Kerenza Hood

Background: Systematic reviews have reported conflicting evidence to confirm if macrolides reduce rates of chronic lung disease of prematurity in at-risk preterm-born infants, including in those colonised with pulmonary Ureaplasma spp. Since an adequately powered trial has been lacking, we conducted a double-blind, randomised, placebo-controlled trial to assess if the macrolide azithromycin improved survival without the development of physiologically defined moderate or severe chronic lung disease of prematurity in infants born at < 30 weeks’ gestation. Methods: Infants recruited from 30 neonatal units (median gestational age 27.0 weeks, interquartile range 25.3–28.6) requiring respiratory support within 72 hours of birth were randomised to intravenous azithromycin 20 mg/kg/day for 3 days followed by 10 mg/kg for 7 days or to placebo. Primary outcome was survival without development of physiologically defined moderate/severe chronic lung disease of prematurity at 36 weeks’ postmenstrual age. A total of 796 infants were required to detect 12% improvement in survival without development of moderate or severe chronic lung disease of prematurity, including 10% dropout, with two-sided α -level of 5% and 90% power. The primary outcome was analysed using three-level logistic regression to account for clustering of multiple births and participants within centres and was adjusted for gestational age as a fixed effect. Secondary outcomes included death, chronic lung disease of prematurity severity, treatment interaction with Ureaplasma spp. colonisation, days of invasive and days of non-invasive respiratory support, treatment for nosocomial infections, treated patent ductus arteriosus, severe intraventricular haemorrhage, necrotising enterocolitis, treated retinopathy of prematurity and emergence of azithromycin resistance in stool and respiratory samples. Quantitative polymerase chain reaction identified respiratory Ureaplasma spp. and antibiotic resistance genes. Safety was also monitored. Findings: After three withdrawals, 796 randomised infants were included in the final analyses. Survivors without physiologically defined moderate/severe chronic lung disease of prematurity were: 166/394 (42.1%) and 179/402 (44.5%) in the intervention and placebo groups, respectively (adjusted odds ratio 0.84; 95% confidence interval 0.55 to 1.29; p = 0.43). Secondary outcomes were not significantly different between the treatment groups, except for treated retinopathy of prematurity in survivors (3.5% vs. 7.4%, azithromycin vs. placebo; odds ratio: 0.42, 95% confidence interval 0.18 to 0.98). Ureaplasma spp. colonisation did not influence treatment effect. No significant serious adverse effects were reported. From 1108 ( n = 541 azithromycin, n = 567 placebo) respiratory aspirates and 709 stool samples from 348 infants, erm (C) and msr (A) were the most prevalent macrolide-resistance genes, but erm (C) increased with azithromycin treatment in both sample types (11% at baseline, 16% at day 14 in respiratory samples; 0% at baseline, 69% at day 14 in stool samples). Interpretation: Prophylactic use of azithromycin did not improve survival without development of physiologically defined chronic lung disease of prematurity regardless of Ureaplasma spp. colonisation. Thus, it cannot be recommended in clinical practice. Since preterm-born infants are exposed to a range of antibiotics, in addition to the trial azithromycin, judicious use of antibiotics is required, given the emergence of multiresistant bacteria in this vulnerable group of infants. Future work: Follow-up at ages 1 and 2 years will assess the medium-term effects. Investigating whether treatment modulated proinflammatory cytokine concentrations, including whether this was more prevalent in the Ureaplasma spp. colonised or non-colonised group, will be crucial to providing further assurances to the clinical community. Limitations: Limitations include the (limited) missed oxygen reduction tests, inadequate collection of respiratory support data and lower-than-anticipated baseline sampling. Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/111/106.

Background: Variation in the way information about potential trial intervention benefits and harms is conveyed within patient information leaflets can cause avoidable information-induced (‘nocebo’) harm, research waste, and may be unethical. Objectives: To develop stakeholder-informed principles to guide how to describe information about potential trial intervention benefits and harms within patient information leaflets. To test whether using these principles are feasible for testing in trials that measure whether they improve recruitment and adverse event rates. To develop and disseminate guidance on how to implement the principles. Methods: We used a mixed methodology consisting of three work packages. Work package 1 involved a modified Delphi survey and consensus meeting to develop the principles for harmonising the way information regarding potential benefits and harms are shared. Work package 2 involved testing whether the principles could be used to transform existing patient information leaflets by recruiting host trials to compare standard patient information leaflets with patient information leaflets developed using the principles ‘principled patient information leaflets’. We also set up an infrastructure to test whether they could reduce variation, impact trial recruitment and reduce reported adverse events. Work package 3 involved developing and disseminating guidance for using the principles. Results: For work package 1, 250 participants completed the Delphi survey and 7 principles were agreed upon: (1) all potential intervention harms should be listed, (2) potential harms should be separated into ‘serious’ and ‘less serious’, (3) if not all potential harms are known, this needs to be explicitly stated, (4) all potential benefits should be listed, (5) potential benefits and harms associated with trial participation need to be compared with those associated with non-participation, (6) suitable visual representations should be added where appropriate, and (7) information about potential benefits and harms should not be separated by more than one page. For work package 2, we developed principled patient information leaflets for five host trials and interviewed two members of each host trial team. Two host trials agreed to compare the patient information leaflets with principled patient information leaflets using Studies Within a Trial, and we published a protocol for a meta-analysis that will synthesise the results. For work package 3, 25 participants attended a hybrid workshop and recommended that researchers and Research Ethics Committee members should use the principles to design and evaluate patient information leaflets. We produced a guidance booklet and website, which are currently being used by some Health Research Authority Research Ethics Committees. Conclusions: A strong consensus was reached regarding seven principles that can harmonise the way information about the potential benefits and harms of trial interventions is shared. The principles are likely to reduce research waste and avoidable information-induced harm, and may enhance clinical trial ethics. Limitations: Due to COVID-19, the National Institute for Health and Care Research review of ongoing trials that resulted in funding termination for several trials, and highly pressured trial staff with limited capacity to add Studies Within a Trial to their trials, we had to modify our second objective. Whereas we initially intended to actually conduct the Studies Within a Trial, we replaced this with: a protocol for a meta-analysis of Studies Within a Trial, additional research on the need to reduce variation, additional dissemination work, and a paper on the ethical requirement to mention potential benefits and harms of trial interventions in patient information leaflets. Future work: Future work could apply these results to explore how to harmonise the way potential benefits and harms are shared during verbal conversations between researchers and patients during the informed consent process. Funding: This award was funded by the Medical Research Council and the National Institute for Health and Care Research (NIHR) Better Methods, Better Research programme (MRC Award Reference: MR/V020706/1) and is published in full in Health Technology Assessment; Vol. 29, No. 43.

Background: Procalcitonin is a biomarker specific for bacterial infection, with a more rapid response than other commonly used biomarkers, such as C-reactive protein, but it is not routinely used in the National Health Service. Objective: To determine if using a procalcitonin-guided algorithm may safely reduce duration of antibiotic therapy compared to standard of care in hospitalised children with suspected or confirmed infection. Design: A pragmatic, multicentre, open-label, parallel two-arm, individually randomised controlled trial with internal pilot phase, qualitative study and health economic evaluations. Setting: Paediatric wards or paediatric intensive care units within children’s hospitals (n = 6) and district general hospitals (n = 9) in the United Kingdom. Participants: Children aged between 72 hours and 18 years admitted to hospital and being treated with intravenous antibiotics for suspected or confirmed bacterial infection. Interventions: Procalcitonin-guided algorithm versus usual standard care alone. Main outcome measures: Coprimary outcomes were duration of intravenous antibiotic use and a composite safety measure. Results: Between 11 June 2018 and 12 October 2022, 1949 children were recruited: 977 to the procalcitonin group [427 female (43.7%), 550 male (56.3%)], and 972 to the usual care group [478 female (49.2%), 494 male (50.8%)]. Duration of intravenous antibiotics was not significantly different between the procalcitonin group (median 96.0 hours) and the usual care group (median 99.7 hours) [hazard ratio = 0.96 (0.87, 1.05)], and the procalcitonin-guided algorithm was non-inferior to usual care [risk difference = −0.81% (95% confidence interval upper bound 1.11%)]. At clinical review, a procalcitonin result was available for 81.8% of the time, which was considered as part of clinical decision-making 66.6% of the time, and the algorithm was adhered to 57.2% of the time. Incremental cost-effectiveness ratio per duration of intravenous antibiotics hour avoided from bootstrapped samples was £467.62 per intravenous antibiotic hour avoided. Cost analysis of complete cases was also higher in the procalcitonin arm for all age groups, and for children aged 5 years and over. The intervention is not cost-effective as it is more expensive with no significant improvement in intravenous antibiotic duration. Limitations: Robust antimicrobial stewardship programmes were already implemented in the lead recruiting sites, and adherence to the algorithm was poor. Clinicians may be reluctant to adhere to biomarker-guided algorithms, due to unfamiliarity with interpreting the test result. Conclusions: In children hospitalised with confirmed or suspected bacterial infection, the addition of a procalcitonin-guided algorithm to usual care is non-inferior in terms of safety, but does not reduce duration of intravenous antibiotics, and is not cost-effective. In the presence of robust antimicrobial stewardship programmes to reduce antibiotic use, a procalcitonin-guided algorithm may offer little added value. Future work: Future trials must include an implementation framework to improve trial intervention fidelity, and repeated cycles of education and training to facilitate implementation of biomarker-guided algorithms into routine clinical care. Trial registration: This trial is registered as ISRCTN11369832. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/188/42) and is published in full in Health Technology Assessment; Vol. 29, No. 16. See the NIHR Funding and Awards website for further award information.

Background: Hidradenitis suppurativa (HS) is a long-term skin condition where evidence for management after first-line treatment fails is limited and practice varies across the UK. Medical and surgical treatment options are potential avenues of treatment. Furthermore, patient perspectives on HS treatments have received little attention in research to date. Objectives: To explore patients’ views and experiences of treatment for HS to inform clinical care. Methods: We conducted a nested qualitative study within a prospective cohort study. Interviews with 35 participants were completed by telephone. Purposive sampling was undertaken. Framework analysis was used to develop themes. Results: Past experiences and knowledge informed patient beliefs and whether an individual felt a treatment option was appropriate or a good ‘fit’ for them at a specific moment in time. Healthcare professional recommendations can influence a patient’s views and which treatment option they ultimately receive. Positive experiences were reported across all treatment types covered in the study. Negative experiences included mediation side-effects, lack of efficacy, delays to procedures and burden of wound care. However, even when personal experiences were not wholly positive for an individual, participants often believed the same treatment may potentially help others with HS, owing to the importance placed on personalization of treatment. Conclusions: This paper has implications for how healthcare professionals discuss treatment options with people with HS. A ‘one-size-fits-all’ approach is inappropriate, and shared decision-making that elicits patients’ beliefs and preferences is crucial.

Background: Lower urinary tract symptoms particularly affect older men and their quality of life. General practitioners currently have no easily available assessment tools to diagnose lower urinary tract symptom causes. Referrals to urology specialists are increasing. General practitioner access to simple, accurate tests and clinical decision tools could facilitate management of lower urinary tract symptoms in primary care. Objectives: To determine which of several index tests in combination, best predicted three diagnoses (detrusor overactivity, bladder outlet obstruction and/or detrusor underactivity) in men presenting with lower urinary tract symptoms in primary care. To develop and validate three diagnostic prediction models, and a prototype primary care clinical decision support tool. Design: Prospective diagnostic accuracy study. Two participant cohorts, for development and validation, underwent simple index tests and a reference standard (invasive urodynamics). Setting: General practices in England and Wales. Participants: Men (16 years and over) consulting their general practitioner with lower urinary tract symptoms. Sample size: Separate calculations for model development and validation cohorts, from literature estimates of detrusor overactivity, bladder outlet obstruction and detrusor underactivity prevalences of 57%, 31% and 16%, respectively. Predictors and index tests: Twelve potential predictors considered for three diagnostic models. Main outcome measures: The primary outcome was diagnostic model sensitivity and specificity for detecting bladder outlet obstruction, detrusor underactivity and detrusor overactivity, with 75.0% considered minimum clinically useful performance. Statistical analysis: Three separate logistic regression models generated with index test variables to predict the presence of bladder outlet obstruction, detrusor overactivity, detrusor underactivity conditions in men with lower urinary tract symptoms. Results: One model each was developed and validated for bladder outlet obstruction and detrusor underactivity, two for detrusor overactivity (detrusor overactivity main, detrusor overactivity sensitivity analysis 2). Age, voiding symptoms subscore, prostate-specific antigen level, median maximum flow rate, median voided volume were predictors for bladder outlet obstruction. Median maximum flow rate and post-void residual volume were predictors for detrusor underactivity. Age, post-void residual volume and median voided volume were included in detrusor overactivity main model, while age and storage symptoms subscore predicted detrusor overactivity sensitivity analysis 2. For all four models, sensitivity of 75.0% could be achieved with a specificity of 74.2%, 47.3%, 45.6% and 46.2% for bladder outlet obstruction, detrusor underactivity, detrusor overactivity main and detrusor overactivity sensitivity analysis 2 models, respectively. Similarly, a specificity of 75.0% could be achieved with a sensitivity of 71.3%, 39.8%, 33.3% and 62.7% for bladder outlet obstruction, detrusor underactivity, detrusor overactivity main and detrusor overactivity sensitivity analysis 2 models, respectively. The prototype tool (not yet intended for use in practice) is available at Primary care Management of lower Urinary tract Symptoms decision aid for lower urinary tract symptoms (shinyapps.io). General practitioner feedback during tool development and small-scale user-testing in simulated consultation scenarios was favourable. Patients supported such management in primary care. Strengths/limitations: This was a prospective, multicentre study in an appropriate primary care population. Most of the index tests are possible routinely in primary care or at home by patients. The diagnostic models were validated in a separate cohort from the same population. Limitations include that target condition prevalences may differ in other populations. Conclusion: We identified sensitivities and specificities of diagnostic models for detrusor overactivity, bladder outlet obstruction and detrusor underactivity in routine United Kingdom practice and developed a prototype clinical decision support tool. Future work: Economic modelling, a feasibility trial and powered randomised controlled trial are needed to evaluate the Primary care Management of lower Urinary tract Symptoms tool in practice. Study registration: Current Controlled Trials ISRCTN10327305. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/40/05) and is published in full in Health Technology Assessment; Vol. 29, No. 1. See the NIHR Funding and Awards website for further award information.

Objectives Many patients presenting with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in primary care do not benefit from antibiotics. Excessive use wastes resources, promotes antimicrobial resistance and can harm patients. Design We conducted a within-trial economic evaluation, using a UK National Health Service perspective, as part of the multicentre, parallel-arm, open, individually randomised, controlled PACE trial. Setting Participating general practices in primary care. Participants PACE included 324 and 325 consenting participants presenting with AECOPD in the usual-care and CRP-guided groups, respectively. Intervention We assessed the cost-effectiveness (CE) of a C-reactive protein point-of-care-test (CRP-POCT) in addition to usual clinical assessment to guide antibiotic prescribing for AECOPD in primary care. Primary and secondary outcome measures A cost-effectiveness analysis (CEA) of incremental cost per 1% antibiotic consumption reduction at 4 weeks and a cost-utility analysis (CUA) at 6 months were performed, based on a modified intention-to-treat population. Sensitivity analyses assessed the impact of uncertainty on the results. CE acceptability curves represent the probability of CRP-POCT being cost-effective at different willingness-to-pay (WTP) thresholds. Results Both groups had similar clinical outcomes, but a 20% absolute reduction in antibiotic consumption was observed in the CRP-guided group. CRP-POCT costs of £11.31 per test were largely offset by savings in healthcare resource use related to COPD. The mean incremental CE ratios of CRP-POCT were £120 per 1% absolute reduction in antibiotic consumption at 4 weeks and £1054 per quality-adjusted life-year (QALY) gained at 6 months. Sensitivity analysis showed that the CEA results were most affected by changes in healthcare costs, while CUA was sensitive due to marginal differences in costs and outcomes. There is a 73% probability of CRP-POCT being cost-effective at WTP ≤£20 000 per QALY gained. Conclusion CRP-POCT is a cost-effective intervention for safely reducing antibiotic consumption in patients with AECOPD. Trial registration number ISRCTN24346473

Background: Clinical trials are fundamental to healthcare, however, they also contribute to anthropogenic climate change. Following previous work to develop and test a method and guidance to calculate the carbon footprint of clinical trials, we have now applied the guidance to 10 further UK and international, academically sponsored clinical trials to continue the identification of hotspots and opportunities for lower carbon trial design. Methods: 10 collaborating clinical trial units (CTUs) self-identified and a trial was selected from their portfolio to represent a variety of designs, health areas and interventions. Trial activity data was collated by trial teams across 10 modules spanning trial setup through to closure, then multiplied by emission factors provided in the guidance to calculate the carbon footprint. Feedback was collected from trial teams on the process, experience and ease of use of the guidance. Results: We footprinted 10 trials: 6 investigational medicinal product trials, 1 nutritional, 1 surgical, 1 health surveillance and one complex intervention trial. Six of these were completed and four ongoing (two in follow-up and two recruiting). The carbon footprint of the 10 trials ranged from 16 to 765 tonnes CO ₂ e. Common hotspots were identified as CTU emissions, trial-specific patient assessments and trial team meetings and travel. Hotspots for specific trial designs were also identified. The time taken to collate activity data and complete carbon calculations ranged from 5 to 60 hours. The draft guidance was updated to include new activities identified from the 10 trials and in response to user feedback. Discussion: There are opportunities to reduce the impact of trials across all modules, particularly trial-specific meetings and travel, patient assessments and laboratory practice. A trial’s carbon footprint should be considered at the design stage, but work is required to make this common place.

Background: Underrepresentation of care home residents in research has resulted in a poorer evidence base for health care in care homes. Fewer opportunities to take part in research, as well as assumptions made by others about their interest or wishes, creates challenges for residents’ inclusion in research. Early discussions about research preferences and wishes may be beneficial. This qualitative study aimed to explore stakeholders’ views about how care home residents can be supported to communicate their wishes about research participation. Method: Semi-structured interviews were conducted with 25 stakeholders: care home residents (n = 5), relatives (n = 5), care home staff (n = 5), other health and social care professionals who work with care homes (n = 6), and care home researchers (n = 4). Interviews were conducted virtually or face-to-face and data were analysed using thematic analysis. Results: Views about resident research participation, the barriers and facilitators to their inclusion, and the role of advance research planning were iteratively organized into three themes: (i) We’re of no value to research; (ii) Research is difficult; and (iii) Advance research planning: good in theory, challenging in practice. Subthemes were also identified, and findings were discussed with a Patient and Public Involvement group for additional reflections. Conclusions: Stakeholders identified a number of barriers to including care home residents in research, including knowing their preferences about research. The development of interventions to facilitate communication that can be adapted to individuals’ requirements are needed to support discussions and decision-making with care home residents about wishes and preferences for future research participation.

Introduction: The impact of multiple health conditions on bowel cancer screening is currently unknown. We explored the impact of multiple health conditions on bowel cancer screening perceptions, experience and clinical management decisions following a positive stool test.Methods: Semi‐structured qualitative interviews were conducted remotely with Bowel Screening Wales staff (n = 16) stratified by regional location and role and with screening participants (n = 19) stratified by age, gender and comorbidity. Interview topics were guided by the Common‐Sense Model.Results: Screening participants, regardless of comorbidity status, placed great emphasis on the importance of early detection of cancer and completing the bowel screening process. Screening staff emphasised comorbidities in the clinical decision‐making process; however, screening participants had low awareness of the impact that comorbidities can have on bowel screening. Participants describe how the presence of multiple health conditions can mask potential bowel symptoms and influence beliefs about follow‐up.Conclusion: Bowel screening staff try to individualise the service to meet participant needs. The potential mismatch in screening staff and participant awareness and expectations of the bowel screening and diagnostic process needs to be addressed. Clearer and more regular communication with screening participants could support the screening process, particularly for those with significant coexisting health conditions or facing time delays. The possible masking effects and misattribution of symptoms because of comorbidities highlight an opportunity for education and raising awareness for screening participants and a potential area of focus for discussions in clinical consultations and staff training.Patient and Public Contribution: Project funding included costs for patients and public contributors to be compensated for their contributions to the project, in line with current standards. A patient and public contributor was involved in the design of the study, including protocol development, and the interpretation of key findings and implications for patients, which are subsequently reflected within the manuscript.

Viral clearance, antibody response and the mutagenic effect of molnupiravir has not been elucidated in at-risk populations. Non-hospitalised participants within 5 days of SARS-CoV-2 symptoms randomised to receive molnupiravir (n = 253) or Usual Care (n = 324) were recruited to study viral and antibody dynamics and the effect of molnupiravir on viral whole genome sequence from 1437 viral genomes. Molnupiravir accelerates viral load decline, but virus is detectable by Day 5 in most cases. At Day 14 (9 days post-treatment), molnupiravir is associated with significantly higher viral persistence and significantly lower anti-SARS-CoV-2 spike antibody titres compared to Usual Care. Serial sequencing reveals increased mutagenesis with molnupiravir treatment. Persistence of detectable viral RNA at Day 14 in the molnupiravir group is associated with higher transition mutations following treatment cessation. Viral viability at Day 14 is similar in both groups with post-molnupiravir treated samples cultured up to 9 days post cessation of treatment. The current 5-day molnupiravir course is too short. Longer courses should be tested to reduce the risk of potentially transmissible molnupiravir-mutated variants being generated. Trial registration: ISRCTN30448031