BACKGROUND: Chronic respiratory morbidity from bronchopulmonary dysplasia (BPD) remains the most common complication of preterm birth and has consequences for later respiratory, cardiovascular and neurodevelopmental outcomes. The early phases of respiratory illness are characterised by rapid consumption of endogenous surfactant and slow replenishment. Exogenous surfactant is routinely administered to infants born before 28 weeks of gestation as prophylaxis. Endogenous surfactant includes four proteins, known as surfactant proteins (SPs) A, B, C and D. Current bovine-derived and porcine-derived surfactant preparations only contain SPs B and C. SP-D has a key role in lung immune homeostasis as part of the innate immune system. Laboratory studies using recombinant SP-D have demonstrated reduced inflammation, which may be a pathway to reducing the associated morbidity from BPD. RESPONSE uses a recombinant fragment of human SP D (rfhSP-D), in a phase I safety and dose-escalation trial as the first stage in determining its effect in humans.
METHODS: This is a single-centre, dose-escalation, phase I safety study aiming to recruit 24 infants born before 30 weeks gestation with respiratory distress syndrome. In addition to routine surfactant replacement therapy, participants will receive three doses of rfhSP-D via endotracheal route at either 1 mg/kg, 2 mg/kg or 4 mg/kg. The study uses a Bayesian continual reassessment method to make dose escalation decisions. Dose-limiting events (DLE) in this trial will be graded according to the published Neonatal Adverse Event Severity Score. The primary outcome of this study is to evaluate the safety profile of rfhSP-D across each dose level based on the profile of DLE to establish the recommended phase 2 dose (RP2D) of rfhSP-D.
BACKGROUND: The RESPONSE study has received ethical approval from London-Brent NHS Research Health Authority ethics committee. Results from the study will be published in peer-reviewed journals and presented at national and international conferences.
BACKGROUND: ISRCTN17083028, NCT05898633.
METHODS: RESPONSE Protocol V.4.0 24th July 2024.

BACKGROUND: Obstructive sleep apnoea (OSA) is a common, but underdiagnosed, sleep disorder. If untreated, it leads to poor health outcomes, including Alzheimer\'s disease, cancer, cardiovascular disease and all-cause mortality. Our aim is to determine the feasibility and cost-effectiveness of moving the testing for OSA into general practice and how general practitioner (GP)-based screening affects overall detection rates.
METHODS: Randomised controlled trial of case finding of OSA in general practice using a novel Medicines and Healthcare products Regulatory Agency-registered device (AcuPebble SA100) compared with usual care with internal feasibility phase. A diverse sample of general practices (approximately 40) from across the West Midlands Clinical Research Network will identify participants from their records. Eligible participants will be aged 50-70 years with body mass index >30 kg/m2 and diabetes (type 1 or 2) and/or hypertension (office blood pressure >145/90 mm Hg or on treatment). They will exclude individuals with known OSA or chronic obstructive pulmonary disease, or those they deem unable to take part. After eligibility screening, consent and baseline assessment, participants will be randomised to either the intervention or control group. Participants in the intervention arm will receive by post the AcuPebble sleep test kit. Those in the control arm will continue with usual care. Follow-up questionnaires will be completed at 6 months. The study is powered (90%) to detect a 5% difference and will require 606 patients in each arm (713 will be recruited to each arm to allow for attrition). Due to the nature of the intervention, participants and GPs will not be blinded to the allocation.
RESULTS: Primary: Detection rate of moderate-to-severe OSA in the intervention group versus control group. Secondary: Time to diagnosis and time to treatment for intervention versus control group for mild, moderate and severe OSA; cost-effectiveness analysis comparing the different testing pathways.
BACKGROUND: The trial started on 1 November 2022. Ethical approval was granted from the South Central Oxford A Research Ethics Committee on 9 June 2023 (23/SC/0188) (protocol amendment version 1.3; update with amendment and approval to renumber to V2.0 on 29 August 2023). Patient recruitment began on 7 January 2024; initial planned end date will be on 31 April 2025.Results will be uploaded to the ISRCTN register within 12 months of the end of the trial date, presented at conferences, submitted to peer-reviewed journals and distributed via our patient and public involvement networks.The University of Warwick will act as the trial sponsor. The trial will be conducted in accordance with the Sponsor and Primary Care Clinical Trials Unit standard operating procedures.
BACKGROUND: ISRCTN 16982033.

BACKGROUND: Oxygen is frequently prescribed in neurocritical care units. Avoiding hypoxaemia is a key objective in patients with acute brain injury (ABI). However, several studies suggest that hyperoxaemia may also be related to higher mortality and poor neurological outcomes in these patients. The evidence in this direction is still controversial due to the limited number of prospective studies, the lack of a common definition for hyperoxaemia, the heterogeneity in experimental designs and the different causes of ABI. To explore the correlation between hyperoxaemia and poor neurological outcomes and mortality in hospitalised adult patients with ABI, we will conduct a systematic review and meta-analysis of observational studies and RCTs.
METHODS: The systematic review methods have been defined according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and follow the PRISMA-Protocols structure. Studies published until June 2024 will be identified in the electronic databases MEDLINE, Embase, Scopus, Web of Science, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature and ClinicalTrials.gov. Retrieved records will be independently screened by four authors working in pairs, and the selected variables will be extracted from studies reporting data on the effect of \'hyperoxaemia\' versus \'no hyperoxaemia on neurological outcomes and mortality in hospitalised patients with ABI. We will use covariate-adjusted ORs as outcome measures when reported since they account for potential cofounders and provide a more accurate estimate of the association between hyperoxaemia and outcomes; when not available, we will use univariate ORs. If the study presents the results as relative risks, it will be considered equivalent to the OR as long as the prevalence of the condition is close to 10%. Pooled estimates of both outcomes will be calculated applying random-effects meta-analysis. Interstudy heterogeneity will be assessed using the I2 statistic; risk of bias will be assessed through Risk Of Bias In Non-Randomised Studies of Interventions, Newcastle-Ottawa or RoB2 tools. Depending on data availability, we plan to conduct subgroup analyses by ABI type (traumatic brain injury, postcardiac arrest, subarachnoid haemorrhage, intracerebral haemorrhage and ischaemic stroke), arterial partial pressure of oxygen values, study quality, study time, neurological scores and other selected clinical variables of interest.
BACKGROUND: Specific ethics approval consent is not required as this is a review of previously published anonymised data. Results of the study will be shared with the scientific community via publication in a peer-reviewed journal and presentation at relevant conferences and workshops. It will also be shared key stakeholders, such as national or international health authorities, healthcare professionals and the general population, via scientific outreach journals and research institutes\' newsletters.

BACKGROUND: Non-ventilator-associated hospital-acquired pneumonia (nv-HAP) is the most common healthcare-associated infection (HCAI), is associated with high mortality and morbidity and places a major burden on healthcare systems. Diagnosis currently relies on chest x-rays to confirm pneumonia and sputum cultures to determine the microbiological cause. This approach leads to over-diagnosis of pneumonia, rarely identifies a causative pathogen and perpetuates unnecessary and imprecise antibiotic use. The HAP-FAST study aims to evaluate the feasibility of a randomised trial to evaluate the clinical impact of low-dose, non-contrast-enhanced thoracic CT scans and rapid molecular sputum analysis using the BIOFIRE® FILMARRAY® pneumonia plus panel (FAPP) for patients suspected with nv-HAP.
METHODS: The HAP-FAST feasibility study consists of a pilot randomised trial, a qualitative study, a costing analysis and exploratory analyses of clinical samples to investigate the immune-pathophysiology of HAP. Participants are identified and recruited from four acute hospitals in the Northwest of the UK. Using a Research Without Prior Consent model, the pilot trial will recruit 220 adult participants, with or without mental capacity, and with suspected HAP. HAP-FAST is a non-blinded, sequential, multiple assignment, randomised trial with two possible stages of randomisation: first, chest x-ray (CXR) or CT; second, if treated as nv-HAP, FAPP or standard microbiological processing alone (no FAPP). Pathogen-specific antibiotic guidance will be provided for FAPP results. Randomisation uses a web-based platform and followed up for 90 days. The feasibility of a future trial will be determined by assessing trial processes, outcome measures and patient and staff experiences.
BACKGROUND: This study has undergone combined review by the UK NHS Research Ethics Committee and Health Research Authority. Results will be disseminated via peer-reviewed journals, via the funders\' website and through a range of media to engage the public.
BACKGROUND: NCT05483309.

BACKGROUND: Spirometry is a point-of-care lung function test that helps support the diagnosis and monitoring of chronic lung disease. The quality and interpretation accuracy of spirometry is variable in primary care. This study aims to evaluate whether artificial intelligence (AI) decision support software improves the performance of primary care clinicians in the interpretation of spirometry, against reference standard (expert interpretation).
METHODS: A parallel, two-group, statistician-blinded, randomised controlled trial of primary care clinicians in the UK, who refer for, or interpret, spirometry. People with specialist training in respiratory medicine to consultant level were excluded. A minimum target of 228 primary care clinician participants will be randomised with a 1:1 allocation to assess fifty de-identified, real-world patient spirometry sessions through an online platform either with (intervention group) or without (control group) AI decision support software report. Outcomes will cover primary care clinicians\' spirometry interpretation performance including measures of technical quality assessment, spirometry pattern recognition and diagnostic prediction, compared with reference standard. Clinicians\' self-rated confidence in spirometry interpretation will also be evaluated. The primary outcome is the proportion of the 50 spirometry sessions where the participant\'s preferred diagnosis matches the reference diagnosis. Unpaired t-tests and analysis of covariance will be used to estimate the difference in primary outcome between intervention and control groups.
BACKGROUND: This study has been reviewed and given favourable opinion by Health Research Authority Wales (reference: 22/HRA/5023). Results will be submitted for publication in peer-reviewed journals, presented at relevant national and international conferences, disseminated through social media, patient and public routes and directly shared with stakeholders.
BACKGROUND: NCT05933694.

BACKGROUND: Childhood pneumonia is a leading cause of morbidity and mortality among children aged 2-59 months, particularly in low-income and middle-income countries (LMICs), where healthcare providers face significant challenges in diagnosing and treating childhood pneumonia. Many LMICs have taken steps to address this issue by revising their national policies and aligning them with WHO\'s revised guidelines for pneumonia management. These revised guidelines aim to facilitate the outpatient management of children aged 2-59 months chest indrawing pneumonia. Despite these efforts, there is limited empirical evidence regarding the management and outcomes of these children in primary-level healthcare settings. This study aims to assess the survival status of children aged 2-59 months with chest indrawing pneumonia presenting at primary healthcare facilities.
METHODS: A prospective, observational cohort study will be conducted in Ethiopia, Nigeria, Uganda, Zambia, India and Pakistan on children aged 2-59 months presenting at selected primary-level healthcare facilities with chest indrawing pneumonia. Eligible participants will be enrolled and managed by facility healthcare providers who are trained in Integrated Management of Childhood Illness and will be followed up on day 15 to record the treatment-related information and vital status, including conducting verbal autopsies in case of child death. The sample size for each site will be 310. The analysis will involve exploring site-specific trends before conducting a pooled analysis of de-identified data from all sites. The first data collection started at the Ethiopian site in September 2022, followed by other sites. The data collection will continue until June 2025.
BACKGROUND: The study protocol, enrolment forms and consent forms will undergo ethical review by the Institutional Review Boards of the University of Gondar, Gondar, Ethiopia; the INCLEN Trust International Independent Ethics Committee, New Delhi, India; Ethical Review Committee of the University of Ibadan, Ethical Review Committees of Lagos State and Ethical Review Committee of University College London, UK; Institutional Review Board, International Research Force, Islamabad, Pakistan; Institutional Review Board, People\'s Primary Healthcare Initiative-Sindh, Karachi and National Bioethics Committee, Islamabad, Pakistan; Makerere University School of Biomedical Sciences Research Ethical Committee, Kampala, Uganda; University of Zambia Biomedical Research Ethics committee, Lusaka, Zambia and Ethical Review Committee of WHO, Geneva, Switzerland. Ethical procedures include WHO and local review board evaluations, parental consent in the local/national language, permits enrolment, follow-up, and, if required, clinical video recording for children with chest indrawing pneumonia, ensuring their eligibility. Adherence to local regulations encompasses precollection ethical approvals, risk management strategies and secure, de-identified data storage. Findings will be disseminated through seminars, publications and meetings, engaging diverse stakeholders to foster collaborations.
BACKGROUND: ISRCTN12687253.

OBJECTIVE: To evaluate asthma characteristics and treatment patterns, including short-acting β2-agonist (SABA) prescriptions, in primary and specialist care in the Singapore cohort of the SABA use IN Asthma (SABINA III) study.
METHODS: Cross-sectional, observational study.
METHODS: Multicentre study conducted at five sites across Singapore.
METHODS: In patients with asthma (aged ≥12 years), data on demographics, disease characteristics and asthma treatment prescriptions were collected using electronic case report forms. Patients were classified by investigator-defined asthma severity (guided by 2017 Global Initiative for Asthma recommendations) and practice type (primary/specialist care).
RESULTS: Of the 205 patients analysed (mean (SD) age, 53.6 (16.8) years; female, 62%), 55.9% were enrolled by specialists and 44.1% by primary care physicians. Most study patients (80.5%) had moderate-to-severe asthma (86.0% in specialist care and 74.4% in primary care). In the 12 months before study enrolment, 18.0% of patients experienced ≥1 severe exacerbation. Asthma was well or partly controlled in 78.0% of patients. Overall, 17.1% of all patients were overprescribed SABA (≥3 SABA canisters/year) in the preceding 12 months, and overprescription was greater in specialist versus primary care (26.3% vs 5.6%). Only 2.9% of patients were prescribed SABA monotherapy, while 41.0% received SABA in addition to maintenance therapy. Among the latter, 40.5% were overprescribed SABA. Overall, a higher percentage of patients prescribed ≥3 SABA canisters (vs 0-2 SABA canisters) were assessed as having uncontrolled asthma during the study visit (42.9% vs 17.6%). Maintenance therapy in the form of inhaled corticosteroids (ICS) or ICS/long-acting β2 agonist fixed-dose combinations were prescribed to 14.1% and 84.9% of patients, respectively, in the 12 months before enrolment.
CONCLUSIONS: In this Singapore cohort, ~17% of all patients and more than 40% of patients prescribed SABA in addition to maintenance therapy were overprescribed SABA. These findings emphasise the need to align clinical practices with the latest evidence-based treatment recommendations.
BACKGROUND: NCT03857178.

BACKGROUND: Smoking during pregnancy is harmful to unborn babies, infants and women. Nicotine replacement therapy (NRT) is offered as the usual stop-smoking support in the UK. However, this is often used in insufficient doses, intermittently or for too short a time to be effective. This randomised controlled trial (RCT) explores whether a bespoke intervention, delivered in pregnancy, improves adherence to NRT and is effective and cost-effective for promoting smoking cessation.
METHODS: A two-arm parallel-group RCT was conducted for pregnant women aged ≥16 years and who smoke ≥1 daily cigarette (pre-pregnancy smoked ≥5) and who agree to use NRT in an attempt to quit. Recruitment is from antenatal care settings and via social media adverts. Participants are randomised using blocked randomisation with varying block sizes, stratified by gestational age (<14 or ≥14 weeks) to receive: (1) usual care (UC) for stop smoking support or (2) UC plus an intervention to increase adherence to NRT, called \'Baby, Me and NRT\' (BMN), comprising adherence counselling, automated tailored text messages, a leaflet and website. The primary outcome is biochemically validated smoking abstinence at or around childbirth, measured from 36 weeks gestation. Secondary outcomes include NRT adherence, other smoking measures and birth outcomes. Questionnaires collect follow-up data augmented by medical record information. We anticipate quit rates of 10% and 16% in the control and intervention groups, respectively (risk ratio=1.6). By recruiting 1320 participants, the trial should have 90% power (alpha=5%) to detect this intervention effect. An economic analysis will use the Economics of Smoking in Pregnancy model to determine cost-effectiveness.
BACKGROUND: Ethics approval was granted by Bloomsbury National Health Service\'s Research Ethics Committee (21/LO/0123). Written informed consent will be obtained from all participants. Findings will be disseminated to the public, funders, relevant practice/policy representatives, researchers and participants.
BACKGROUND: ISRCTN16830506.
METHODS: 5.0, 10 Oct 2023.

BACKGROUND: Regular clinical reviews of people with COPD provide an opportunity to optimise management and are recommended in national and international guidelines. However, there are limited data about the relationship between having an annual review and other aspects of care quality, which might influence decision-making by healthcare professionals and commissioners.
METHODS: Using data from 74 827 people with COPD completing the Asthma+Lung UK COPD Patient Passport, between 2014 and 2022, we conducted adjusted logistic regression (adjusting for year) and compared receipt of key items of care between those reporting that they had had an annual review (65.3%) and those who did not (34.7%). To further capture patient experience, we also analysed 4228 free-text responses to the 2021 Asthma+Lung UK annual COPD survey to the question \'What is the one thing that could improve your COPD care?\'
RESULTS: We found that the absence of an annual review was associated with significantly worse COPD care across all domains studied; in particular, inhaler training (yes: 80.8% vs no: 38.4%, adjusted OR (AOR): 8.18, 95% CI (7.89 to 8.47), having a written care plan (89.6% vs 56.9%, AOR 6.68 (95% CI 6.35 to 7.05) and medication knowledge (72.6% vs 33.6%, AOR 5.73 (95% CI 5.51 to 5.96). Thematic analysis of the 2021 COPD survey responses identified three areas to improve care: (1) access and support from healthcare services, (2) improved treatment effectiveness and (3) interaction between COPD and the social environment.
CONCLUSIONS: Failure to deliver annual COPD reviews is associated with worse patient-reported experience of care quality. In parallel, people with COPD express a desire for greater support and access to healthcare services.

Management of chronic obstructive pulmonary disease (COPD) with inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) improves lung function and health status and reduces COPD exacerbation risk versus monotherapy. This study described treatment use, healthcare resource utilisation (HCRU), healthcare costs and outcomes following initiation of single-device ICS/LABA as initial maintenance therapy (IMT).
Retrospective cohort study.
Primary care, England.
Linked data from the Clinical Practice Research Datalink Aurum and Hospital Episode Statistics datasets.
Patients with COPD and ≥1 single-device ICS/LABA prescription between July 2015 and December 2018 were included.
Treatment pathways, COPD-related HCRU and healthcare costs, COPD exacerbations, time to triple therapy, medication adherence (proportion of days covered ≥80%) and indexed treatment time to discontinuation. Data for patients without prior maintenance therapy history (IMT users) and non-triple users were assessed over a 12-month follow-up period.
Of 13 451 new ICS/LABA users, 5162 were IMT users (budesonide/formoterol, n=1056; beclomethasone dipropionate/formoterol, n=2427; other ICS/LABA, n=1679), for whom at 3 and 12 months post-index, 45.6% and 39.4% were still receiving any ICS/LABA. At >6 to ≤12 months, the proportion of IMT users with ≥1 outpatient visit (10.1%) and proportion with ≥1 inpatient stay (12.6%) had increased from those at 3 months (9.0% and 7.4%, respectively). Inpatient stays contributed most to total COPD-related healthcare costs. For non-triple IMT users, at 3 and 12 months post-index, 4.5% and 13.7% had ≥1 moderate-to-severe COPD exacerbation. Time to triple therapy initiation and time to discontinuation of index medication ranged from 45.9 to 50.2 months and 2.3 to 2.8 months between treatments. Adherence was low across all time points (21.5-27.6%). Results were similar across indexed therapies.
In the year following treatment initiation, ICS/LABA adherence was poor and many patients discontinued or switched therapies, suggesting that more consideration and optimisation of treatment is required in England for patients initiating single-device ICS/LABA therapy.