-adjusted life-year metric. However, this approach is limited in its ability to capture the full range of relevant outcomes, especially in the context of medical devices. This study assessed the potential cost-effectiveness of HICK, PICC, and PORT in routine clinical practice. METHODS: This is a cost-consequence analysis to determine the trade-offs between the following outcomes: complication, infection, noninfection, chemotherapy interruption, unplanned device removals, health utilities, device insertion cost, follow-up cost, and total cost, using data from the Cancer and Venous Access clinical trial. We conducted value of implementation analysis of a PORT service. RESULTS: PORT was superior in terms of overall complication rate compared with both HICK (incidence rate ratio 0.422; 95% CI 0.286-0.622) and PICC (incidence rate ratio 0.295; 95% CI 0.189-0.458) and less likely to lead to an unplanned device removal. There was no difference in chemotherapy interruption or health utilities. Total cost with device in situ was lower on PORT than HICK (-£98.86; 95% CI -189.20 to -8.53) and comparable with PICC -£48.57 (95% CI -164.99 to 67.86). Value of implementation analysis found that PORT was likely to be considered cost-effective within the National Health Service. CONCLUSION: Decision makers should consider including PORT within the suite of venous access devices available within in the National Health Service.

Setting a tariff for IVF and ICSI treatment: a cost analysis.

In-vitro fertilisation (IVF) and intra-cytoplasmatic sperm injection (ICSI) are available in Scotland through the National Health Service (NHS) according to specific criteria. There is no standardised NHS tariff for these treatments in Scotland, and variation exists amongst different centres providing NHS services. The aim of this study was to calculate the mean cost of IVF and ICSI cycles for NHS-funded treatment in Scotland. A detailed cost analysis of fresh and frozen cycles was performed, and a breakdown of the various cost components was presented. A deterministic approach was applied using NHS-funded individual cycle data from 2015-2018 and aggregate data. All costs were calculated in UK pounds sterling (£- using 2018 prices). Resource use was assigned to individual cycles based on cycle-level data or expert-informed assumptions; whenever needed, average aggregate costs were assigned to cycles. A total of 9442 NHS-funded cycles were included in the analysis. The average cost of fresh IVF and ICSI cycles was £3247 [£1526-£4215] and £3473 [£1526-£4416], respectively. Frozen cycles averaged £938 [£272-£1085]. This data can be useful to decision-makers, especially where IVF/ICSI is publicly funded, as it delivers a detailed IVF/ICSI cost breakdown. It is an opportunity for other authorities to estimate IVF/ICSI costs, as the methods applied are clear and reproducible.

Effect of Medication Therapy Management by Pharmaceutical Care on Blood Pressure and Cardiovascular Risk in Hypertension: A Systematic Review, Meta-Analysis, and Meta-Regression.

Medication therapy management by pharmaceutical care (MTM-PC) has been shown to improve the effectiveness of antihypertensive treatments. The aim was to answer the question: what are the MTM-PC models and their impact on hypertensive patients' outcomes? This is a systematic review with meta-analysis. The search strategies were run on 27 September 2022 in the following databases: PubMed, EMBASE, Scopus, LILACs, Central Cochrane Library, Web of Science; and International Pharmaceutical Abstracts. The quality and bias risk was assessed by the Downs and Black instrument. Forty-one studies met the eligibility criteria and were included, Kappa = 0.86; 95% CI, 0.66-1.0; (p < 0.001). Twenty-seven studies (65.9%) had MTM-PC models outlined by the clinical team, showing as characteristics the mean of 10.0 ± 10.7 months of follow-up of hypertensive patients, with 7.7 ± 4.9 consultations. Instruments to assess the quality of life measured the enhancement by 13.4 ± 10.7% (p = 0.047). The findings of the meta-analysis show a mean reduction of -7.71 (95% CI, -10.93 to -4.48) and -3.66 (95% CI, -5.51 to -1.80), (p < 0.001) in mmHg systolic and diastolic pressures, respectively. Cardiovascular relative risk (RR) over ten years was 0.561 (95% CI, 0.422 to 0.742) and RR = 0.570 (95% CI, 0.431 to 0.750), considering homogeneous studies, I² = 0%. This study shows the prevalence of MTM-PC models outlined by the clinical team, in which there are differences according to the models in reducing blood pressure and cardiovascular risk over ten years with the improvement in quality of life.

Almanac: Retrieval-Augmented Language Models for Clinical Medicine.

Large-language models have recently demonstrated impressive zero-shot capabilities in a variety of natural language tasks such as summarization, dialogue generation, and question-answering. Despite many promising applications in clinical medicine, adoption of these models in real-world settings has been largely limited by their tendency to generate incorrect and sometimes even toxic statements. In this study, we develop Almanac, a large language model framework augmented with retrieval capabilities for medical guideline and treatment recommendations. Performance on a novel dataset of clinical scenarios (n= 130) evaluated by a panel of 5 board-certified and resident physicians demonstrates significant increases in factuality (mean of 18% at p-value < 0.05) across all specialties, with improvements in completeness and safety. Our results demonstrate the potential for large language models to be effective tools in the clinical decision-making process, while also emphasizing the importance of careful testing and deployment to mitigate their shortcomings.

Financial incentives for quitting smoking in pregnancy: Are they cost-effective?

AIMS: To evaluate whether adding financial incentives to usual care is cost-effective in encouraging pregnant women to quit tobacco smoking, compared with usual care alone. DESIGN: Cost-effectiveness analysis (CEA) and cost-utility analysis (CUA) from a health-care provider's perspective, embedded in the Smoking Cessation in Pregnancy Incentives Trial (CPIT III). Long-term analyses were conducted from the same perspective, using an existing Markov model over a life-time horizon. SETTING: Seven maternity smoking cessation sites in Scotland, England and Northern Ireland in the United Kingdom. PARTICIPANTS: In the short-term analysis, CPIT III participants were assessed: women 16 years or older, self-reporting as smokers, fewer than 24 weeks pregnant and English-speaking (n = 944). The same population was used for the life-time analysis, plus their infants. MEASUREMENTS: Costs included financial incentive vouchers and postage, cessation support and nicotine replacement therapy and neonatal stays. The outcome measure was a biochemically verified quit rate for the CEA and quality-adjusted life-years (QALYs) for CUA. Costs are presented in 2020 GBP sterling (£). Data for the life-time analysis came from the trial and were combined with data from published literature embedded in the model, reporting incremental cost per quitter and QALY. A 3.5% discount rate was applied. FINDINGS: The short-term incremental cost per quitter was £4400 and cost per QALY was £150 000. Results of sensitivity analyses confirmed these results. The long-term analysis combined costs and outcomes for mother and infants; results showed a cost saving of £37 [95% confidence interval (CI]) = £35-106] and increase in QALYs of 0.171 (95% CI = 0.124-0.229). These findings indicate that, over a life-time, financial incentives are cost-saving and improve health outcomes. CONCLUSIONS: In the United Kingdom, offering up to £400 financial incentives, in addition to usual care, to support pregnant women to stop smoking appears to be highly cost-effective over a life-time for mother and infants.

Implementation of a national smoke-free prison policy: an economic evaluation within the Tobacco in Prisons (TIPs) study.

OBJECTIVE: To determine the cost-effectiveness of a smoke-free prison policy in Scotland, through assessments of the trade-offs between costs (healthcare and non-healthcare-related expenditure) and outcomes (health and non-health-related non-monetary consequences) of implementing the policy. DESIGN: A health economic evaluation consisting of three analyses (cost-consequence, cost-effectiveness and cost-utility), from the perspectives of the healthcare payer, prison service, people in custody and operational staff, assessed the trade-offs between costs and outcomes. Costs associated with the implementation of the policy, healthcare resource use and personal spend on nicotine products were considered, alongside health and non-health outcomes. The cost-effectiveness of the policy was evaluated over 12-month and lifetime horizons (short term and long term). SETTING: Scotland's national prison estate. PARTICIPANTS: People in custody and operational prison staff. INTERVENTION: Implementation of a comprehensive (indoor and outdoor) smoke-free policy. MAIN OUTCOME MEASURES: Concentration of secondhand smoke, health-related quality of life (health utilities and quality-adjusted life-years (QALY)) and various non-health outcomes (eg, incidents of assaults and fires). RESULTS: The short-term analyses suggest cost savings for people in custody and staff, improvements in concentration of secondhand smoke, with no consistent direction of change across other outcomes. The long-term analysis demonstrated that implementing smoke-free policy was cost-effective over a lifetime for people in custody and staff, with approximate cost savings of £28 000 and £450, respectively, and improvement in health-related quality of life of 0.971 QALYs and 0.262, respectively. CONCLUSION: Implementing a smoke-free prison policy is cost-effective over the short term and long term for people in custody and staff.

Say My Name: Understanding the Power of Names, Correct Pronunciation, and Personal Narratives.

Introduction: Names are a reflection of identity and often have personal meaning. The chronic mispronunciation of names can undermine one's identity and be experienced as a microaggression. This workshop aims to provide historical context for names as well as resources for correct name pronunciation. Methods: We developed a 60-minute interactive virtual workshop with didactics, small-group sharing of personal experiences, and case discussions. We used an anonymous postworkshop survey to evaluate workshop effectiveness. Results: We presented the workshop at one local academic conference and two local educational conferences to learners of all levels from medical students to faculty. We collected postworkshop survey results from 78 participants of diverse racial and ethnic backgrounds. Participants reported learning historical context, ways to ask about correct name pronunciation, correcting name mispronunciation, documenting pronunciation, and sources for applications to practice. The main barriers to implementing workshop lessons included personal and structural factors. Discussion: This workshop effectively fills an educational gap by addressing the importance of correct name pronunciation in order to provide a more inclusive environment for clinicians and patients alike.

Effect of financial voucher incentives provided with UK stop smoking services on the cessation of smoking in pregnant women (CPIT III): pragmatic, multicentre, single blinded, phase 3, randomised controlled trial.

OBJECTIVE: To examine effectiveness, cost effectiveness, generalisability, and acceptability of financial incentives for smoking cessation during pregnancy in addition to variously organised UK stop smoking services. DESIGN: Pragmatic, multicentre, single blinded, phase 3, randomised controlled trial (Cessation in Pregnancy Incentives Trial phase 3 (CPIT III)). SETTING: Seven UK stop smoking services provided in primary and secondary care facilities in Scotland, Northern Ireland, and England. PARTICIPANTS: 944 pregnant women (age ≥16 years) who self-reported as being smokers (at least one cigarette in the past week) when asked at first maternity visit, less than 24 weeks' gestation, and notified to the trial team by routine stop smoking services. INTERVENTIONS: Participants in the control group were offered the standard stop smoking services, which includes the offer of counselling by specially trained workers using withdrawal orientated therapy and the offer of free nicotine replacement therapy. The intervention was the offer of usual support from the stop smoking services and the addition of up to £400 ($440; €455) of LoveToShop financial voucher incentives for engaging with current stop smoking services or to stop smoking, or both, during pregnancy. MAIN OUTCOME MEASURES: Self-reported smoking cessation in late pregnancy (between 34 and 38 weeks' gestation) corroborated by saliva cotinine (and anabasine if using nicotine replacement products). Results were adjusted for age, smoking years, index of multiple deprivation, Fagerström score, before or after covid, and recruitment site. Secondary outcomes included point and continuous abstinence six months after expected date of delivery, engagement with stop smoking services, biochemically validated abstinence from smoking at four weeks after stop smoking date, birth weight of baby, cost effectiveness, generalisability documenting formats of stop smoking services, and acceptability to pregnant women and their carers. RESULTS: From 9 January 2018 to 4 April 2020, of 4032 women screened by stop smoking services, 944 people were randomly assigned to the intervention group (n=471) or the control group (n=470). Three people asked for their data to be removed. 126 (27%) of 471 participants stopped smoking from the intervention group and 58 (12%) of 470 from the control group (adjusted odds ratio 2.78 (1.94 to 3.97) P<0.001). Serious adverse events were miscarriages and other expected pregnancy events requiring hospital admission; all serious adverse events were unrelated to the intervention. Most people who stopped smoking from both groups relapsed after their baby was born. CONCLUSIONS: The offer of up to £400 of financial voucher incentives to stop smoking during pregnancy as an addition to current UK stop smoking services is highly effective. This bolt-on intervention supports new guidance from the UK National Institute for Health and Care Excellence, which includes the addition of financial incentives to support pregnant women to stop smoking. Continuing incentives to 12 months after birth is being examined to prevent relapse. TRIAL REGISTRATION: ISRCTN Registry ISRCTN15236311.

Beyond 10-Year Risk: A Cost-Effectiveness Analysis of Statins for the Primary Prevention of Cardiovascular Disease.

BACKGROUND: Cholesterol guidelines typically prioritize primary prevention statin therapy on the basis of 10-year risk of cardiovascular disease. The advent of generic pricing may justify expansion of statin eligibility. Moreover, 10-year risk may not be the optimal approach for statin prioritization. We estimated the cost-effectiveness of expanding preventive statin eligibility and evaluated novel approaches to prioritization from a Scottish health sector perspective. METHODS: A computer simulation model predicted long-term health and cost outcomes in Scottish adults ≥40 years of age. Epidemiologic analysis was completed using the Scottish Heart Health Extended Cohort, Scottish Morbidity Records, and National Records of Scotland. A simulation cohort was constructed with data from the Scottish Health Survey 2011 and contemporary population estimates. Treatment and cost inputs were derived from published literature and health service cost data. The main outcome measure was the lifetime incremental cost-effectiveness ratio, evaluated as cost (2020 GBP) per quality-adjusted life-year (QALY) gained. Three approaches to statin prioritization were analyzed: 10-year risk scoring using the ASSIGN score, age-stratified risk thresholds to increase treatment rates in younger individuals, and absolute risk reduction (ARR)-guided therapy to increase treatment rates in individuals with elevated cholesterol levels. For each approach, 2 policies were considered: treating the same number of individuals as those with an ASSIGN score ≥20% (age-stratified risk threshold 20, ARR 20) and treating the same number of individuals as those with an ASSIGN score ≥10% (age-stratified risk threshold 10, ARR 10). RESULTS: Compared with an ASSIGN score ≥20%, reducing the risk threshold for statin initiation to 10% expanded eligibility from 804 000 (32% of adults ≥40 years of age without CVD) to 1 445 500 individuals (58%). This policy would be cost-effective (incremental cost-effectiveness ratio, £12 300/QALY [95% CI, £7690/QALY-£26 500/QALY]). Incremental to an ASSIGN score ≥20%, ARR 20 produced ≈8800 QALYs and was cost-effective (£7050/QALY [95% CI, £4560/QALY-£10 700/QALY]). Incremental to an ASSIGN score ≥10%, ARR 10 produced ≈7950 QALYs and was cost-effective (£11 700/QALY [95% CI, £9250/QALY-£16 900/QALY]). Both age-stratified risk threshold strategies were dominated (ie, more expensive and less effective than alternative treatment strategies). CONCLUSIONS: Generic pricing has rendered preventive statin therapy cost-effective for many adults. ARR-guided therapy is more effective than 10-year risk scoring and is cost-effective.

The Best Services Trial (BeST?): a cluster randomised controlled trial comparing the clinical and cost-effectiveness of New Orleans Intervention Model with services as usual (SAU) for infants and young children entering care.

BACKGROUND: Abused and neglected children are at increased risk of health problems throughout life, but negative effects may be ameliorated by nurturing family care. It is not known whether it is better to place these children permanently with substitute (foster or adoptive) families or to attempt to reform their birth families. Previously, we conducted a feasibility randomised controlled trial (RCT) of the New Orleans Intervention Model (NIM) for children aged 0-60 months coming into foster care in Glasgow. NIM is delivered by a multidisciplinary health and social care team and offers families, whose child has been taken into foster care, a structured assessment of family relationships followed by a trial of treatment aiming to improve family functioning. A recommendation is then made for the child to return home or for adoption. In the feasibility RCT, families were willing to be randomised to NIM or optimised social work services as usual and equipoise was maintained. Here we present the protocol of a substantive RCT of NIM including a new London site. METHODS: The study is a multi-site, pragmatic, single-blind, parallel group, cluster randomised controlled superiority trial with an allocation ratio of 1:1. We plan to recruit approximately 390 families across the sites, including those recruited in our feasibility RCT. They will be randomly allocated to NIM or optimised services as usual and followed up to 2.5 years post-randomisation. The principal outcome measure will be child mental health, and secondary outcomes will be child quality of life, the time taken for the child to be placed in permanent care (rehabilitation home or adoption) and the quality of the relationship with the primary caregiver. DISCUSSION: The study is novel in that infant mental health professionals rarely have a role in judicial decisions about children's care placements, and RCTs are rare in the judicial context. The trial will allow us to determine whether NIM is clinically and cost-effective in the UK and findings may have important implications for the use of mental health assessment and treatment as part of the decision-making about children in the care system.

Pharmacogenetic testing for adverse drug reaction prevention: systematic review of economic evaluations and the appraisal of quality matters for clinical practice and implementation.

BACKGROUND: Genetic testing has potential roles in identifying whether an individual would have risk of adverse drug reactions (ADRs) from a particular medicine. Robust cost-effectiveness results on genetic testing would be useful for clinical practice and policy decision-making on allocating resources effectively. This study aimed to update a systematic review on economic evaluations of pharmacogenetic testing to prevent ADRs and critically appraise the quality of reporting and sources of evidence for model input parameters. METHODS: We searched studies through Medline via PubMed, Scopus and CRD's NHS Economic Evaluation up to October 2019. Studies investigating polymorphism-based pharmacogenetic testing, which guided drug therapies to prevent ADRs, using economic evaluation methods were included. Two reviewers independently performed data extraction and assessed the quality of reporting using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) guidelines and the quality of data sources using the hierarchy of evidence developed by Cooper et al. RESULTS: Fifty-nine economic evaluations of pharmacogenetic testing to avoid drug-induced ADRs were found between 2002 and 2018. Cost-utility and cost-effectiveness analyses were the most common methods of economic evaluation of pharmacogenetic testing. Most studies complied with the CHEERS checklist, except for single study-based economic evaluations which did not report uncertainty analysis (78%). There was a lack of high-quality evidence not only for estimating the clinical effectiveness of pharmacogenetic testing, but also baseline clinical data. About 14% of the studies obtained clinical effectiveness data of testing from a meta-analysis of case-control studies with direct comparison, which was not listed in the hierarchy of evidence used. CONCLUSIONS: Our review suggested that future single study-based economic evaluations of pharmacogenetic testing should report uncertainty analysis, as this could significantly affect the robustness of economic evaluation results. A specific ranking system for the quality of evidence is needed for the economic evaluation of pharmacogenetic testing of ADRs. Differences in parameters, methods and outcomes across studies, as well as population-level and system-level differences, may lead to the difficulty of comparing cost-effectiveness results across countries.

A prognostic model, including quantitative fetal fibronectin, to predict preterm labour: the QUIDS meta-analysis and prospective cohort study.

BACKGROUND: The diagnosis of preterm labour is challenging. False-positive diagnoses are common and result in unnecessary, potentially harmful treatments (e.g. tocolytics, antenatal corticosteroids and magnesium sulphate) and costly hospital admissions. Measurement of fetal fibronectin in vaginal fluid is a biochemical test that can indicate impending preterm birth. OBJECTIVES: To develop an externally validated prognostic model using quantitative fetal fibronectin concentration, in combination with clinical risk factors, for the prediction of spontaneous preterm birth and to assess its cost-effectiveness. DESIGN: The study comprised (1) a qualitative study to establish the decisional needs of pregnant women and their caregivers, (2) an individual participant data meta-analysis of existing studies to develop a prognostic model for spontaneous preterm birth within 7 days in women with symptoms of preterm labour based on quantitative fetal fibronectin and clinical risk factors, (3) external validation of the prognostic model in a prospective cohort study across 26 UK centres, (4) a model-based economic evaluation comparing the prognostic model with qualitative fetal fibronectin, and quantitative fetal fibronectin with cervical length measurement, in terms of cost per QALY gained and (5) a qualitative assessment of the acceptability of quantitative fetal fibronectin. DATA SOURCES/SETTING: The model was developed using data from five European prospective cohort studies of quantitative fetal fibronectin. The UK prospective cohort study was carried out across 26 UK centres. PARTICIPANTS: Pregnant women at 22+0-34+6 weeks' gestation with signs and symptoms of preterm labour. HEALTH TECHNOLOGY BEING ASSESSED: Quantitative fetal fibronectin. MAIN OUTCOME MEASURES: Spontaneous preterm birth within 7 days. RESULTS: The individual participant data meta-analysis included 1783 women and 139 events of spontaneous preterm birth within 7 days (event rate 7.8%). The prognostic model that was developed included quantitative fetal fibronectin, smoking, ethnicity, nulliparity and multiple pregnancy. The model was externally validated in a cohort of 2837 women, with 83 events of spontaneous preterm birth within 7 days (event rate 2.93%), an area under the curve of 0.89 (95% confidence interval 0.84 to 0.93), a calibration slope of 1.22 and a Nagelkerke R2 of 0.34. The economic analysis found that the prognostic model was cost-effective compared with using qualitative fetal fibronectin at a threshold for hospital admission and treatment of ≥ 2% risk of preterm birth within 7 days. LIMITATIONS: The outcome proportion (spontaneous preterm birth within 7 days of test) was 2.9% in the validation study. This is in line with other studies, but having slightly fewer than 100 events is a limitation in model validation. CONCLUSIONS: A prognostic model that included quantitative fetal fibronectin and clinical risk factors showed excellent performance in the prediction of spontaneous preterm birth within 7 days of test, was cost-effective and can be used to inform a decision support tool to help guide management decisions for women with threatened preterm labour. FUTURE WORK: The prognostic model will be embedded in electronic maternity records and a mobile telephone application, enabling ongoing data collection for further refinement and validation of the model. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015027590 and Current Controlled Trials ISRCTN41598423. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 52. See the NIHR Journals Library website for further project information.

Identifying which women with symptoms of labour will give birth early is challenging, so many women unnecessarily receive therapies aimed at preventing complications in preterm birth. A test called quantitative fetal fibronectin, which uses vaginal swab samples, may help to improve the diagnosis of preterm labour. Fetal fibronectin is a protein that is released from the fetal membranes that surround the developing baby in the womb. The lower the concentration of fetal fibronectin, the less likely the occurrence of preterm birth. Our aim was to see if quantitative fetal fibronectin, in combination with some features of pregnancy (e.g. previous pregnancy history and twin pregnancy), can accurately predict preterm birth in women who have symptoms of preterm labour. We asked women, their partners, doctors and midwives what information would be most useful to them, and how this should be presented. We then analysed previous research data; we used quantitative fetal fibronectin and clinical risk factors together to predict the chance of preterm birth. We explored which features could predict preterm birth most effectively while still being good value to the NHS. To ensure that this risk predictor worked in UK populations, we undertook a research study across 26 UK hospitals. Women who had symptoms of preterm labour were invited to participate. We collected information from these women (approximately 3000 women), including quantitative fetal fibronectin results. We found that a risk predictor comprising quantitative fetal fibronectin and four other features performed best at predicting whether or not preterm birth will occur within the next week for women with symptoms of preterm labour, and that this had potential to be clinically useful and cost-effective. The quantitative fetal fibronectin testing process was acceptable to women, and clinicians found the risk predictor useful. We used our findings to develop a risk calculator to help women and clinicians assess how likely preterm birth is, and decide whether or not to start treatment.

Evaluation of a national smoke-free prisons policy using medication dispensing: an interrupted time-series analysis.

BACKGROUND: Internationally, smoking prevalence among people in prison custody (ie, people on remand awaiting trial, awaiting sentencing, or serving a custodial sentence) is high. In Scotland, all prisons implemented a comprehensive smoke-free policy in 2018 after a 16-month anticipatory period. In this study, we aimed to use data on medication dispensing to assess the impact of this policy on cessation support, health outcomes, and potential unintended consequences among people in prison custody. METHODS: We did an interrupted time-series analysis using dispensing data for 44 660 individuals incarcerated in 14 closed prisons in Scotland between March 30, 2014, and Nov 30, 2019. We estimated changes in dispensing rates associated with the policy announcement (July 17, 2017) and full implementation (Nov 30, 2018) using seasonal autoregressive integrated moving average models. Medication categories of primary interest were treatments for nicotine dependence (as an indicator of smoking cessation or abstinence attempts), acute smoking-associated illnesses, and mental health (antidepressants). We included antiepileptic medications as a negative control. FINDINGS: A 44% step increase in dispensing of treatments for nicotine dependence was observed at implementation (2250 items per 1000 people in custody per fortnight, 95% CI 1875 to 2624) due primarily to a 42% increase in dispensing of nicotine replacement therapy (2109 items per 1000 people in custody per fortnight, 1701 to 2516). A 9% step decrease in dispensing for smoking-related illnesses was observed at implementation, largely accounted for by respiratory medications (-646 items per 1000 people in custody per fortnight, -1111 to -181). No changes associated with announcement or implementation were observed for mental health dispensing or antiepileptic medications (control). INTERPRETATION: Smoke-free prison policies might improve respiratory health among people in custody and encourage smoking abstinence or cessation without apparent short-term adverse effects on mental health dispensing. FUNDING: National Institute of Health Research Public Health Research programme, Scottish Government Chief Scientist Office, and UK Medical Research Council.

Framework for the development and evaluation of complex interventions: gap analysis, workshop and consultation-informed update.

BACKGROUND: The Medical Research Council published the second edition of its framework in 2006 on developing and evaluating complex interventions. Since then, there have been considerable developments in the field of complex intervention research. The objective of this project was to update the framework in the light of these developments. The framework aims to help research teams prioritise research questions and design, and conduct research with an appropriate choice of methods, rather than to provide detailed guidance on the use of specific methods. METHODS: There were four stages to the update: (1) gap analysis to identify developments in the methods and practice since the previous framework was published; (2) an expert workshop of 36 participants to discuss the topics identified in the gap analysis; (3) an open consultation process to seek comments on a first draft of the new framework; and (4) findings from the previous stages were used to redraft the framework, and final expert review was obtained. The process was overseen by a Scientific Advisory Group representing the range of relevant National Institute for Health Research and Medical Research Council research investments. RESULTS: Key changes to the previous framework include (1) an updated definition of complex interventions, highlighting the dynamic relationship between the intervention and its context; (2) an emphasis on the use of diverse research perspectives: efficacy, effectiveness, theory-based and systems perspectives; (3) a focus on the usefulness of evidence as the basis for determining research perspective and questions; (4) an increased focus on interventions developed outside research teams, for example changes in policy or health services delivery; and (5) the identification of six 'core elements' that should guide all phases of complex intervention research: consider context; develop, refine and test programme theory; engage stakeholders; identify key uncertainties; refine the intervention; and economic considerations. We divide the research process into four phases: development, feasibility, evaluation and implementation. For each phase we provide a concise summary of recent developments, key points to address and signposts to further reading. We also present case studies to illustrate the points being made throughout. LIMITATIONS: The framework aims to help research teams prioritise research questions and design and conduct research with an appropriate choice of methods, rather than to provide detailed guidance on the use of specific methods. In many of the areas of innovation that we highlight, such as the use of systems approaches, there are still only a few practical examples. We refer to more specific and detailed guidance where available and note where promising approaches require further development. CONCLUSIONS: This new framework incorporates developments in complex intervention research published since the previous edition was written in 2006. As well as taking account of established practice and recent refinements, we draw attention to new approaches and place greater emphasis on economic considerations in complex intervention research. We have introduced a new emphasis on the importance of context and the value of understanding interventions as 'events in systems' that produce effects through interactions with features of the contexts in which they are implemented. The framework adopts a pluralist approach, encouraging researchers and research funders to adopt diverse research perspectives and to select research questions and methods pragmatically, with the aim of providing evidence that is useful to decision-makers. FUTURE WORK: We call for further work to develop relevant methods and provide examples in practice. The use of this framework should be monitored and the move should be made to a more fluid resource in the future, for example a web-based format that can be frequently updated to incorporate new material and links to emerging resources. FUNDING: This project was jointly funded by the Medical Research Council (MRC) and the National Institute for Health Research (Department of Health and Social Care 73514).

Interventions are actions taken to make a change, for example heart surgery, an exercise programme or a smoking ban in public. Interventions are described as complex if they comprise several stages or parts or if the context in which they are delivered is complex. A framework on how to develop and evaluate complex interventions was last published by the Medical Research Council in 2006 (Craig P, Dieppe P, Macintyre S, Michie S, Nazareth I, Petticrew M. Developing and Evaluating Complex Interventions. London: Medical Research Council; 2006). This document describes how the framework has been updated to include advances in research methods and thinking and presents the new framework document. The updating process had four stages: (1) review of the literature to identify areas requiring update; (2) workshop of experts to discuss topics to update; (3) open consultation on a draft of the framework; and (4) writing the framework. The updated framework divides the research process into four phases: development, feasibility, evaluation and implementation. Key updates include: the definition of a complex intervention was changed to include both the content of the intervention and the context in which it is conductedaddition of systems thinking methods: an approach that considers the broader system an intervention sits withinmore emphasis on interventions that are not developed by researchers (e.g. policy changes and health services delivery)emphasis on the usefulness of evidence as the key goal of complex intervention researchidentification of six elements to be addressed throughout the research process: context; theory refinement and testing; stakeholder involvement; identification of key uncertainties; intervention refinement; and economic considerations. The updated framework is intended to help those involved in funding and designing research to consider a range of approaches, questions and methods and to choose the most appropriate. It also aims to help researchers conduct and report research that is as useful as possible to users of research.

Do clinical trials change practice? A longitudinal, international assessment of colorectal cancer prescribing practices.

INTRODUCTION: Over half of the 1.5 million individuals globally who are diagnosed with colorectal cancer (CRC) present with stage II-III disease. Understanding clinician attitudes towards treatment for this group is paramount to contextualise real-world outcomes and plan future trials. The aim of this study was to assess clinician awareness of trials assessing the optimal duration of CRC adjuvant therapy, their attitudes towards shorter treatment and their self-reported practice. METHODS: A survey was developed using OnlineSurveys® and distributed to clinicians in April 2019, with a follow-up survey disseminated to a subset of respondents in August 2020. Microsoft Excel® and Stata® were used for analysis. RESULTS: 265 clinicians replied to the first survey, with the majority aware of findings from the International Duration Evaluation of Adjuvant Therapy collaboration and contributory trials. Practice change was greatest for patients under 70 with low-risk stage III CRC, with most uncertainty around using 3-months of doublet chemotherapy for high-risk stage II disease. In August 2020, clinicians (n = 106) were more likely to use 3-months of FOLFOX for low-risk stage III disease and 3-months of CAPOX for stage II disease compared to April 2019. There was no indication that the COVID-19 pandemic had enduring changes on treatment decisions beyond those made in response to trial evidence. DISCUSSION: Clinicians use a risk-stratified approach to treat CRC the adjuvant setting. Lower utilisation of doublet chemotherapy for older and stage II patients has affected the extent of trial implementation. Active dialogue regarding how trial results apply to these groups may improve consensus.

How has implementation been incorporated in health technology assessments in the United Kingdom? A systematic rapid review.

OBJECTIVES: Health interventions in a clinical setting may be complex. This is particularly true of clinical interventions which require systems reorganization or behavioural change, and/or when implementation involves additional challenges not captured within a clinical trial setting. Medical Research Council guidance on complex interventions highlights the need to consider economic evaluation alongside implementation. However, the extent to which this guidance has been adhered to, and how, is unclear. The failure to incorporate implementation within the evaluation of an intervention may hinder the translation of research findings into routine practice. This will have consequences for patient care. This study examined the methods used to address implementation within health research conducted through funding from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme. METHODS: We conducted a rapid review using a systematic approach. We included all NIHR HTA monographs which contained the word "implementation" within the title or abstract published between 2014 and 2020. We assessed the studies according to existing recommendations for specifying and reporting implementation approaches in research. Additional themes which were not included in the recommendation, but were of particular relevance to our research question, were also identified and summarized in a narrative synthesis. RESULTS: The extent to which implementation was formally incorporated, and defined, varied among studies. Methods for examining implementation ranged from single stakeholder engagement events to the more comprehensive process evaluation. There was no obvious pattern as to whether approaches to implementation had evolved over recent years. Approximately 50% (22/42) of studies included an economic evaluation. Of these, two studies included the use of qualitative data obtained within the study to quantitatively inform aspects relating to implementation and economic evaluation in their study. DISCUSSION: A variety of approaches were identified for incorporating implementation within an HTA. However, they did not go far enough in terms of incorporating implementation into the actual design and evaluation. To ensure the implementation of clinically effective and cost-effective interventions, we propose that further guidance on how to incorporate implementation within complex interventions is required. Incorporating implementation into economic evaluation provides a step in this direction.