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Summary: Background: People with diabetes are at increased risk of hospitalisation, morbidity, and mortality following SARS-CoV-2 infection. Long-term outcomes for people with diabetes previously hospitalised with COVID-19 are, however, unknown. This study aimed to determine the longer-term physical and mental health effects of COVID-19 in people with and without diabetes. Methods: The PHOSP-COVID study is a multicentre, long-term follow-up study of adults discharged from hospital between 1 February 2020 and 31 March 2021 in the UK following COVID-19, involving detailed assessment at 5 and 12 months after discharge. The association between diabetes status and outcomes were explored using multivariable linear and logistic regressions. Findings: People with diabetes who survived hospital admission with COVID-19 display worse physical outcomes compared to those without diabetes at 5- and 12-month follow-up. People with diabetes displayed higher fatigue (only at 5 months), frailty, lower physical performance, and health-related quality of life and poorer cognitive function. Differences in outcomes between diabetes status groups were largely consistent from 5 to 12-months. In regression models, differences at 5 and 12 months were attenuated after adjustment for BMI and presence of other long-term conditions. Interpretation: People with diabetes reported worse physical outcomes up to 12 months after hospital discharge with COVID-19 compared to those without diabetes. These data support the need to reduce inequalities in long-term physical and mental health effects of SARS-CoV-2 infection in people with diabetes. Funding: UK Research and Innovation and National Institute for Health Research. The study was approved by the Leeds West Research Ethics Committee (20/YH/0225) and is registered on the ISRCTN Registry (ISRCTN10980107).

Background The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p

Summary: Background: The scale of COVID-19 and its well documented long-term sequelae support a need to understand long-term outcomes including frailty. Methods: This prospective cohort study recruited adults who had survived hospitalisation with clinically diagnosed COVID-19 across 35 sites in the UK (PHOSP-COVID). The burden of frailty was objectively measured using Fried's Frailty Phenotype (FFP). The primary outcome was the prevalence of each FFP group—robust (no FFP criteria), pre-frail (one or two FFP criteria) and frail (three or more FFP criteria)—at 5 months and 1 year after discharge from hospital. For inclusion in the primary analysis, participants required complete outcome data for three of the five FFP criteria. Longitudinal changes across frailty domains are reported at 5 months and 1 year post-hospitalisation, along with risk factors for frailty status. Patient-perceived recovery and health-related quality of life (HRQoL) were retrospectively rated for pre-COVID-19 and prospectively rated at the 5 month and 1 year visits. This study is registered with ISRCTN, number ISRCTN10980107. Findings: Between March 5, 2020, and March 31, 2021, 2419 participants were enrolled with FFP data. Mean age was 57.9 (SD 12.6) years, 933 (38.6%) were female, and 429 (17.7%) had received invasive mechanical ventilation. 1785 had measures at both timepoints, of which 240 (13.4%), 1138 (63.8%) and 407 (22.8%) were frail, pre-frail and robust, respectively, at 5 months compared with 123 (6.9%), 1046 (58.6%) and 616 (34.5%) at 1 year. Factors associated with pre-frailty or frailty were invasive mechanical ventilation, older age, female sex, and greater social deprivation. Frail participants had a larger reduction in HRQoL compared with before their COVID-19 illness and were less likely to describe themselves as recovered. Interpretation: Physical frailty and pre-frailty are common following hospitalisation with COVID-19. Improvement in frailty was seen between 5 and 12 months although two-thirds of the population remained pre-frail or frail. This suggests comprehensive assessment and interventions targeting pre-frailty and frailty beyond the initial illness are required. Funding: UK Research and Innovation and National Institute for Health Research.

Background Pre-existing cardiovascular disease (CVD) or cardiovascular risk factors have been associated with an increased risk of complications following hospitalisation with COVID-19, but their impact on the rate of recovery following discharge is not known.Objectives To determine whether the rate of patient-perceived recovery following hospitalisation with COVID-19 was affected by the presence of CVD or cardiovascular risk factors.Methods In a multicentre prospective cohort study, patients were recruited following discharge from the hospital with COVID-19 undertaking two comprehensive assessments at 5 months and 12 months. Patients were stratified by the presence of either CVD or cardiovascular risk factors prior to hospitalisation with COVID-19 and compared with controls with neither. Full recovery was determined by the response to a patient-perceived evaluation of full recovery from COVID-19 in the context of physical, physiological and cognitive determinants of health.Results From a total population of 2545 patients (38.8% women), 472 (18.5%) and 1355 (53.2%) had CVD or cardiovascular risk factors, respectively. Compared with controls (n=718), patients with CVD and cardiovascular risk factors were older and more likely to have had severe COVID-19. Full recovery was significantly lower at 12 months in patients with CVD (adjusted OR (aOR) 0.62, 95% CI 0.43 to 0.89) and cardiovascular risk factors (aOR 0.66, 95% CI 0.50 to 0.86).Conclusion Patients with CVD or cardiovascular risk factors had a delayed recovery at 12 months following hospitalisation with COVID-19. Targeted interventions to reduce the impact of COVID-19 in patients with cardiovascular disease remain an unmet need.Trail registration number ISRCTN10980107.

Background: The anti-IgE monoclonal antibody omalizumab is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during 1 year of omalizumab treatment. Methods: One-year open-label Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 patients with severe (Global Initiative for Asthma step 4/5) uncontrolled atopic asthma (at least two severe exacerbations in the previous year) taking high-dose inhaled corticosteroids and long-acting β-agonists with or without maintenance oral corticosteroids. It had two phases: 0-16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE); and 16-52 weeks, to assess late responses based on ⩾50% reduction in exacerbations or mOCS dose. All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment. Measurements and Main Results: A total of 191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ⩾50% and 57% (37 of 65) taking mOCSs had reduced their dose by ⩾50%. The primary outcomes 2,3-dinor-11-β-PGF2α, GETE score, and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five volatile organic compounds and five plasma lipid biomarkers strongly predicted the ⩾50% reduction in exacerbations (receiver operating characteristic areas under the curve of 0.780 and 0.922, respectively) and early responses (areas under the curve of 0.835 and 0.949, respectively). In an independent cohort, gas chromatography/mass spectrometry biomarkers differentiated between severe and mild asthma. Conclusions: This is the first discovery of omics biomarkers that predict improvement in asthma with biologic agent treatment. Prospective validation and development for clinical use is justified.

To investigate the symptoms of SARS-CoV-2 infection, their dynamics and their discriminatory power for the disease using longitudinally, prospectively collected information reported at the time of their occurrence. We have analysed data from a large phase 3 clinical UK COVID-19 vaccine trial. The alpha variant was the predominant strain. Participants were assessed for SARS-CoV-2 infection via nasal/throat PCR at recruitment, vaccination appointments, and when symptomatic. Statistical techniques were implemented to infer estimates representative of the UK population, accounting for multiple symptomatic episodes associated with one individual. An optimal diagnostic model for SARS-CoV-2 infection was derived. The 4-month prevalence of SARS-CoV-2 was 2.1%; increasing to 19.4% (16.0%-22.7%) in participants reporting loss of appetite and 31.9% (27.1%-36.8%) in those with anosmia/ageusia. The model identified anosmia and/or ageusia, fever, congestion, and cough to be significantly associated with SARS-CoV-2 infection. Symptoms' dynamics were vastly different in the two groups; after a slow start peaking later and lasting longer in PCR+ participants, whilst exhibiting a consistent decline in PCR- participants, with, on average, fewer than 3 days of symptoms reported. Anosmia/ageusia peaked late in confirmed SARS-CoV-2 infection (day 12), indicating a low discrimination power for early disease diagnosis.

Background: Increased serum interleukin (IL)-33 predicts poor outcomes in patients hospitalised with coronavirus disease 2019 (COVID-19). We examined the efficacy and safety of tozorakimab, a monoclonal antibody that neutralises IL-33, in improving outcomes in ACCORD-2 (EudraCT: 2020-001736-95)., Methods: ACCORD-2 was an open-label, phase 2a study in adults hospitalised with COVID-19. Patients were randomised 1:1 to tozorakimab 300 mg plus standard of care (SoC) or SoC alone. The primary end-point was time to clinical response (sustained clinical improvement of ≥2 points on the World Health Organization ordinal scale, discharge from hospital or fit for discharge) by day 29. Other end-points included death or respiratory failure, mortality and intensive care unit admission by day 29, and safety. Serum IL-33/soluble stimulated-2 (sST2) complex levels were measured by high-sensitivity immunoassay., Results: Efficacy analyses included 97 patients (tozorakimab+SoC, n=53; SoC, n=44). Median time to clinical response did not differ between the tozorakimab and SoC arms (8.0 and 9.5 days, respectively; HR 0.96, 80% CI 0.70-1.31; one-sided p=0.33). Tozorakimab was well tolerated and the OR for risk of death or respiratory failure with treatment versus SoC was 0.55 (80% CI 0.27-1.12; p=0.26), while the OR was 0.31 (80% CI 0.09-1.06) in patents with high baseline serum IL-33/sST2 complex levels., Conclusions: Overall, ACCORD-2 results suggest that tozorakimab could be a novel therapy for patients hospitalised with COVID-19, warranting further investigation in confirmatory phase 3 studies., Competing Interests: Conflict of interest: T. Wilkinson has received grants and fees from AstraZeneca, Bergenbio, Boehringer Ingelheim, Chiesi, GSK, Janssen, Olam, MMH, Synairgen, Union Chimique Belge and Valneva. M. Carroll has received consulting fees from OxDx Ltd and VacciTech Ltd. C. Page has received personal fees from EpiEndo, Eurodrug, Glycosynnovation, Helperby, PrEP Biopharma and Recipharm, and owns stock in Verona Pharma. J.D. Chalmers has received research grants from AstraZeneca, Boehringer Ingelheim, GSK, Gilead Sciences, Insmed and Novartis, has received consultancy or speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Insmed, Janssen, Novartis and Zambon, and is a member of the Editorial Board of ERJ Open Research. A. De Soyza has received grants and fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Gilead Sciences, GSK and Insmed. S. Siddiqui has received speaker/consultancy fees or research grants from AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, GSK, Novartis and Owlstone Medical. A. Ustianowski has received speaker and/or advisory board fees from AstraZeneca, Gilead Sciences, GSK and Merck/MSD. M.G. Crooks has received grants, fees and non-financial support from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Pfizer and Philips. A. Horsley has received personal fees from Roche-Genentech and Vertex Pharmaceuticals, and is supported by the NIHR Manchester Biomedical Research Centre. H. Pandya, R. Moate, N. van Zuydam, C. Kell, F. Reid and I.C. Scott are employees of AstraZeneca and may hold stock or stock options in AstraZeneca. G. Griffiths has received funding from Astex, AstraZeneca, BionTech, Bristol Myers Squibb, British Lung Foundation, Cancer Research UK, Celldex, GSK, Heartflow, Janssen-Cilag, NIHR, Novartis, Roche and Unitaid for unrelated academic clinical trials and programme funding, and personal fees from AstraZeneca to deliver continuing professional development training courses. M. Shankar-Hari has received funding from the NIHR, has received a grant from the Chief Scientists Office, Scotland, and reports industry interactions for the TRAITS research programme (www.ed.ac.uk/inflammation-research/clinical-trials/traits-ci-trial). D. Singh has received personal fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, EpiEndo, Genentech, Glenmark, Gossamer Bio, GSK, Kinaset, Menarini, Novartis, Pulmatrix, Sanofi, Synairgen, Teva Pharmaceuticals, Theravance Biopharma and Verona. L-P. Ho, D. Saralaya, B. Lara, J. Raw, A. Woodcock and B. Mishra have no conflicts of interest to disclose., (Copyright ©The authors 2023.)

Background: The omicron BA.1 bivalent booster is used globally. Previous open-label studies of the omicron BA.1 (Moderna mRNA-1273.214) booster showed superior neutralising antibody responses against omicron BA.1 and other variants compared with the original mRNA-1273 booster. We aimed to compare the safety and immunogenicity of omicron BA.1 monovalent and bivalent boosters with the original mRNA-1273 vaccine in a large, randomised controlled trial., Methods: In this large, randomised, observer-blind, active-controlled, phase 3 trial in the UK (28 hospital and vaccination clinic sites), individuals aged 16 years or older who had previously received two injections of any authorised or approved COVID-19 vaccine, with or without an mRNA vaccine booster (third dose), were randomly allocated (1:1) using interactive response technology to receive 50 μg omicron BA.1 monovalent or bivalent vaccines or 50 μg mRNA-1273 administered as boosters via deltoid intramuscular injection. The primary outcomes were safety and immunogenicity at day 29, including prespecified non-inferiority and superiority of booster immune responses, based on the neutralising antibody geometric mean concentration (GMC) ratios of the monovalent and bivalent boosters compared with mRNA-1273. Safety was assessed in all participants who received first or second boosters, and primary immunogenicity outcomes were assessed in all participants who received the planned booster dose, had pre-booster and day 29 antibody data, had no major protocol deviations, and who were SARS-CoV-2-negative. The study is registered with EudraCT (2022-000063-51) and ClinicalTrials.gov (NCT05249829) and is ongoing., Findings: Between Feb 16 and March 24, 2022, 724 participants were randomly allocated to receive omicron BA.1 monovalent (n=366) or mRNA-1273 (n=357), and between April 2 and June 17, 2022, 2824 participants were randomly allocated to receive omicron BA.1 bivalent (n=1418) or mRNA-1273 (n=1395) vaccines as second boosters. Median durations (months) between the most recent COVID-19 vaccine and study boosters were similar for omicron BA.1 monovalent (4·0 months [IQR 3·6-4·7]) and mRNA-1273 (4·1 [3·5-4·7]), and for the omicron BA.1 bivalent (5·5 [4·8-6·2]) and mRNA-1273 (5·4 [4·8-6·2]) boosters. The omicron BA.1 monovalent and bivalent boosters elicited superior neutralising GMCs against the omicron BA.1 variant compared with mRNA-1273, with GMC ratios of 1·68 (99% CI 1·45-1·95) and 1·53 (1·41-1·67) at day 29 post-booster doses in participants without previous SARS-CoV-2 infection. Both boosters induced non-inferior ancestral SARS-CoV-2 (Asp614Gly) immune responses with GMCs that were similar for the bivalent (2987·2 [95% CI 2814·9-3169·9]) versus mRNA-1273 (2911·3 [2750·9-3081·0]) and lower for the monovalent (2699·7 [2431·3-2997·7] vs 3020·6 [2776·5-3286·2]) boosters, with respective GMC ratios of 1·05 (99% CI 0·96-1·15) and 0·82 (95% CI 0·74-0·91). Results were comparable regardless of previous SARS-CoV-2 infection status. Incidences of solicited adverse reactions with the omicron BA.1 monovalent (335 [91·3%] of 367 participants) and omicron BA.1 bivalent (1285 [90·4%] of 1421 participants) boosters were similar to those observed previously for mRNA-1273, with no new safety concerns identified and no occurrences of fatal adverse events., Interpretation: Omicron-containing booster vaccines generated superior immunogenicity against omicron BA.1 and comparable immunogenicity against the original strain with no new safety concerns. It remains important to continuously monitor the immune responses and real-world vaccine effectiveness as divergent SARS-CoV-2 variants emerge., Funding: Moderna., Competing Interests: Declaration of interests ITL, BG, CP, DR, SM, EdW, AS, SC, WD, XC, JF, LT, HZ, JMM, and RD are employees of Moderna and hold stock or stock options in the company. PM reports being a speaker or adviser for and receiving research grants from GSK, Sanofi, Novavax, Moderna, MSD, Janssen, Medicago, and AstraZeneca. CB reports being a National Specialty Advisor (NHS England) Immunology and Allergy and receiving funding to their institution to undertake vaccine trials for Janssen, Moderna, AstraZeneca, and Valneva. RN reports being Research Lead for Cambridge and Peterborough Integrated Care Board; and receiving grants from GSK and Novavax. PAK reports being a speaker or adviser for and receiving travel or research grants from GSK, Pfizer, Pharmacosmos, Astellas, Vifor, AstraZeneca, Bayer, Unicyte, Evotec, Fresenius, and Otsuka. PID reports receiving research grants for COVID-19 research studies from Moderna, AstraZeneca, Janssen, and Atea. MBo reports being a speaker or adviser for GSK, Atea, ViiV, MSD, Janssen, Gilead, Cipla, Mylan, and Roche; and receiving research grants from ViiV, MSD, Janssen, Gilead, Novavax, Valneva, and Moderna. FB reports receiving speaker fees and a research grant to their institution from Gilead Sciences. CJAD reports receiving grants from the Wellcome Trust and the Medical Research Council. ASFR reports receiving research grants (to their organisation) from Pfizer, Novavax, Valneva, Moderna, and Janssen. PTH reports being a speaker or adviser for and receiving research grants from Pfizer, Novavax, Valneva, Moderna, and Janssen. JET and FJD are Moderna contractors. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose in June 2021. Monovalent messenger RNA (mRNA) COVID-19 vaccines were subsequently widely used for the third and fourth-dose vaccination campaigns in high-income countries. Real-world vaccine effectiveness against symptomatic infections following third doses declined during the Omicron wave. This report compares the immunogenicity and kinetics of responses to third doses of vaccines from day (D) 28 to D242 following third doses in seven study arms., Methods: The trial initially included ten experimental vaccine arms (seven full-dose, three half-dose) delivered at three groups of six sites. Participants in each site group were randomised to three or four experimental vaccines, or MenACWY control. The trial was stratified such that half of participants had previously received two primary doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) and half had received two doses of BNT162b2 (Pfizer-BioNtech, hereafter referred to as BNT). The D242 follow-up was done in seven arms (five full-dose, two half-dose). The BNT vaccine was used as the reference as it was the most commonly deployed third-dose vaccine in clinical practice in high-income countries. The primary analysis was conducted using all randomised and baseline seronegative participants who were SARS-CoV-2 naïve during the study and who had not received a further COVID-19 vaccine for any reason since third dose randomisation., Results: Among the 817 participants included in this report, the median age was 72 years (IQR: 55-78) with 50.7% being female. The decay rates of anti-spike IgG between vaccines are different among both populations who received initial doses of ChAd/ChAd and BNT/BNT. In the population that previously received ChAd/ChAd, mRNA vaccines had the highest titre at D242 following their vaccine dose although Ad26. COV2. S (Janssen; hereafter referred to as Ad26) showed slower decay. For people who received BNT/BNT as their initial doses, a slower decay was also seen in the Ad26 and ChAd arms. The anti-spike IgG became significantly higher in the Ad26 arm compared to the BNT arm as early as 3 months following vaccination. Similar decay rates were seen between BNT and half-BNT; the geometric mean ratios ranged from 0.76 to 0.94 at different time points. The difference in decay rates between vaccines was similar for wild-type live virus-neutralising antibodies and that seen for anti-spike IgG. For cellular responses, the persistence was similar between study arms., Conclusions: Heterologous third doses with viral vector vaccines following two doses of mRNA achieve more durable humoral responses compared with three doses of mRNA vaccines. Lower doses of mRNA vaccines could be considered for future booster campaigns., Competing Interests: Declaration of Competing Interest KC acts on behalf of University Hospital Southampton as an investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Janssen, Medimmune, Merck, Pfizer, Sanofi and Valneva. She receives no personal financial payment for this work. SNF acts on behalf of University Hospital Southampton NHS Foundation Trust as an Investigator and/or providing consultative advice on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers including Janssen, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Sanofi, Medimmune, Merck and Valneva vaccines and antimicrobials. He receives no personal financial payment for this work. ALG is named as an inventor on a patent covering use of a particular promoter construct that is often used in ChAdOx1-vectored vaccines and is incorporated in the ChAdOx1 nCoV-19 vaccine. ALG may benefit from royalty income paid to the University of Oxford from sales of this vaccine by AstraZeneca and its sublicensees under the University’s revenue-sharing policy. JH has received payments for presentations for AstraZeneca, Boehringer Ingelheim, Chiesi, Ciple & Teva. VL acts on behalf of University College London Hospitals NHS Foundation Trust as an Investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers including Pfizer, AstraZeneca and Valneva. He receives no personal financial payment for this work. PM acts on behalf of University Hospital Southampton NHS Foundation Trust and The Adam Practice as an investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Novavax, Medicago, and Sanofi. He received no personal financial payment for this work. JSN-V-T was seconded to the Department of Health and Social Care, England until 31st March 2022. He has subsequently received lecture fees from AstraZeneca, Sanofi Pasteur and has performed paid consultancy for Janssen and Seqirus. MR has provided post marketing surveillance reports on vaccines for Pfizer and GSK for which a cost recover charge is made. MDS acted until September 2022 on behalf of the University of Oxford as an investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Pfizer, Novavax. Janssen, Medimmune and MCM vaccines. He received no personal financial payment for this work. MDS became an employee of Moderna in September 2022 and holds stock options in this company. He did not perform this study in relation to his new employment and Moderna have had no a priori access to the data., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The recombinant protein-based vaccine, NVX-CoV2373, demonstrated 89.7% efficacy against coronavirus disease 2019 (COVID-19) in a phase 3, randomized, observer-blinded, placebo-controlled trial in the United Kingdom. The protocol was amended to include a blinded crossover. Data to the end of the placebo-controlled phase are reported., Methods: Adults aged 18-84 years received 2 doses of NVX-CoV2373 or placebo (1:1) and were monitored for virologically confirmed mild, moderate, or severe COVID-19 (onset from 7 days after second vaccination). Participants who developed immunoglobulin G (IgG) against nucleocapsid protein but did not show symptomatic COVID-19 were considered asymptomatic. Secondary outcomes included anti-spike (S) IgG responses, wild-type virus neutralization, and T-cell responses., Results: Of 15 185 participants, 13 989 remained in the per-protocol efficacy population (6989 NVX-CoV2373, 7000 placebo). At a maximum of 7.5 months (median, 4.5) postvaccination, there were 24 cases of COVID-19 among NVX-CoV2373 recipients and 134 cases among placebo recipients, a vaccine efficacy of 82.7% (95% confidence interval [CI], 73.3%-88.8%). Vaccine efficacy was 100% (95% CI, 17.9%-100.0%) against severe disease and 76.3% (95% CI, 57.4%-86.8%) against asymptomatic disease. High anti-S and neutralization responses to vaccination were evident, together with S-protein-specific induction of interferon-γ secretion in peripheral blood T cells. Incidence of serious adverse events and adverse events of special interest were similar between groups., Conclusions: A 2-dose regimen of NVX-CoV2373 conferred a high level of ongoing protection against asymptomatic, symptomatic, and severe COVID-19 through >6 months postvaccination. A gradual decrease of protection suggests that a booster may be indicated., Clinical Trials Registration: EudraCT, 2020-004123-16., Competing Interests: Potential conflicts of interest. K. A., I. C., L. F., G. G., I. Mc., E. J. R., A. R., K. S., and S. T. are employees of Novavax Inc and receive a salary for their work. K. S. reports stock received as part of employment compensation from Novavax. A. R. reports stock or stock options from Novavax. E. J. R. and I. Mc. report Novavax stock. K. A. reports vested and unvested Novavax stock/restricted stock units. I. C. reports Novavax stock and stock options and salary and bonus as an employee of Novavax. L. F. reports consulting fees as a prior full-time employee, now contractor to, Novavax reimbursed hourly for work performed on this study and in analyses and drafting this report, and shares and stock options from Novavax. G. G. reports stock-related compensations from Novavax. S. T. reports royalties or licenses, salary and stock, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events, and a leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, as an employee of Novavax. Guy's and St Thomas' National Health Service (NHS) Foundation Trust (with which A. L. G. is affiliated) received funding from Novavax for this trial. Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19. A. L. G. is named as an inventor on a patent covering use of a particular promoter construct that is often used in vectored vaccines and is incorporated in the ChAdOx1 nCoV-19 vaccine, and may benefit from royalty income paid to the University of Oxford from sales of this vaccine by AstraZeneca and its sublicensees under the university's revenue sharing policy. M. B. reports a research grant to institution from Novavax related to this manuscript, advisory/speaker fees or grants to the institution from GSK, ViiV, Gilead, Janssen, Moderna, Pfizer, Valneva, MSD, Roche, Cipla, and Mylan and support for attending the online World AIDS conference from ViiV. D. R. C. reports a research grant to institution from Gilead Sciences, unpaid participation as an Independent Data Monitoring Board (IDMB) member for the FLARE Trial, and unpaid role as a British HIV Association trustee member. J. G. reports a research contract with institution from Novavax. C. A. C. reports a research grant to institution from Novavax related to this manuscript, and a research grant to institution from Moderna. P. T. H. reports a research grant to institution from Novavax related to this manuscript, research grants to institution from Pfizer, AstraZeneca, Moderna, Valneva, and Janssen, and payment to institution for educational events from Novavax. P. A. K. reports a research grant to institution from Novavax related to this manuscript, grants or contracts unrelated to this work from Vifor, Astellas, Evotec, Pharmacosmos, and Unicyte; consulting fees from AstraZeneca, Vifor, Unicyte, and UCB; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Vifor, AstraZeneca, Pfizer, Pharmacosmos, Napp, and Bayer; and support for attending meetings and/or travel from Pharmacosmos and Vifor. J. P. reports a research grant to institution from Novavax related to this manuscript, and being co-applicant for a Haywood Foundation grant and for a National Institute for Health and Care Research (NIHR)/Clinical Research Network (CRN) COVID Innovation and Insight grant. P. A. S. reports a research grant to institution from Novavax related to this manuscript, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer and AstraZeneca; support for attending meetings and/or travel from Bayer; and participation on a DSMB or advisory board for Bayer. E. C. T. reports a research grant to institution from Novavax related to this manuscript, research grants to institution from Valneva, COV-BOOST, Medical Research Council (MRC), Wellcome, and Public Health Scotland; payment to author for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Wellcome Connecting Science—Sanger Institute; support for attending meetings and/or travel, paid to author, from Wellcome Connecting Science—Sanger Institute, University of Oxford, University of Cambridge, and University of Manchester; and unpaid leadership or fiduciary roles with the Scottish Committee for Pandemic Preparedness, UK Health Security Agency (HSA) technical groups, and the Scottish Genomics Oversight Group. J. T. reports Quin Technologies consulting fees; participation as chair of the Data Monitoring and Ethics Committee (DMEC) for the NIFTY Trial, an NIHR-funded trial; and a role as clinical advisor to Parathyroid UK, a patient support charity. S. I., C. J., H. N., D. B., A. Hi., R. S., I. M., A. M., R. C., D. N. B., D. S., E. P. G., J. B., R. L. S., A. He., C. M., C. P., and F. B. report a research grant to institution from Novavax related to this manuscript. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19., Methods: The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 μg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 μg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (anti-spike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing., Findings: Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6-77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3-214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030-27 162), which increased to 37 460 ELU/mL (31 996-43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41-1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996-30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826-64 452), with a geometric mean fold change of 2·19 (1·90-2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37-14·32) and 15·90 (12·92-19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24-16·54] in the BNT162b2 group and 6·22 [3·90-9·92] in the mRNA-1273 group)., Interpretation: Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose., Funding: UK Vaccine Task Force and National Institute for Health Research., Competing Interests: Declaration of interests KCa acts on behalf of University Hospital Southampton as an investigator on studies funded or sponsored by vaccine manufacturers, including AstraZeneca, GlaxoSmithKline, Janssen, Medimmune, Merck, Pfizer, Sanofi, and Valneva, and receives no personal financial payment for this work. SNF acts on behalf of University Hospital Southampton NHS Foundation Trust as an investigator or consults on clinical trials and studies of COVID-19 vaccines and other vaccines funded or sponsored by vaccine manufacturers, including Janssen, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Sanofi, Medimmune, Merck, and Valneva, and receives no personal financial payment for this work. ALG is named as an inventor on a patent covering the use of a particular promoter construct that is often used in ChAdOx1-vectored vaccines and is incorporated in the ChAdOx1 nCoV-19 vaccine and could benefit from royalty income paid to the University of Oxford from sales of this vaccine by AstraZeneca and its sublicensees under the university's revenue sharing policy. JH has received payments for presentations for AstraZeneca, Boehringer Ingelheim, Chiesi, and Cipla & Teva. VL acts on behalf of University College London Hospitals NHS Foundation Trust as an investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers, including Pfizer, AstraZeneca, and Valneva, and receives no personal financial payment for this work. PM acts on behalf of University Hospital Southampton NHS Foundation Trust and The Adam Practice as an investigator on studies funded or sponsored by vaccine manufacturers, including AstraZeneca, GlaxoSmithKline, Novavax, Medicago, and Sanofi, and receives no personal financial payment for this work. JSN-V-T was seconded to the Department of Health and Social Care, England, until March 31, 2022. MR has provided post-marketing surveillance reports on vaccines for Pfizer and GlaxoSmithKline, for which a cost recovery charge is made. MDS acts on behalf of the University of Oxford as an investigator on studies funded or sponsored by vaccine manufacturers, including AstraZeneca, GlaxoSmithKline, Pfizer, Novavax, Janssen, Medimmune, and MCM, and has received no personal financial payment for this work. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Prostaglandin D 2 receptor 2 (DP 2 ) antagonists inhibit prostaglandin D 2 -induced effects, including recruitment and activation of cells driving asthma pathogenesis. However, challenges identifying target population and end points persist., Research Question: What is the effect of the DP 2 antagonist GB001 on asthma worsening in patients with moderate to severe eosinophilic asthma?, Study Design and Methods: In this phase IIb, randomized, double-blind, placebo-controlled, dose-ranging, parallel-group, multicenter study, GB001 or placebo was added to standard-of-care treatment in patients with moderate to severe asthma with a blood eosinophil count ≥ 250 cells/μL. Patients aged ≥ 18 years to < 75 years received one of four once-daily treatments (GB001 20 mg, 40 mg, or 60 mg or placebo). The primary end point was the proportion of patients who experienced asthma worsening by 24 weeks. Efficacy analyses were performed for the intention-to-treat population and safety analyses for patients who received at least one dose of study treatment., Results: A total of 480 patients were treated. The ORs for asthma worsening for GB001 20 mg, 40 mg, and 60 mg vs placebo were 0.674 (95% CI, 0.398-1.142), 0.677 (95% CI, 0.399-1.149), and 0.651 (95% CI, 0.385-1.100), respectively. Analysis according to baseline blood eosinophil levels and/or fractional exhaled nitric oxide did not show greater treatment effects with higher values. Elevated liver aminotransferase levels and adverse events leading to discontinuation were more frequent for GB001 60 mg than with placebo, GB001 20 mg, and GB001 40 mg., Interpretation: Although GB001 did not significantly reduce the odds of asthma worsening, reductions favoring GB001 were observed. Treatment effects were consistent regardless of high/low type 2 phenotype. The overall safety profile was acceptable, although GB001 60 mg was associated with risk of liver injury., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT03683576; URL: www., Clinicaltrials: gov., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the persistence of immunogenicity three months after third dose boosters., Methods: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose. The analysis was conducted using all randomised participants who were SARS-CoV-2 naïve during the study., Results: Amongst the 2883 participants randomised, there were 2422 SARS-CoV-2 naïve participants until D84 visit included in the analysis with median age of 70 (IQR: 30-94) years. In the participants who had two initial doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd), schedules using mRNA vaccines as third dose have the highest anti-spike IgG at D84 (e.g. geometric mean concentration of 8674 ELU/ml (95% CI: 7461-10,085) following ChAd/ChAd/BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT)). However, in people who had two initial doses of BNT there was no significant difference at D84 in people given ChAd versus BNT (geometric mean ratio (GMR) of 0.95 (95%CI: 0.78, 1.15). Also, people given Ad26.COV2.S (Janssen; hereafter referred to as Ad26) as a third dose had significantly higher anti-spike IgG at D84 than BNT (GMR of 1.20, 95%CI: 1.01,1.43). Responses at D84 between people who received BNT (15 μg) or BNT (30 μg) after ChAd/ChAd or BNT/BNT were similar, with anti-spike IgG GMRs of half-BNT (15 μg) versus BNT (30 μg) ranging between 0.74-0.86. The decay rate of cellular responses were similar between all the vaccine schedules and doses., Conclusions: 84 days after a third dose of COVID-19 vaccine the decay rates of humoral response were different between vaccines. Adenoviral vector vaccine anti-spike IgG concentrations at D84 following BNT/BNT initial doses were similar to or even higher than for a three dose (BNT/BNT/BNT) schedule. Half dose BNT immune responses were similar to full dose responses. While high antibody tires are desirable in situations of high transmission of new variants of concern, the maintenance of immune responses that confer long-lasting protection against severe disease or death is also of critical importance. Policymakers may also consider adenoviral vector, fractional dose of mRNA, or other non-mRNA vaccines as third doses., Competing Interests: Declaration of Competing Interest KC acts on behalf of University Hospital Southampton as an investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Janssen, Medimmune, Merck, Pfizer, Sanofi and Valneva. She receives no personal financial payment for this work. SNF acts on behalf of University Hospital Southampton NHS Foundation Trust as an Investigator and/or providing consultative advice on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers including Janssen, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Sanofi, Medimmune, Merck and Valneva vaccines and antimicrobials. He receives no personal financial payment for this work. ALG is named as an inventor on a patent covering use of a particular promoter construct that is often used in ChAdOx1-vectored vaccines and is incorporated in the ChAdOx1 nCoV-19 vaccine. ALG may benefit from royalty income paid to the University of Oxford from sales of this vaccine by AstraZeneca and its sublicensees under the University's revenue sharing policy. JH has received payments for presentations for AstraZeneca, Boehringer Ingelheim, Chiesi, Ciple & Teva. VL acts on behalf of University College London Hospitals NHS Foundation Trust as an Investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers including Pfizer, AstraZeneca and Valneva. He receives no personal financial payment for this work. PM acts on behalf of University Hospital Southampton NHS Foundation Trust and The Adam Practice as an investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Novavax, Medicago and Sanofi. He received no personal financial payment for this work. JSN-V-T is seconded to the Department of Health and Social Care, England until 31st March 2022. MR has provided post marketing surveillance reports on vaccines for Pfizer and GSK for which a cost recover charge is made. MDS acts on behalf of the University of Oxford as an investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Pfizer, Novavax. Janssen, Medimmune and MCM vaccines. He received no personal financial payment for this work., (Copyright © 2022. Published by Elsevier Ltd.)

Background: The Digihaler ® is a Food and Drug Administration-approved, digital multidose dry powder inhaler with an integrated electronic module that provides patients and health care professionals with feedback on inhalation parameters, including usage, adherence, and technique. This study compared inhalation parameters measured using the Digihaler with readings made simultaneously using an inhalation profile recorder (IPR). Methods: This single-visit, open-label study enrolled children (4-17 years) and adults (18-55 years) with asthma, and adults (≥55 years) with chronic obstructive pulmonary disease (COPD). Participants made three separate inhalations using an empty Digihaler device, each measured simultaneously by the Digihaler and IPR. Inhalation profiles were downloaded from the devices at the end of the study. Inhalation parameters measured included peak inspiratory flow (PIF) and inhaled volume (inhV). The profile with the highest PIF and corresponding IPR profile were analyzed. Results: Overall, 150 participants were enrolled; inhalation data were available for 148 (50 children and 49 adults with asthma, and 49 with COPD). Mean (standard deviation [SD]) age was 39.1 (24.5) years; 51% of participants were male. Overall mean (SD) PIFs as measured by the Digihaler and IPR were 70.62 (17.73) L/min and 72.55 (19.42) L/min, respectively, with a mean percentage difference of -1.75% (95% confidence interval [CI]: -3.64 to 0.15). Mean percentage differences between the Digihaler and IPR measurements of PIF ranged from -2.97% among adults with COPD to 0.16% among children with asthma. Overall mean (SD) inhV for the Digihaler and IPR were 1.57 (0.69) L and 1.67 (0.73) L, respectively, with a mean percentage difference of -6.11 (95% CI: -8.08 to -4.13). There was a strong correlation between PIF and inhV measurements taken by the Digihaler and those taken by the IPR (Spearman's correlation coefficient = 0.96). Conclusions: Our findings confirm the ability of the Digihaler to provide accurate measurement of inhalation parameters when used by patients.

Aims: Tuberculosis (TB) is one of the biggest communicable causes of mortality worldwide. While incidence in the UK has continued to fall since 2011, Bradford retains one of the highest TB rates in the UK. This study aims to examine the local disease burden of musculoskeletal (MSK) TB, by analyzing common presenting factors within the famously diverse population of Bradford., Methods: An observational study was conducted, using data from the Bradford Teaching Hospitals TB database of patients with a formal diagnosis of MSK TB between January 2005 and July 2017. Patient data included demographic data (including nationality/date of entry to the UK), disease focus, microbiology, and management strategies. Disease incidence was calculated using population data from the Office for National Statistics. Poisson confidence intervals were calculated to demonstrate the extent of statistical error. Disease incidence and nationality were also analyzed, and correlation sought, using the chi-squared test., Results: Between January 2005 and July 2017, 109 cases of MSK TB were diagnosed in Bradford. Mean incidence was 1.65 per 100,000 population, per calendar year (SD 0.75). A total of 38 cases required surgical intervention. Low rates of antimicrobial resistance were encountered. A low rate of loss to follow-up was observed (four patients; 3.7%). Overall, 94.5% of patients (n = 103) were successfully treated. 67% of patients (n = 73) reported their country of origin as either India, Pakistan, or Bangladesh. These ethnicities account for around 25% of the local population., Conclusion: Bradford maintains a high prevalence of MSK TB infection relative to national data; the prevalence within the local immigrant population remains grossly disproportionate. Typical associated factors (HIV/hepatitis coinfection, drug resistance), have only modest prevalence in our dataset. However, local socioeconomic factors such as deprivation and poverty appear germane as suggested by global literature. We advocate a high degree of suspicion in treatment of atypical infection in any area with similar population factors to ensure timely diagnosis. Cite this article: Bone Jt Open  2022;3(5):432-440.

Background: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with changes in the sputum microbiome, including an increased prevalence of pathogenic bacteria. Vaccination against the most frequent bacteria identified in AECOPD might reduce exacerbation frequency. We assessed the efficacy, safety, and immunogenicity of a candidate vaccine containing surface proteins from non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) in patients with COPD., Methods: This multicentre, randomised, observer-blinded, placebo-controlled, proof-of-concept, phase 2b trial recruited patients with stable COPD, moderate-to-very severe airflow limitation (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 2, 3, or 4), at 67 clinical sites in Belgium, Canada, France, Germany, Italy, Spain, UK, and USA. Eligible patients were aged 40-80 years and had a history of at least one moderate or severe exacerbation in the previous year. Patients were allocated (1:1) using a minimisation algorithm to receive two intramuscular injections of NTHi-Mcat vaccine or placebo 60 days apart, in addition to standard care. The allocation algorithm considered age category, number of previous exacerbations, COPD severity at study entry, and country as minimisation factors, to guarantee treatment balance within each factor. Vaccine recipients and those responsible for evaluating study endpoints were masked to group allocation. In the analysis of efficacy, the primary outcome was the rate of any moderate or severe AECOPD occurring within a 1-year period, starting 1 month after the second dose in patients who received two vaccine doses (modified total vaccinated cohort). Safety was assessed in the total vaccinated cohort. The trial is registered with ClinicalTrials.gov, number NCT03281876, and is complete., Findings: Between Nov 27, 2017, and Nov 30, 2018, 606 adults were enrolled and included in the total vaccinated cohort (304 in the NTHi-Mcat vaccine group, 302 in the placebo group); 571 received two doses and were included in the primary efficacy analysis (279 in the NTHi-Mcat vaccine group, 292 in the placebo group). 23 participants dropped-out in the NTHi-Mcat vaccine group and 39 in the placebo group; this included 4 patients in the NTHi-Mcat vaccine group and 15 in the placebo group who withdrew from the study because of an adverse event. The primary analysis included 340 exacerbations (in follow-up time 102 123 days) in the NTHi-Mcat vaccine group and 333 (in 104 443 days) in the placebo group, with a yearly rate of moderate or severe AECOPD of 1·22 in the NTHi-Mcat vaccine group and 1·17 in the placebo group, with vaccine efficacy in reducing the yearly rate of moderate or severe AECOPD estimated to be zero (vaccine efficacy point estimate 2·26% [87% CI -18·27 to 11·58]; p=0·82). Solicited local adverse events were more frequent in the NTHi-Mcat vaccine group (216 [72%] of 301 patients) than with placebo (34 [11%] of 299 patients), and the frequency of solicited general adverse events was similar between groups (239 [79%] of 301 vs 235 [79%] of 299 patients). There was one death in the NTHi-Mcat vaccine group (acute respiratory failure, not related to vaccination) and ten in the placebo group (seven due in part to COPD or respiratory failure). There were 158 serious adverse events (89 [29%] of 304 patients) in the NTHi-Mcat vaccine group, not related to vaccination, and 214 (99 [33%] of 302 patients) in the placebo group., Interpretation: NTHi-Mcat vaccine administered to patients with COPD did not show efficacy in reducing the yearly rate of moderate or severe exacerbations. No safety concerns were identified., Funding: GlaxoSmithKline Biologicals SA., Competing Interests: Declaration of interests SA reports grants and personal fees from Boehringer Ingelheim, grants from Pfizer, and personal fees from Novartis, AstraZeneca, the GlaxoSmithKline (GSK) group of companies, Chiesi, and Merini, outside of the submitted work. AKA, DC, GDM, ML, LM, SS, and AT are employees of the GSK group of companies. MT was an employee of the GSK group of companies when this study was conducted and is now an employee of Janssen–Cilag SpA. ML and SS also hold shares in the GSK group of companies. GB reports having received honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, the GSK group of companies, Novartis, and Teva, and for advisory boards from Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, the GSK group of companies, Novartis, Sanofi–Regeneron, and Teva, all outside of the submitted work. WJ reports grants from AstraZeneca, Chiesi, Roche, and Boehringer Ingelheim outside of the submitted work. EK has served on advisory boards and received consulting fees and travel reimbursements from Amphastar, AstraZeneca, Boehringer Ingelheim, Chiesi, Connect Biopharmaceuticals, the GSK group of companies, Mylan, Novartis, Sunovion, and Theravance, outside of the submitted work. AP reports receiving fees for board membership, consultancy, payment for lectures, grants for research, travel expense reimbursement from Chiesi, AstraZeneca, the GSK group of companies, Boehringer Ingelheim, and Teva; fees for board membership, consultancy, payment for lectures, travel expense reimbursement from Mundipharma, Novartis, Zambon, and Sanofi–Regeneron; and grants for research, payment for lectures, travel expenses reimbursement from Menarini, fees for board membership, consultancy, travel expenses reimbursement from Roche, grants for research from Fondazione Maugeri, Fondazione Chiesi, and consultancy fees from Edmondpharma, all outside of the submitted work. LP-M reports, outside of the submitted work, financial support for educational activities and advisory from AstraZeneca, financial support for educational activities and a grant for non-committed investigation from the GSK group of companies, investigation grant from Esteve and Menarini, travel bourses from Boerhinger Ingelheim and Teva, travel bourse, and personal fees for educational activities from Novartis, financial support for educational activities from Chiesi, and personal fees for advisory from Merck Sharpe & Dohme and Boston Scientific. DS, BP, and LB declare no financial and non-financial relationships and activities and no conflicts of interest. HW reports a grant to his employer from the GSK group of companies during the conduct of this study, and grants or personal fees from the GSK group of companies, AstraZeneca, Boehringer Ingelheim, Novartis, Chiesi, Menarini, Takeda, and Bayer outside of the submitted work. TMAW received grants from the GSK group of companies during the conduct of this study. TMAW also received grants from AstraZeneca, Synairgen, UK Research and Innovation, and MyMHealth, and fees or non-financial support from Boehringer Ingelheim, Chiesi, and AstraZeneca, outside of the submitted work. TMAW is an inventor on patent applications: 2018 US Patent application 62/479562—immunogenic composition, use and methods of treatment—a novel vaccine to prevent exacerbations of COPD pending to the GSK group of companies; and US patent application 62/479550 (novel COPD vaccine). TMAW is the founder and director of MyMHealth Ltd. FM reports a grant paid to his institution by the GSK group of companies during the conduct of this study, and grants paid to his institution by the GSK group of companies, AstraZeneca, Sanofi; unrestricted grant paid to his institution by Novartis, Boehringer Ingelheim, Grifols; personal fees for participating in speaker bureau from the GSK group of companies, Boehringer Ingelheim, Grifols, Novartis; and financial participation in Oxynov, all outside of the submitted work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Rationale: The long-acting β 2 -agonist/long-acting muscarinic antagonist combination indacaterol/glycopyrronium (IND/GLY) elicits bronchodilation, improves symptoms, and reduces exacerbations in COPD. Magnetic resonance imaging (MRI) of the lung with hyperpolarized gas and gadolinium contrast enhancement enables assessment of whole lung functional responses to IND/GLY., Objectives: The primary objective was assessment of effect of IND/GLY on global ventilated lung volume (%VV) versus placebo in COPD. Lung function, regional ventilation and perfusion in response to IND/GLY were also measured., Methods: This double-blind, randomized, placebo-controlled, crossover study assessed %VV and pulmonary perfusion in patients with moderate-to-severe COPD after 8 days of once-daily IND/GLY treatment (110/50 µg) followed by 8 days of placebo, or vice versa, using inhaled hyperpolarized 3 He gas and gadolinium contrast-enhanced MRI, respectively. Lung function measures including spirometry were performed for each treatment after 8 days., Measurements and Main Results: Of 31 patients randomized, 29 completed both treatment periods. IND/GLY increased global %VV versus placebo (61.73% vs. 56.73%, respectively, least squares means treatment difference: 5.00% [90% CI 1.40 to 8.60]; P = 0.025). IND/GLY improved whole lung index of ventilation volume to perfusion volume (V/Q) ratio versus placebo; 94% (90% CI 83 to 105) versus 86% (90% CI 75 to 97; P = 0.047), respectively. IND/GLY showed a trend to improve diffusing capacity for carbon monoxide (DL CO ) (+ 0.66 mL/min/mmHg; P = 0.082). By Day 8, forced expiratory volume in 1 s (FEV 1 ) was increased by 0.32 L versus placebo (90% CI 0.26 to 0.38; P < 0.0001), substantiating earlier findings and providing evidence of assay sensitivity for this trial., Conclusions: IND/GLY improved lung ventilation assessed by 3 He MRI after 1 week of treatment. This observation may provide mechanistic support for the symptomatic clinical benefit shown with IND/GLY in COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02634983)., (© 2022. The Author(s).)

Background: Few data exist on the comparative safety and immunogenicity of different COVID-19 vaccines given as a third (booster) dose. To generate data to optimise selection of booster vaccines, we investigated the reactogenicity and immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT)., Methods: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of third dose booster vaccination against COVID-19. Participants were aged older than 30 years, and were at least 70 days post two doses of ChAd or at least 84 days post two doses of BNT primary COVID-19 immunisation course, with no history of laboratory-confirmed SARS-CoV-2 infection. 18 sites were split into three groups (A, B, and C). Within each site group (A, B, or C), participants were randomly assigned to an experimental vaccine or control. Group A received NVX-CoV2373 (Novavax; hereafter referred to as NVX), a half dose of NVX, ChAd, or quadrivalent meningococcal conjugate vaccine (MenACWY)control (1:1:1:1). Group B received BNT, VLA2001 (Valneva; hereafter referred to as VLA), a half dose of VLA, Ad26.COV2.S (Janssen; hereafter referred to as Ad26) or MenACWY (1:1:1:1:1). Group C received mRNA1273 (Moderna; hereafter referred to as m1273), CVnCov (CureVac; hereafter referred to as CVn), a half dose of BNT, or MenACWY (1:1:1:1). Participants and all investigatory staff were blinded to treatment allocation. Coprimary outcomes were safety and reactogenicity and immunogenicity of anti-spike IgG measured by ELISA. The primary analysis for immunogenicity was on a modified intention-to-treat basis; safety and reactogenicity were assessed in the intention-to-treat population. Secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ISRCTN, number 73765130., Findings: Between June 1 and June 30, 2021, 3498 people were screened. 2878 participants met eligibility criteria and received COVID-19 vaccine or control. The median ages of ChAd/ChAd-primed participants were 53 years (IQR 44-61) in the younger age group and 76 years (73-78) in the older age group. In the BNT/BNT-primed participants, the median ages were 51 years (41-59) in the younger age group and 78 years (75-82) in the older age group. In the ChAd/ChAD-primed group, 676 (46·7%) participants were female and 1380 (95·4%) were White, and in the BNT/BNT-primed group 770 (53·6%) participants were female and 1321 (91·9%) were White. Three vaccines showed overall increased reactogenicity: m1273 after ChAd/ChAd or BNT/BNT; and ChAd and Ad26 after BNT/BNT. For ChAd/ChAd-primed individuals, spike IgG geometric mean ratios (GMRs) between study vaccines and controls ranged from 1·8 (99% CI 1·5-2·3) in the half VLA group to 32·3 (24·8-42·0) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·1 (95% CI 0·7-1·6) for ChAd to 3·6 (2·4-5·5) for m1273. For BNT/BNT-primed individuals, spike IgG GMRs ranged from 1·3 (99% CI 1·0-1·5) in the half VLA group to 11·5 (9·4-14·1) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·0 (95% CI 0·7-1·6) for half VLA to 4·7 (3·1-7·1) for m1273. The results were similar between those aged 30-69 years and those aged 70 years and older. Fatigue and pain were the most common solicited local and systemic adverse events, experienced more in people aged 30-69 years than those aged 70 years or older. Serious adverse events were uncommon, similar in active vaccine and control groups. In total, there were 24 serious adverse events: five in the control group (two in control group A, three in control group B, and zero in control group C), two in Ad26, five in VLA, one in VLA-half, one in BNT, two in BNT-half, two in ChAd, one in CVn, two in NVX, two in NVX-half, and one in m1273., Interpretation: All study vaccines boosted antibody and neutralising responses after ChAd/ChAd initial course and all except one after BNT/BNT, with no safety concerns. Substantial differences in humoral and cellular responses, and vaccine availability will influence policy choices for booster vaccination., Funding: UK Vaccine Taskforce and National Institute for Health Research., Competing Interests: Declaration of interests KCa acts on behalf of University Hospital Southampton as an investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Janssen, Medimmune, Merck, Pfizer, Sanofi, and Valneva. She receives no personal financial payment for this work. SNF acts on behalf of University Hospital Southampton National Health Service (NHS) Foundation Trust as an investigator or providing consultative advice, or both, on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers including Janssen, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Sanofi, Medimmune, Merck, and Valneva. He receives no personal financial payment for this work. ALG is named as an inventor on a patent covering use of a particular promoter construct that is often used in ChAdOx1-vectored vaccines and is incorporated in the ChAdOx1 nCoV-19 vaccine. ALG might benefit from royalty income paid to the University of Oxford from sales of this vaccine by AstraZeneca and its sublicensees under the University's revenue sharing policy. JH has received payments for presentations for AstraZeneca, Boehringer Ingelheim, Chiesi, Ciple, and Teva. VL acts on behalf of University College London Hospitals NHS Foundation Trust as an investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers including Pfizer, AstraZeneca, and Valneva. He receives no personal financial payment for this work. PM acts on behalf of University Hospital Southampton NHS Foundation Trust and The Adam Practice as an investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Novavax, Medicago, and Sanofi. He received no personal financial payment for this work. JSN-V-T is seconded to the Department of Health and Social Care, England. MR has provided post marketing surveillance reports on vaccines for Pfizer and GlaxoSmithKline for which a cost recover charge is made. MDS acts on behalf of the University of Oxford as an investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Pfizer, Novavax, Janssen, Medimmune, and MCM vaccines. He received no personal financial payment for this work. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. Published by Elsevier Ltd.. All rights reserved.)

Background: Early clinical data from studies of the NVX-CoV2373 vaccine (Novavax), a recombinant nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that contains the full-length spike glycoprotein of the prototype strain plus Matrix-M adjuvant, showed that the vaccine was safe and associated with a robust immune response in healthy adult participants. Additional data were needed regarding the efficacy, immunogenicity, and safety of this vaccine in a larger population., Methods: In this phase 3, randomized, observer-blinded, placebo-controlled trial conducted at 33 sites in the United Kingdom, we assigned adults between the ages of 18 and 84 years in a 1:1 ratio to receive two intramuscular 5-μg doses of NVX-CoV2373 or placebo administered 21 days apart. The primary efficacy end point was virologically confirmed mild, moderate, or severe SARS-CoV-2 infection with an onset at least 7 days after the second injection in participants who were serologically negative at baseline., Results: A total of 15,187 participants underwent randomization, and 14,039 were included in the per-protocol efficacy population. Of the participants, 27.9% were 65 years of age or older, and 44.6% had coexisting illnesses. Infections were reported in 10 participants in the vaccine group and in 96 in the placebo group, with a symptom onset of at least 7 days after the second injection, for a vaccine efficacy of 89.7% (95% confidence interval [CI], 80.2 to 94.6). No hospitalizations or deaths were reported among the 10 cases in the vaccine group. Five cases of severe infection were reported, all of which were in the placebo group. A post hoc analysis showed an efficacy of 86.3% (95% CI, 71.3 to 93.5) against the B.1.1.7 (or alpha) variant and 96.4% (95% CI, 73.8 to 99.5) against non-B.1.1.7 variants. Reactogenicity was generally mild and transient. The incidence of serious adverse events was low and similar in the two groups., Conclusions: A two-dose regimen of the NVX-CoV2373 vaccine administered to adult participants conferred 89.7% protection against SARS-CoV-2 infection and showed high efficacy against the B.1.1.7 variant. (Funded by Novavax; EudraCT number, 2020-004123-16.)., (Copyright © 2021 Massachusetts Medical Society.)

Objective: To describe the impact of omalizumab on asthma management in patients treated as part of normal clinical practice in the UK National Health Service (NHS)., Design: A non-interventional, mixed methodology study, combining retrospective and prospective data collection for 12 months pre-omalizumab and post-omalizumab initiation, respectively., Setting: Data were collected in 22 UK NHS centres, including specialist centres and district general hospitals in the UK., Participants: 258 adult patients (aged ≥16 years; 65% women) with severe persistent allergic asthma treated with omalizumab were recruited, of whom 218 (84.5%) completed the study., Primary and Secondary Outcome Measures: The primary outcome measure was change in mean daily dose of oral corticosteroids (OCS) between the 12-month pre-omalizumab and post-omalizumab initiation periods. A priori secondary outcome measures included response to treatment, changes in OCS dosing, asthma exacerbations, lung function, employment/education, patient-reported outcomes and hospital resource utilisation., Results: The response rate to omalizumab at 16 weeks was 82.4%. Comparing pre-omalizumab and post-omalizumab periods, the mean (95% CIs) daily dose of OCS decreased by 1.61 (-2.41 to -0.80) mg/patient/day (p<0.001) and hospital exacerbations decreased by 0.97 (-1.19 to -0.75) exacerbations/patient (p<0.001). Compared with baseline, lung function, assessed by percentage of forced expiratory volume in 1 s, improved by 4.5 (2.7 to 6.3)% at 16 weeks (p<0.001; maintained at 12 months) and patient quality of life (Asthma Quality of Life Questionnaire) improved by 1.38 (1.18 to 1.58) points at 16 weeks (p<0.001, maintained at 12 months). 21/162 patients with complete employment data gained employment and 6 patients lost employment in the 12-month post-omalizumab period. The mean number of A&E visits, inpatient hospitalisations, outpatient visits (excluding for omalizumab) and number of bed days/patient decreased significantly (p<0.001) in the 12-month post-omalizumab period., Conclusions: These data support the beneficial effects of omalizumab on asthma-related outcomes, quality of life and resource utilisation in unselected patients treated in 'real-world' clinical practice., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Morning symptoms associated with COPD have a negative impact on patients' quality of life. Long-acting bronchodilators with rapid onset may relieve patients' symptoms. In the Symptoms and Pulmonary function in the moRnING study, we prospectively compared the rapid onset bronchodilator profile of glycopyrronium (GLY) and tiotropium (TIO) during the first few hours after dosing in patients with moderate-to-severe COPD., Methods: Patients were randomized (1:1) to receive either once-daily GLY (50 μg) or TIO (18 μg) and corresponding placebos in a cross-over design for 28 days. The primary objective was to demonstrate the superiority of GLY versus TIO in area under the curve from 0 to 4 hours (AUC0-4h) forced expiratory volume in 1 second (FEV1) after the first dose. The secondary objective was to compare GLY versus TIO using the patient reported outcomes Morning COPD Symptoms Questionnaire 3 hours post-inhalation., Results: One-hundred and twenty-six patients were randomized (male 70.2%; mean age 65.7 years) and 108 patients completed the study. On Day 1, GLY resulted in significantly higher FEV1 AUC0-4h after the first dose versus TIO (treatment difference [Δ], 0.030 L, 95% confidence interval 0.004-0.056, P=0.025). Improvements in morning COPD symptoms from baseline at Days 1 and 28 were similar between GLY and TIO. Post hoc analysis of the FEV1 AUC0-4h by time point on Day 1 showed significant improvements in patients receiving GLY versus TIO at 5 minutes (Δ=0.029 L, P=0.015), 15 minutes (Δ=0.033 L, P=0.026), and 1 hour (Δ=0.044 L, P=0.014). Safety results were comparable between both treatments., Conclusion: The SPRING study demonstrates the superiority of GLY versus TIO in terms of superior bronchodilation in the first 4 hours after administration, thus extending the clinical data that support a faster onset of action of GLY versus TIO.

Background: Spiromax® is a novel dry-powder inhaler containing formulations of budesonide plus formoterol (BF). The device is intended to provide dose equivalence with enhanced user-friendliness compared to BF Turbuhaler® in asthma and chronic obstructive pulmonary disease (COPD). The present study was performed to compare inhalation parameters with empty versions of the two devices, and to investigate the effects of enhanced training designed to encourage faster inhalation., Methods: This randomised, open-label, cross-over study included children with asthma (n = 23), adolescents with asthma (n = 27), adults with asthma (n = 50), adults with COPD (n = 50) and healthy adult volunteers (n = 50). Inhalation manoeuvres were recorded with each device after training with the patient information leaflet (PIL) and after enhanced training using an In-Check Dial device., Results: After PIL training, peak inspiratory flow (PIF), maximum change in pressure (∆P) and the inhalation volume (IV) were significantly higher with Spiromax than with the Turbuhaler device (p values were at least <0.05 in all patient groups). After enhanced training, numerically or significantly higher values for PIF, ∆P, IV and acceleration remained with Spiromax versus Turbuhaler, except for ∆P in COPD patients. After PIL training, one adult asthma patient and one COPD patient inhaled <30 L/min through the Spiromax compared to one adult asthma patient and five COPD patients with the Turbuhaler. All patients achieved PIF values of at least 30 L/min after enhanced training., Conclusions: The two inhalers have similar resistance so inhalation flows and pressure changes would be expected to be similar. The higher flow-related values noted for Spiromax versus Turbuhaler after PIL training suggest that Spiromax might have human factor advantages in real-world use. After enhanced training, the flow-related differences between devices persisted; increased flow rates were achieved with both devices, and all patients achieved the minimal flow required for adequate drug delivery. Enhanced training could be useful, especially in COPD patients.

Background: The characteristics of each inhalation maneuver when patients use dry powder inhalers (DPIs) are important, because they control the quality of the emitted dose., Methods: We have measured the inhalation profiles of asthmatic children [CHILD; n=16, mean forced expiratory volume in 1 sec (FEV1) 79% predicted], asthmatic adults (ADULT; n=53, mean predicted FEV1 72%), and chronic obstructive pulmonary disease (COPD; n=29, mean predicted FEV1 42%) patients when they inhaled through an Aerolizer, Diskus, Turbuhaler, and Easyhaler using their "real-life" DPI inhalation technique. These are low-, medium-, medium/high-, and high-resistance DPIs, respectively. The inhalation flow against time was recorded to provide the peak inhalation flow (PIF; in L/min), the maximum pressure change (ΔP; in kPa), acceleration rates (ACCEL; in kPa/sec), time to maximum inhalation, the length of each inhalation (in sec), and the inhalation volume (IV; in liters) of each inhalation maneuver., Results: PIF, ΔP, and ACCEL values were consistent with the order of the inhaler's resistance. For each device, the inhalation characteristics were in the order ADULT>COPD>CHILD for PIF, ΔP, and ACCEL (p<0.001). The results showed a large variability in inhalation characteristics and demonstrate the advantages of ΔP and ACCEL rather than PIFs. Overall inhaled volumes were low, and only one patient achieved an IV >4 L and ΔP >4 kPa., Conclusion: The large variability of these inhalation characteristics and their range highlights that if inhalation profiles were used with compendial in vitro dose emission measurements, then the results would provide useful information about the dose patients inhale during routine use. The inhalation characteristics highlight that adults with asthma have greater inspiratory capacity than patients with COPD, whereas children with asthma have the lowest. The significance of the inhaled volume to empty doses from each device requires investigation.

Background: Patients often experience problems using metered dose inhalers (MDIs), particularly poor coordination between inhalation start and dose actuation (TsIn: time difference between the start of an inhalation and the actuation of a dose), and fast peak inspiratory flow (PIF). We investigated if a coordination cap (CAP), with instruction to prolong inhalation, solved these problems., Methods: Inhalation profiles [PIF, TsIn, inhalation volume (Vi), inhalation time (Ti)] of patients with stable asthma prescribed an MDI were measured using their real-life technique (MDI). Inhalation profiles were then measured with the cap fitted (MDI+CAP). These patients were then instructed to inhale through the MDI+CAP for 5 sec, and inhalation profiles measured (MDI+CAP+TRAIN). TsIn was only measured for the MDI., Results: Resistances of MDI and MDI+CAP were 0.0135 and 0.0243 (cm H2O)(½)/(L/min), respectively. Seventy-one patients were evaluated, with mean [standard deviation (SD)] forced expiratory volume over 1 sec % predicted normal of 78.3% (21.0). Following MDI, MDI+CAP, and MDI+CAP+TRAIN: mean (SD) PIF was 155.6 (61.5), 112.3 (48.4), and 73.8 (34.9) L/min, respectively (p<0.001); mean (SD) Ti was 1.60 (0.60), 1.92 (0.80), and 2.99 (1.03) sec, respectively (p<0.001); and Vi was similar between stages. Twelve patients used a slow flow with the MDI alone, but only two of these patients demonstrated good coordination. With the cap in place (which ensures good coordination), the number of patients using a slow flow increased to 25 for MDI+CAP and to 50 following MDI+CAP+TRAIN., Conclusions: The cap with its effect of increasing resistance to airflow combined with the instruction to prolong inhalation time significantly decreased the inhalation flow.

Pegylated interferon (Peg-IFN) in combination with ribavirin is the standard of care in the treatment of chronic hepatitis C (HCV). Peg-IFN is known to have a number of side effects but severe respiratory complications are uncommon. We report two cases, one of Peg-IFN induced interstitial pneumonitis (IP) and the other of bronchiolitis obliterans organising pneumonia (BOOP) in patients with chronic hepatitis C infection. In general, respiratory complications of Peg-IFN are mild and resolve with withdrawal of Peg-IFN. However, as illustrated in our first case fatal interstitial pneumonitis can occur. We present a review of the available literature on Peg-IFN induced lung toxicity. In conclusion, pulmonary toxicity with Peg-IFN is rare but fatality can occur. We highlight the importance of maintaining a high index of suspicion for early diagnosis and prompt treatment, which includes withdrawal of Peg-IFN and consideration of corticosteroid treatment.

Background: Tuberculosis (TB) has increased within the UK and, in response, targets for TB control have been set and interventions recommended. The question was whether these had been implemented and, if so, had they been effective in reducing TB cases., Methods: Epidemiological data were obtained from enhanced surveillance and clinics. Primary care trusts or TB clinics with an average of > 100 TB cases per year were identified and provided reflections on the reasons for any change in their local incidence, which was compared to an audit against the national TB plan., Results: Access to data for planning varied (0-22 months). Sputum smear status was usually well recorded within the clinics. All cities had TB networks, a key worker for each case, free treatment and arrangements to treat HIV co-infection. Achievement of targets in the national plan correlated well with change in workload figures for the commissioning organizations (Spearman's rank correlation R = 0.8, P < 0.01) but not with clinic numbers. Four cities had not achieved the target of one nurse per 40 notifications (Birmingham, Bradford, Manchester and Sheffield). Compared to other cities, their loss to follow-up during treatment was usually > 6% (χ2 = 4.2, P < 0.05), there was less TB detected by screening and less outreach. Manchester was most poorly resourced and showed the highest rate of increase of TB. Direct referral from radiology, sputum from primary care and outreach workers were cited as important in TB control., Conclusion: TB control programmes depend on adequate numbers of specialist TB nurses for early detection and case-holding.Please see related article: http://www.biomedcentral.com/1741-7015/9/127.

Introduction: Tuberculosis (TB) remains the most common cause of death from infectious disease world-wide. In the UK, the incidence of TB has risen by 25% over the last 10 years; extrapulmonary diagnosis remains challenging and can be delayed. This study evaluates the epidemiology of musculoskeletal tuberculosis in a large multi-ethnic UK city., Patients and Methods: A review of prospectively recorded data of incidence, anatomical site, ethnic distribution, treatment and drug resistance of musculoskeletal tuberculosis over a 6-year period was performed., Results: From January 1999 to December 2004, there were 729 TB notifications; 61 cases (8.4%) had musculoskeletal involvement. Of the patients, 74% were immigrants from the Indian subcontinent; nearly 50% had spinal involvement; 24 patients underwent surgical intervention; 29 were subjected to either diagnostic or therapeutic radiological intervention; and resolution of symptoms was achieved in 59 out of 61 cases., Conclusions: This study highlights the high proportion of musculoskeletal TB in immigrant patients in an area with a relatively large at-risk population, but will also serve to alert physicians, in areas with smaller at-risk populations, of the possibility of musculoskeletal TB.

Objectives: Linezolid is a new oxazolidinone antibiotic with efficacy against a broad range of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). In this study, we have determined the serum and sputum linezolid concentrations in adults with cystic fibrosis (CF) following oral drug administration., Methods: Eleven adult patients with CF were recruited. Subjects received 600 mg of linezolid orally every 12 h for a total of six doses. Serum and sputum levels were measured just before and at 2 h after the final dose of linezolid. A further serum level was measured at 4 h., Results: Ten adult patients completed the study. Mean (s.d.) serum linezolid concentrations were 2.3 mg/L (1.5) at 12 h following the fifth dose. At 2 and 4 h following the sixth dose, concentrations were 13.5 (4.3) and 8.1 (3.3). Mean (s.d.) linezolid sputum concentrations were 3.6 (2.1) and 17.4 (7.2) mg/L at 0 and 2 h following drug administration., Conclusions: The oral administration of linezolid results in good sputum penetration in patients with CF. Mean levels exceed the required MIC for the treatment of MRSA for >80% of the dosing period for serum and the majority of the dosing period for sputum.

Background: Improvements in driving simulator performance have been demonstrated in patients with sleep apnoea hypopnoea syndrome (SAHS) after several months of treatment, but it is not known how quickly these improvements are achieved and lost. The aim of this study was to assess the time course of changes in driving simulator performance in patients with SAHS following treatment with continuous positive airways pressure (CPAP)., Methods: Eighteen patients with severe SAHS performed a driving simulator test at baseline (before treatment) and at days 1, 3, and 7 of a 2 week CPAP trial period. CPAP was then discontinued and the patients performed three further driving simulator tests after 1, 3, and 7 days. Eighteen patients with severe SAHS acted as controls and performed the driving simulator test on seven occasions in a pattern similar to that of the treated patients., Results: Significant improvements in tracking error (p=0.004), reaction time (p=0.036), and the number of off road events per hour (p=0.032) were seen in the CPAP treated group compared with the controls at 7 days. Following discontinuation of CPAP for 7 days a significant difference in driving simulator performance persisted between the two groups, but the size of the difference had reduced., Conclusion: Driving simulator performance in patients with severe SAHS improves within the first few days of starting CPAP and these improvements appear to be sustained for up to 1 week after withdrawal. Further data about the usefulness of driving simulators in predicting safe driving are needed before these results can be used in advising patients on driving. However, the data appear to suggest that driving can be safely resumed after a few days of effective CPAP treatment.