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Introduction Health research bodies recommend patient involvement and engagement in research and healthcare planning, although their implementation is not yet widespread. This deficiency extends to progressive pulmonary fibrosis (PPF), where crucial aspects remain unknown, including causal mechanisms, curative treatments and optimal symptom management. This study addresses these gaps by seeking stakeholders’ perspectives to guide research and treatment directions.Method A priority-setting partnership was established to explore stakeholders’ priorities in the diagnosis, treatment, management and care of PPF, including idiopathic pulmonary fibrosis which is the archetypal PPF. Stakeholders included people living with PPF, their carers, relatives and healthcare professionals involved in their management.Results Through an online open-ended survey, 2542 responses were collected from 638 stakeholders. Thematic analysis identified 48 specific research questions, which were then cross-referenced with academic literature to pinpoint research gaps. Following the evidence check, 44 unanswered questions were shortlisted by 834 stakeholders in a second online survey. Ultimately, a top 10 priority list was established through consensus.The prioritised research questions include (1) improved diagnosis accuracy and timing, (2) development of new treatments, (3) enhanced accuracy in primary care, (4) optimal timing for drug and non-drug interventions, (5) effective cough treatment, (6) early intervention for PPF, (7) improved survival rates, (8) symptom reduction, (9) impact of interventions on life expectancy and (10) new treatments with reduced side effects.Conclusion Stakeholders’ priorities can be summarised into five areas: early diagnosis, drug and non-drug treatments, survival and symptom management. Ideally, these topics should guide funding bodies and health policies.

Summary: Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%–68.2%), compared with 63.4% in the control group (95% CI 61.8%–65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%–20.7%), compared with 18.8% in the control group (95% CI 17.4%–20.2%) a difference of +0.6 percentage points (95% CI −1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.

Objectives Mycophenolate mofetil (MMF) and azathioprine (AZA) are immunomodulatory treatments in interstitial lung disease (ILD). This systematic review aimed to evaluate the efficacy of MMF or AZA on pulmonary function in ILD.Design Population included any ILD diagnosis, intervention included MMF or AZA treatment, outcome was delta change from baseline in per cent predicted forced vital capacity (%FVC) and gas transfer (diffusion lung capacity of carbon monoxide, %DLco). The primary endpoint compared outcomes relative to placebo comparator, the secondary endpoint assessed outcomes in treated groups only.Eligibility criteria Randomised controlled trials (RCTs) and prospective observational studies were included. No language restrictions were applied. Retrospective studies and studies with high-dose concomitant steroids were excluded.Data synthesis The systematic search was performed on 9 May. Meta-analyses according to drug and outcome were specified with random effects, I2 evaluated heterogeneity and Grading of Recommendations, Assessment, Development and Evaluation evaluated certainty of evidence. Primary endpoint analysis was restricted to RCT design, secondary endpoint included subgroup analysis according to prospective observational or RCT design.Results A total of 2831 publications were screened, 12 were suitable for quantitative synthesis. Three MMF RCTs were included with no significant effect on the primary endpoints (%FVC 2.94, 95% CI −4.00 to 9.88, I2=79.3%; %DLco −2.03, 95% CI −4.38 to 0.32, I2=0.0%). An overall 2.03% change from baseline in %FVC (95% CI 0.65 to 3.42, I2=0.0%) was observed in MMF, and RCT subgroup summary estimated a 4.42% change from baseline in %DLCO (95% CI 2.05 to 6.79, I2=0.0%). AZA studies were limited. All estimates were considered very low certainty evidence.Conclusions There were limited RCTs of MMF or AZA and their benefit in ILD was of very low certainty. MMF may support preservation of pulmonary function, yet confidence in the effect was weak. To support high certainty evidence, RCTs should be designed to directly assess MMF efficacy in ILD.PROSPERO registration number CRD42023423223.

Summary: Background: The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. Methods: Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. Findings: Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E. coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. Interpretation: ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. Funding: Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children’s. BRACE trial funding is detailed in acknowledgements.

Background Interstitial lung disease frequently complicates systemic autoimmune disorders including scleroderma, idiopathic inflammatory myositis and mixed connective tissue disease, resulting in considerable morbidity and mortality. Based on the results of trials undertaken in scleroderma, cyclophosphamide is the standard of care for individuals with severe or progressive connective tissue disease-associated interstitial lung disease. Observational studies suggest that the anti-CD20 monoclonal antibody, rituximab is an effective rescue therapy in treatment of refractory connective tissue disease-associated interstitial lung disease, but it has not been studied as first-line therapy in clinical trials. Objectives To compare the safety and efficacy of rituximab against that of cyclophosphamide as treatment for individuals with severe, progressive interstitial lung disease associated with scleroderma, idiopathic inflammatory myositis or mixed connective tissue disease. Methods This was a Phase IIb, multicentre, randomised, double-blind, double-dummy study assessing the superiority of rituximab compared with cyclophosphamide, conducted in rheumatology or interstitial lung disease units at 11 UK centres. The study recruited individuals with extensive and/or progressive connective tissue disease-associated interstitial lung disease, excluding those with significant comorbidities, including airflow obstruction. Participants were randomised 1 : 1 to receive either rituximab 1 g given intravenously, twice at an interval of 2 weeks, or intravenous cyclophosphamide given monthly for 6 months at a dose of 600 mg/m2 body surface area. The primary end point for the study was the change in forced vital capacity at 24 weeks. Secondary end points included safety and tolerability, corticosteroid exposure, forced vital capacity change at 48 weeks and patient-reported quality of life. A cost-effectiveness analysis was undertaken to assess the impact of rituximab use in the United Kingdom National Health Service. Results One hundred and one subjects (70 females) with a mean age of 56.3 years were randomised; 51 to rituximab and 50 to cyclophosphamide. Ninety-seven were included in the modified intention-to-treat population for the primary and secondary efficacy analyses (49 in the rituximab group and 48 in the cyclophosphamide group). 38.6% had scleroderma, 44.6% idiopathic inflammatory myositis and 16.8% mixed connective tissue disease. Four subjects withdrew prior to the first dose of therapy (two in each arm). At 24 weeks, both rituximab and cyclophosphamide improved forced vital capacity from baseline [(mean ± standard deviation) 97 ± 234 and 99 ± 329 ml, respectively]. Using an adjusted mixed-effects model corrected for diagnosis and baseline forced vital capacity the difference in forced vital capacity at 24 weeks between rituximab and cyclophosphamide was −40 ml (95% CI −153 to 74 ml), p = 0.49. Other physiological and quality-of-life parameters improved in both arms following treatment but were not statistically significantly different between groups. Numerically fewer adverse events were reported by subjects receiving rituximab. Corticosteroid exposure over the 48 weeks of the trial was numerically less in the rituximab arm [13,291 (±14,657) mg of hydrocortisone equivalent per subject in the cyclophosphamide arm versus 11,469 (±10,041) mg per subject in the rituximab group; these differences did not reach statistical significance]. Limitations of the study include a disproportionate number of subjects being recruited from a single centre and insufficient subjects in each subgroup to determine whether there were treatment differences between individual connective tissue diseases. Based on the results of the trial, from a UK healthcare payer perspective, rituximab is more cost-effective than cyclophosphamide as a treatment for severe or progressive connective tissue disease-interstitial lung disease. Conclusions Rituximab improved forced vital capacity and patient-reported quality of life at 24 weeks but was not superior to cyclophosphamide. Rituximab should be considered as a therapeutic alternative to cyclophosphamide in individuals with connective tissue disease-associated interstitial lung disease requiring systemic therapy. Future work should explore the role of repeated dosing of rituximab and the use of rituximab earlier in the course of connective tissue disease-associated interstitial lung disease. Trial registration This trial is registered as ISRCTN16474148. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (NIHR award ref: 11/116/03) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 4. See the NIHR Funding and Awards website for further award information. Plain language summary Interstitial lung disease, a condition characterised by inflammation and scarring of the lungs, is the leading cause of death in systemic sclerosis (an autoimmune disease that typically causes thickening and scarring of the skin and which is associated with internal organ problems such as interstitial lung disease and kidney failure), and a major cause of morbidity (illness) in many other connective tissue diseases; a group of conditions that are caused by over activity of the immune system. When interstitial lung disease associated with connective tissue disease gets worse over time, treatment such as intravenous cyclophosphamide is required to slow down lung scarring. Occasionally, standard immunosuppressive drugs fail to control lung inflammation and scaring and this can result in death. Rituximab, a novel therapy, has been proven to be of benefit in suppressing inflammation associated with immune system over activity. Observational studies suggest that rituximab may be an effective treatment for pulmonary inflammation in connective tissue diseases. The study was designed to determine how well rituximab works compared to cyclophosphamide in treating patients with severe connective tissue disease-associated interstitial lung disease. We recruited 101 participants from 11 hospitals throughout the UK who were randomly allocated to one of two groups. Those in the first group were given rituximab on day 1 of the study and then on day 14. They were then given a placebo every 4 weeks for the next 18 weeks. Those in the second group were given cyclophosphamide every 4 weeks from day 1 of the study to week 20. On day 14, they were given a placebo. Lung function for all participants was assessed at 24 weeks. Our results suggest that rituximab improved lung function and quality of life but was not better than cyclophosphamide. Rituximab was associated with fewer unexpected medical events and a trend towards reduction in corticosteroid use and should be considered as a therapeutic alternative to cyclophosphamide. Scientific summary Background Interstitial lung disease (ILD) is characterised by inflammation and/or fibrosis within the parenchymal compartment bounded by the alveolar epithelium and capillary endothelium and frequently results in breathlessness progressing over time to respiratory failure. Autoimmune injury to the lung is a frequent cause of ILD. As such, the connective tissue diseases (CTDs), including systemic sclerosis (SSc), the inflammatory myopathies and mixed connective tissue disease (MCTD), are important causes of ILD. For individuals with CTD the development of ILD is an important cause of morbidity and mortality; for people with scleroderma, ILD is now the leading cause of death. Despite this there are few evidence-based treatments for CTD-associated ILD. At the time of planning this research there were no approved therapies available for CTD-ILD and all of the trial data which existed had been generated in the context of scleroderma-associated ILD. The Scleroderma Lung Study I assessed the efficacy of 52 weeks of treatment with oral cyclophosphamide (CP) compared to placebo in individuals with systemic sclerosis-associated ILD and evidence of an active inflammatory cell infiltrate on bronchoalveolar lavage. The trial demonstrated a positive effect of CP at 52 weeks but the drug was poorly tolerated and the benefit compared with placebo had disappeared by 2 years. A smaller 52-week study, also conducted in individuals with scleroderma-associated ILD, compared placebo to once-monthly intravenous CP given for 6 months followed by azathioprine and low dose prednisolone for the subsequent 6 months and showed a trend towards benefit in the active treatment arm. In the absence of treatment guidelines or evidence generated in other forms of CTD-ILD, most centres in the UK were routinely using intravenous CP as first-line therapy for individuals with clinically advanced or rapidly progressive ILD arising in the context of CTD. Rituximab, a chimeric (human/mouse) monoclonal antibody with a high affinity for the CD20 surface antigen expressed on B-lymphocytes, results in rapid depletion of B cells from the peripheral circulation for 6–9 months. Evidence for the efficacy of B cell depletion exists in a number of immune-mediated conditions, including rheumatoid arthritis, antineutrophil cytoplasmic antibody-associated vasculitis and immune thrombocytopenic purpura. Several case series suggest rituximab may also be effective in ILD occurring in the context of immunological over-activity, with favourable responses reported in antisynthetase-associated ILD and SSc-ILD. Our own clinical experience suggested that rituximab is an effective, potentially life-saving therapeutic intervention in the treatment of very severe, progressive CTD-ILD unresponsive to conventional immunosuppression. In head-to-head studies in the context of other autoimmune diseases rituximab has been shown to have a favourable safety and tolerability profile compared to CP. The absence of high-quality evidence to guide treatment of CTD-ILD provided an opportunity to assess the efficacy of rituximab compared to the accepted standard of care, CP. Objectives The primary objective of the study was to demonstrate that intravenous rituximab has superior efficacy compared to current best treatment (intravenous CP) for CTD-ILD as measured by assessment of change in forced vital capacity (FVC) at 24 weeks. Secondary objectives were: to compare the safety profile of rituximab to intravenous CP in individuals with CTD-ILD to assess the health economic benefits of rituximab compared to current standard of care for CTD-ILD – including measurements of healthcare utilisation, quality of life (QoL) and carer burden to evaluate a range of exploratory biomarkers for disease severity, prognosis and treatment response in CTD-ILD. Methods The study was a Phase IIb, UK multicentre, prospective, randomised, double-blind, double-dummy trial of intravenous rituximab compared with intravenous CP in patients with severe, progressive CTD-ILD. Patients were randomised 1 : 1 to two groups, both groups received placebo to match the different regimens. Patients were followed for 48 weeks after first treatment; after 24 weeks subjects were permitted additional immunotherapy as determined by their treating physician. Study settings The study was conducted in rheumatology or ILD units at 11 UK centres. Participant inclusion criteria A diagnosis of CTD, based on internationally accepted criteria, in one of the following categories: systemic sclerosis idiopathic interstitial myopathy (including polymyositis/dermatomyositis) MCTD. Severe and/or progressive ILD associated with the underlying CTD. Chest high-resolution computer tomography performed within 12 months of randomisation. Intention of the caring physician to treat the ILD with intravenous CP. Able to provide written informed consent. Participant exclusion criteria Previous treatment with rituximab and/or intravenous CP. Age 80 years. Known hypersensitivity to rituximab or CP or their components. Significant (in the opinion of the investigator) other organ comorbidity including cardiac, hepatic or renal impairment. Coexistent obstructive pulmonary disease (e.g. asthma, chronic obstructive pulmonary disease, emphysema) with pre-bronchodilator forced expiratory volume in 1 second (FEV1) and FVC ratio < 70%. Patients at significant risk for infectious complications following immunosuppression including those with human immunodeficiency virus positive or other immunodeficiency syndromes (including hypogammaglobulinemia). Suspected or proven untreated tuberculosis. Viral hepatitis. Infection requiring antibiotic treatment in the preceding 4 weeks. Unexplained neurological symptoms (which may be suggestive of progressive multifocal leucoencephalopathy). Neurological symptoms arising because of the underlying CTD do not necessitate exclusion. Other investigational therapy (participation in research trial) received within 8 weeks of randomisation. Immunosuppressive or CTD modifying therapy (other than corticosteroids) received within 2 weeks of the first intravenous treatment. Pregnant or breastfeeding women, or women of child-bearing potential, not using a reliable contraceptive method for up to 12 months following IMP. Unexplained haematuria, or previous bladder carcinoma. Computerised tomography scan > 12 months from randomisation. Unable to provide informed written consent. Interventions Patients were randomised to receive either: Rituximab 1000 mg for two doses at day 0 and day 14. Placebo was administered monthly from week 4 to week 20. CP given at a dose of 600 mg/m2 body surface area rounded to the nearest 100 mg every 4 weeks from day 0 to week 20. Placebo was given at day 14. Patients were pre-medicated on day 0 with hydrocortisone, paracetamol, chlorpheniramine and mesna, at day 14 with hydrocortisone, paracetamol and chlorpheniramine and at visits from week 4 to 20 with mesna. Measurements Wherever possible, even if treatment could not be given, spirometry was undertaken at the time of each planned visit and performed according to standards outlined in the American Thoracic Society/European Respiratory Society guidelines. Lung function tests (plethysmography and gas transfer) were measured at screening, baseline, week 12, week 24 and week 48. Assessment for adverse events (AEs) and clinical end points began from randomisation and continued for the individual patient until they completed their follow-up at 48 weeks. At each study visit the investigator or designee made an assessment of safety and reviewed the clinical history and investigation findings with regard to the occurrence of adverse or serious adverse events (SAEs). Peripheral blood was taken at the time of each planned visit. Collection of blood for laboratory analyses included full blood count, erythrocyte sedimentation rate, urea and electrolytes, glucose, hepatitis A, B and C serology (screening only) and liver function tests. Blood for lymphocyte subsets and biomarker analysis was taken at day 0, week 12, 24 and 48 only. Quality of life was assessed by self-administered validated questionnaires undertaken at baseline and repeated at the primary end point visit at 24 weeks and at the final follow-up visit at 48 weeks. The instruments used were: the Short Form 36 (SF36) questionnaire EuroQol-5 Dimensions (EQ-5D) St George’s Respiratory Questionnaire (SGRQ) King’s Brief Interstitial Lung Disease (K-BILD) Scleroderma Health Assessment (SHA) Questionnaire which was disease-specific. For individuals with scleroderma, assessment of skin thickening was undertaken using the modified Rodnan skin score at baseline, 24 and 48 weeks. Sample size The primary outcome was changed in FVC at 24 weeks. The trial was designed to have 90% power to detect a 5% difference in 24-week FVC between treatment groups with a significance level (alpha) of 0.05 (two-tailed). The target sample size was 116 with the anticipation that 52 patients would reach the end-of-study in each arm with an expected 10% drop out. Because of the COVID-19 pandemic and an anticipated prolonged interruption to recruitment, trial enrolment was halted in March 2020 after randomisation of 101 subjects. Statistical analysis No formal interim analysis was planned. A statistical analysis plan was produced and agreed prior to analysis. Analysis of the primary outcome was by modified intention to treat. In other words, data were included in respect of all subjects who met all the entry criteria for the trial and had been randomised and received at least one dose of study drug. Results The study recruitment period was from December 2014 until March 2020 from 11 sites. In total 145 subjects were assessed for eligibility and of these 104 participants were enrolled. Three of these failed screening and were excluded. One hundred and one subjects were therefore randomised and 97 subjects received at least one dose of study drug and were included in the modified intention-to-treat population for the primary and secondary efficacy analyses (49 in the rituximab group and 48 in the CP group). Overall, baseline characteristics between the rituximab and CP arms were well balanced albeit with slightly more male participants in the rituximab arm. For the total cohort the mean ± S.D. age was 56 ± 11.4 years. Seventy subjects (69.3%) were female, 70 (69.3%) were white, 16 (15.8%) Asian and 12 (11.9%) black. The most frequently encountered CTD was idiopathic inflammatory myopathy (44.6%), followed by scleroderma (38.6%) and then MCTD (16.8%). Primary outcome At week 24 the unadjusted mean [± standard deviation (SD)] change in FVC in the CP treatment arm was a gain of 99 ± 329 ml. In the rituximab arm the change was 97 ± 234 ml. The relative change from baseline for each arm was 4.35 ± 15.67% for CP and for rituximab 4.31 ± 11.80%. Using a mixed-effects model adjusted for baseline FVC and diagnosis the difference (and 95% confidence interval) at 24 weeks between rituximab and CP was −40 ml [95% confidence interval (CI) −153 to 74 ml], p = 0.49. Secondary outcomes The unadjusted change in FVC at 48 weeks was 138 ± 440 ml in the CP arm and 112 ± 249 ml in the rituximab group. In relative terms, over 48 weeks, the improvement in the CP group was 5.08 ± 19.96% and in the rituximab group 4.22 ± 10.31%. An adjusted mixed-effects model demonstrated a −58 (95% CI −178 to 62) ml difference at 48 weeks between the rituximab and CP arms (p = 0.251). At week 24 the mean relative change in diffusing capacity of the lung for carbon monoxide (DLco) in the CP arm was 1.43 ± 23.05% compared to 6.98 ± 17.19% in the rituximab arm. At 48 weeks the changes in DLco were 3.00 ± 31.35% and 7.43 ± 16.08% in the CP and rituximab arms, respectively. For 6-minute walk distance the 24-week change in the CP and rituximab arms was 10.4 ± 78.6 and 10.9 ± 74.2 m, respectively. At week 48 the changes were 15.1 ± 82.8 and −6.8 ± 69.8 m. Using an adjusted mixed-effects model the differences between the rituximab and CP arms were −0.72 (−24.76 to 23.32) m, p = 0.953 at 24 weeks and −22.46 (−48.43 to 3.51) m, p = 0.090 at 48 weeks. Quality of life was assessed using the K-BILD questionnaire. Change at 24 weeks was 9.4 ± 20.8 in the CP arm and 8.8 ± 17.0 in the rituximab arm. At 48 weeks the difference compared to baseline was 5.6 ± 25.6 and 6.4 ± 16.2 in the CP and rituximab arms, respectively. Analysis in an adjusted mixed-effects model showed the difference between rituximab and CP was 0.4 (−5.73 to 6.52) and 1.15 (−5.34 to 7.64) at weeks 24 and 48, respectively. Survival Over the 48-week course of the study there were five deaths. All were deemed to be due to complications of either CTD or ILD. Three occurred in subjects receiving rituximab and two in subjects receiving CP. There was no difference between groups in time to death as assessed by an adjusted Cox proportional hazards model [hazard ratio (HR) 1.72 (95% CI 0.311 to 9.56, p = 0.534)]. The rates of progression-free survival [HR 1.11 (95% CI 0.625 to 1.99, p = 0.715)], and time to treatment failure [HR 1.25 (95% CI 0.34 to 4.65, p = 0.742)] did not differ between treatment arms. Corticosteroids The mean per-subject total steroid exposure during the study (measured in hydrocortisone equivalents) was 13,291 (±14,657) mg in the CP and 11,469 (±10,041) mg in the rituximab group; a 12% reduction in corticosteroid exposure in the rituximab arm. The daily mean dose per patient was 42.89 mg hydrocortisone/day in the CP and 37.61 mg hydrocortisone/day in the rituximab group. Safety All subjects in both arms experienced at least one AE. There were more AEs reported in the CP arm (646) than in the rituximab arm (445). The imbalance was less marked for SAEs with 33 and 29 in the CP and rituximab arms, respectively. Gastrointestinal disorders (170 vs. 71), general disorders and administration site reactions (91 vs. 52) and nervous system disorders (72 vs. 35) were more common in the CP arm. The frequency of other AEs was balanced between groups including infections and infestations (50 vs. 46). One patient in each arm withdrew because of side effects. There were no reported cases of COVID-19 during the trial. Cost-effectiveness Over the 48-week trial period treatment with CP was associated with a cost of £94,338 compared with a cost of £93,227 for rituximab; a difference of £1110 in favour of rituximab. Rituximab was associated with a 0.022 gain in quality-adjusted life-years over that seen with CP. The incremental net monetary benefit was significantly higher in the rituximab group under a wide range of monetary values and quality-adjusted life-years. Conclusion This study demonstrated that both rituximab and CP improve FVC and QoL in patients with CTD-ILD. There were numerically fewer AEs and a trend towards reduction in corticosteroid exposure in the rituximab-treated subjects. Rituximab should therefore be considered as a treatment option in patients with severe or rapidly progressive CTD-associated ILD. Implications for health care Although this study failed to show superiority of rituximab over CP in improving FVC when used as first-line treatment for CTD-ILD, the consistent positive effects of rituximab on physiological end points, QoL, and corticosteroid requirements support the clinical use of this drug in what is a population of patients with high unmet need (especially in situations where CP is contraindicated or likely to cause deleterious effects such as gonad failure or bladder malignancy). Implications for research Further trials will be necessary to confirm whether repeated dosing with rituximab confers additional benefit as compared to a single baseline dose. Similarly, additional studies are necessary to confirm findings in individual CTDs and to assess the optimal longer-term therapeutic regimen following initial intravenous therapy. Trial registration This trial is registered as ISRCTN16474148. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (NIHR award ref: 11/116/03) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 4. See the NIHR Funding and Awards website for further award information.

Background Opportunities for home-monitoring are increasing exponentially. Home- spirometry is reproducible and reliable in interstitial lung disease (ILD), yet patients’ experiences are not reported. Given the morbidity and mortality associated with ILDs, maintaining health-related quality-of-life is vital. We report our findings from a codesigned, qualitative study capturing the perspectives and experiences of patients using home-spirometry in a UK regional ILD National Health Service England (NHSE) commissioned service.Methods Patients eligible for home-spirometry as routine clinical care, able to give consent and able to access a smart phone were invited to participate. In-depth, semistructured interviews were conducted at serial time points (baseline, 1, 3 and 6 months), recorded, transcribed and analysed thematically.Results We report on the experiences of 10 recruited patients (8 males; median age 66 years, range 50–82 years; 7 diagnosed with idiopathic pulmonary fibrosis, 3 other ILDs) who generally found spirometry convenient and easy to use, but their relationships with forced vital capacity results were complex. Main themes emerging were: (1) anticipated benefits—to identify change, trigger action and aid understanding of condition; (2) needs—clinical oversight and feedback, understanding of results, ownership, need for data and a need ‘to know’; (3) emotional impact—worry, reassurance, ambivalence/conflicting feelings, reminder of health issues, indifference; (4) ease of home-spirometry—simplicity, convenience and (5) difficulties with home-spirometry—technical issues, technique, physical effort.Conclusion Home-spirometry has many benefits, but in view of the potential risks to psychological well-being, must be considered on an individual basis. Informed consent and decision-making are essential and should be ongoing, acknowledging potential limitations as well as benefits. Healthcare support is vital.

Summary: Background: Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods: In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2−8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27–2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32–0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69–3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26–0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3–2.6%, p = 0.02). There were no safety concerns. Interpretation: BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Funding: Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.

Background Nintedanib slows lung function decline for patients with non-idiopathic pulmonary fibrosis progressive pulmonary fibrosis (PPF) in clinical trials, but the real-world safety and efficacy are not known. Methods In this retrospective cohort study, standardised data were collected from patients in whom nintedanib was initiated for PPF between 2019 and 2020 through an early-access programme across eight centres in the United Kingdom. Rate of lung function change in the 12 months pre- and post-nintedanib initiation was the primary analysis. Symptoms, drug safety, tolerability and stratification by interstitial lung disease subtype and computed tomography pattern were secondary analyses. Results 126 patients were included; 67 (53%) females; mean±sd age 60±13 years. At initiation of nintedanib, mean forced vital capacity (FVC) was 1.87 L (58% predicted) and diffusing capacity of the lung for carbon monoxide (DLCO) was 32.7% predicted. 68% of patients were prescribed prednisolone (median dose 10 mg) and 69% were prescribed a steroid-sparing agent. In the 12 months after nintedanib initiation, lung function decline was significantly lower than in the preceding 12 months: FVC −88.8 mL versus −239.9 mL (p=0.004), and absolute decline in DLCO −2.1% versus −6.1% (p=0.004). Response to nintedanib was consistent in sensitivity and secondary analyses. 89 (71%) out of 126 patients reported side-effects, but 86 (80%) of the surviving 108 patients were still taking nintedanib at 12 months with patients reporting a reduced perception of symptom decline. There were no serious adverse events. Conclusion In PPF, the real-world efficacy of nintedanib replicated that of clinical trials, significantly attenuating lung function decline. Despite the severity of disease, nintedanib was safe and well tolerated in this real-world multicentre study.

Summary: Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease trajectory. The aim of this study was to assess the potential of neutrophil-to-lymphocyte ratio (NLR) to predict outcomes in IPF. Methods: We adopted a two-stage discovery (n = 71) and validation (n = 134) design using patients from the UCL partners (UCLp) cohort. We then combined discovery and validation cohorts and included an additional 794 people with IPF, using real-life data from 5 other UK centers, to give a combined cohort of 999 patients. Data were collected from patients presenting over a 13-year period (2006–2019) with mean follow up of 3.7 years (censoring: 2018–2020). Findings: In the discovery analysis, we showed that high values of NLR (>/ = 2.9 vs

Summary: Large-scale, high-throughput specificity assays to characterize binding properties within a competitive and complex environment of potential binder-target pairs remain challenging and cost prohibitive. Barcode cycle sequencing (BCS) is a molecular binding assay for proteins, peptides, and other small molecules that is built on a next-generation sequencing (NGS) chip. BCS uses a binder library and targets labeled with unique DNA barcodes. Upon binding, binder barcodes are ligated to target barcodes and sequenced to identify encoded binding events.For complete details on the use and execution of this protocol, please refer to Hong et al. (2022). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Summary: We demonstrate early progress toward constructing a high-throughput, single-molecule protein sequencing technology utilizing barcoded DNA aptamers (binders) to recognize terminal amino acids of peptides (targets) tethered on a next-generation sequencing chip. DNA binders deposit unique, amino acid-identifying barcodes on the chip. The end goal is that, over multiple binding cycles, a sequential chain of DNA barcodes will identify the amino acid sequence of a peptide. Toward this, we demonstrate successful target identification with two sets of target-binder pairs: DNA-DNA and Peptide-Protein. For DNA-DNA binding, we show assembly and sequencing of DNA barcodes over six consecutive binding cycles. Intriguingly, our computational simulation predicts that a small set of semi-selective DNA binders offers significant coverage of the human proteome. Toward this end, we introduce a binder discovery pipeline that ultimately could merge with the chip assay into a technology called ProtSeq, for future high-throughput, single-molecule protein sequencing.

Introduction BCG vaccination modulates immune responses to unrelated pathogens. This off-target effect could reduce the impact of emerging pathogens. As a readily available, inexpensive intervention that has a well-established safety profile, BCG is a good candidate for protecting healthcare workers (HCWs) and other vulnerable groups against COVID-19.Methods and analysis This international multicentre phase III randomised controlled trial aims to determine if BCG vaccination reduces the incidence of symptomatic and severe COVID-19 at 6 months (co-primary outcomes) compared with no BCG vaccination. We plan to randomise 10 078 HCWs from Australia, The Netherlands, Spain, the UK and Brazil in a 1:1 ratio to BCG vaccination or no BCG (control group). The participants will be followed for 1 year with questionnaires and collection of blood samples. For any episode of illness, clinical details will be collected daily, and the participant will be tested for SARS-CoV-2 infection. The secondary objectives are to determine if BCG vaccination reduces the rate, incidence, and severity of any febrile or respiratory illness (including SARS-CoV-2), as well as work absenteeism. The safety of BCG vaccination in HCWs will also be evaluated. Immunological analyses will assess changes in the immune system following vaccination, and identify factors associated with susceptibility to or protection against SARS-CoV-2 and other infections.Ethics and dissemination Ethical and governance approval will be obtained from participating sites. Results will be published in peer-reviewed open-access journals. The final cleaned and locked database will be deposited in a data sharing repository archiving system.Trial registration ClinicalTrials.gov NCT04327206

This paper combines a synthetic jet actuator (SJA) and a leeward porous coating to alter the aerodynamic forces on a cylinder in crossflow at Re = 4.2 × 104. While SJAs and porous coatings are known to be effective flow control methods in isolation, their combined effect has not been studied. A 2D numerical model was created of a cylinder with a SJA at 90° and 100° leeward porous coating. The model was validated using accompanying water tunnel tests. The combined model was tested for dimensionless frequencies 0.15 1, the combined SJA and porous coating configuration did not differ from the SJA only configuration, achieving the largest drag reduction of 45% at f+ = 4. The flow control mechanisms of the SJA and porous coating do not combine constructively in this current setup. However, the porous coating is beneficial for f+< 1, causing an overall drag reduction even when the active SJA tends to increase drag.

Methods A retrospective, multicentre, observational UK cohort study.Results Patients with fHP were significantly younger than those with idiopathic pulmonary fibrosis (IPF) (median age fHP 73 vs IPF 75 years) and were much more likely to be woman (fHP 61% vs IPF 26%). In almost half of all fHP cases (49%, n=104/211), no causative antigen was identified from either the history or specific antigen testing. Overall, fHP was associated with a better survival than IPF, although median survival of both groups was poor (fHP 62 months vs IPF 52 months).IPF survival in patients with a high NLR was significantly lower than those with a low NLR (44 vs 83 months). A monocyte count ≥0.95 K/uL also predicted significantly poorer outcomes for patients with IPF compared with

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and terminal interstitial lung disease (ILD) with a median survival of 3–5 years. The British Thoracic Society (BTS) established the UK IPF Registry in 2013 as a platform to collect data on clinical characteristics, treatments and outcomes for this cohort in the UK. Between 1 January 2013 and 31 October 2019, 2474 cases were registered. Most patients were male (79%) with a mean±sd age of 74±8.3 years and 66% were ex-smokers. Over time we observed an increase in the number of patients aged over 70 years. However, we have not seen a trend towards earlier presentation as symptoms of breathless and/or cough were present for >12 months in 63% of the cohort. At presentation, mean±sd % predicted forced vital capacity (FVC) was 78.2±18.3%, median 76.2% (interquartile range (IQR) 22.4%) and transfer factor of the lung for carbon monoxide (TLCO) 48.4±16.0, median 47.5 (IQR 20.1). Most cases were discussed at an ILD multidisciplinary meeting, with an increase over this time in the number of cases reported as having possible usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography (HRCT) thorax. We noted a reduction in the number of patients undergoing surgical lung biopsy or bronchoalveolar lavage. Although more patients were prescribed anti-fibrotic therapies from 2013 to 2019, 43% were ineligible for treatment based upon National Institute for Health and Care Excellence (NICE) prescribing criteria. Hypertension, ischaemic heart disease, diabetes mellitus and gastro-oesophageal reflux were the most common comorbidities. In conclusion, we have presented baseline demographics as well as diagnostic and treatment strategies from the largest single-country IPF registry, reflecting changes in UK practices over this period.

Introduction Cardiopulmonary exercise testing (CPET) provides a series of biomarkers, such as peak oxygen uptake, which could assess the development of disease status in interstitial lung disease (ILD). However, despite use in research and clinical settings, the feasibility of CPET in this patient group has yet to be established.Methods Twenty-six patients with ILD (19 male) were recruited to this study. Following screening for contraindications to maximal exercise, participants underwent an incremental CPET to volitional exhaustion. Feasibility of CPET was assessed by the implementation, practicality, acceptability and demand, thus providing clinical-driven and patient-driven information on this testing procedure.Results Of the 26 recruited participants, 24 successfully completed at least one CPET, with 67/78 prospective tests being completed. Contraindications included hypertension, low resting oxygen saturation and recent pulmonary embolism. Of the CPETs undertaken, 63% successfully reached volitional exhaustion, with 31% being terminated early by clinicians due to excessive desaturation. Quantitative and qualitative feedback from participants revealed a positive experience of CPET and desire for it to be included as a future monitoring tool.Conclusion CPET is feasible in patients with ILD. Identification of common clinical contraindications, and understanding of patient perspectives will allow for effective design of future studies utilising CPET as a monitoring procedure.

Background Establishing whether patients are exposed to a ‘known cause’ is a key element in both the diagnostic assessment and the subsequent management of hypersensitivity pneumonitis (HP).Objective This study surveyed British interstitial lung disease (ILD) specialists to document current practice and opinion in relation to establishing causation in HP.Methods British ILD consultants (pulmonologists) were invited by email to take part in a structured questionnaire survey, to provide estimates of demographic data relating to their service and to rate their level of agreement with a series of statements. A priori ‘consensus agreement’ was defined as at least 70% of participants replying that they ‘Strongly agree’ or ‘Tend to agree’.Results 54 consultants took part in the survey from 27 ILD multidisciplinary teams. Participants estimated that 20% of the patients in their ILD service have HP, and of these, a cause is identifiable in 32% of cases. For patients with confirmed HP, an estimated 40% have had a bronchoalveolar lavage for differential cell counts, and 10% a surgical biopsy. Consensus agreement was reached for 25 of 33 statements relating to causation and either the assessment of unexplained ILD or management of confirmed HP.Conclusions This survey has demonstrated that although there is a degree of variation in the diagnostic approach for patients with suspected HP in Britain, there is consensus opinion for some key areas of practice. There are several factors in clinical practice that currently act as potential barriers to identifying the cause for British HP patients.

Real-world studies include a broader patient population for a longer duration than randomised controlled trials (RCTs) and can provide relevant insights for clinical practice. PASSPORT was a multicentre, prospective, post-authorisation study of patients who were newly prescribed pirfenidone and followed for 2 years after initiating treatment. Physicians collected data on adverse drug reactions (ADRs), serious ADRs (SADRs) and ADRs of special interest (ADRSI) at baseline and then every 3 months. Post hoc stepwise logistic regression models were used to identify baseline characteristics associated with discontinuing treatment due to an ADR. Patients (n=1009, 99.7% with idiopathic pulmonary fibrosis) had a median pirfenidone exposure of 442.0 days. Overall, 741 (73.4%) patients experienced ADRs, most commonly nausea (20.6%) and fatigue (18.5%). ADRs led to treatment discontinuation in 290 (28.7%) patients after a median of 99.5 days. Overall, 55 (5.5%) patients experienced SADRs, with a fatal outcome in six patients. ADRSI were reported in 693 patients, most commonly gastrointestinal symptoms (38.3%) and photosensitivity reactions/skin rashes (29.0%). Older age and female sex were associated with early treatment discontinuation due to an ADR. Findings were consistent with the known safety profile of pirfenidone, based on RCT data and other post-marketing experience, with no new safety signals observed.

Review of the following volume: Mission to the World; Communicating the Gospel in the 21st Century. Essays in Honour of Knud Jørgensen. Ed. by Tormod Engelsviken, Ernst Harbakk, Rolv Olsen, & Thor Strandenæs. (Regnum Books and Egede International: 2008)

Arnason and Raaflaub’s edited volume, The Roman Empire in Context: Historical and Comparative Perspectives, is the fifth volume in a series entitled The Ancient World: Comparative Histories. The overarching aim of the series is to bring a comparative perspective to studies of ancient histories, and earlier titles focus either on content or geography. This is the only volume to date that focuses on a specific civilization, and Rome is of course significant enough to merit its own volume.

A review of Felice Vinci, The Baltic Origins of Homer’s Epic Tales; The Iliad, They Odyssey, and the Migration of Myth (Rochester, Vermont: Inner Traditions, 2006)