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Background Non-typeable Haemophilus influenza (NTHi) infection is common in COPD. Corticosteroids can have limited therapeutic effects in COPD patients. NTHi causes corticosteroid insensitive cytokine production from COPD alveolar macrophages. We investigated the mechanisms by which NTHi causes corticosteroid insensitive inflammatory responses, and the effects of NTHi exposure on COPD macrophage polarisation. Method Alveolar macrophages from COPD patients and controls were exposed to NTHi in conjunction with the corticosteroid dexamethasone and/or the p38 MAPK inhibitor BIRB-796. Cytokine release, GR phosphorylation and modulation and macrophage phenotype were analysed. Results Dexamethasone significantly inhibited NTHi induced TNF-α, IL-6 and IL-10 from COPD macrophages but, CXCL8 was not suppressed. BIRB-796 combined with dexamethasone caused significantly greater inhibition of all cytokines than either drug alone ( p  < 0.05 all comparisons). NTHi caused phosphorylation of GR S226 reducing GR nuclear localisation, an effect regulated by p38 MAPK. NTHi altered macrophage polarisation by increasing IL-10 and decreasing CD36, CD206, CD163 and HLA-DR. Conclusion NTHi exposure causes p38 MAPK dependent GR phosphorylation associated with decreased GR function in COPD alveolar macrophages. Combining a p38 MAPK inhibitor with corticosteroids can enhance anti-inflammatory effects during NTHi exposure of COPD alveolar macrophages. NTHi causes macrophage polarisation that favours bacterial persistence.

•BCG-primed, Ad5-85A boosted cattle present Ag85A specific mycobacteriocidal T cells.•Along with mycobacteriocidal activity Ad5-85A boosting induces IL-10 transcription.•Ad5-85A boosting does not alter the transcription pattern of pro-inflammatory cytokines. There is a need to improve the efficacy of the BCG vaccine against human and bovine tuberculosis. Previous data showed that boosting bacilli Calmette-Guerin (BCG)-vaccinated cattle with a recombinant attenuated human type 5 adenovirally vectored subunit vaccine (Ad5-85A) increased BCG protection and was associated with increased frequency of Ag85A-specific CD4+ T cells post-boosting. Here, the capacity of Ag85A-specific CD4+ T cell lines – derived before and after viral boosting – to interact with BCG-infected macrophages was evaluated. No difference before and after boosting was found in the capacity of these Ag85A-specific CD4+ T cell lines to restrict mycobacterial growth, but the secretion of IL-10 in vitro post-boost increased significantly. Furthermore, cell lines derived post-boost had no statistically significant difference in the secretion of pro-inflammatory cytokines (IL-1β, IL-12, IFNγ or TNFα) compared to pre-boost lines. In conclusion, the protection associated with the increased number of Ag85A-specific CD4+ T cells restricting mycobacterial growth may be associated with anti-inflammatory properties to limit immune-pathology.

•BCG-Ad5-85A protection was associated with higher CD4+ Ag85A-specific cell frequency.•BCG-Ad5-85A protection was not associated with increased CD4+ Ag85A-specific avidity.•BCG-Ad5-85A protection was not associated with epitope spreading. There is a need to improve the efficacy of Bacille Calmette-Guérin (BCG) vaccination against tuberculosis in humans and cattle. Previously, we found boosting BCG-primed cows with recombinant human type 5 adenovirus expressing antigen 85A (Ad5-85A) increased protection against Mycobacterium bovis infection compared to BCG vaccination alone. The aim of this study was to decipher aspects of the immune response associated with this enhanced protection. We compared BCG-primed Ad5-85A-boosted cattle with BCG-vaccinated cattle. Polyclonal CD4+ T cell libraries were generated from pre-boost and post-boost peripheral blood mononuclear cells – using a method adapted from Geiger et al. (2009) – and screened for antigen 85A (Ag85A) specificity. Ag85A-specific CD4+ T cell lines were analysed for their avidity for Ag85A and their Ag85A epitope specificity was defined. Boosting BCG with Ad5-85A increased the frequencies of post-boost Ag85A-specific CD4+ T cells which correlated with protection (reduced pathology). Boosting Ag85A-specific CD4+ T cell responses did not increase their avidity. The epitope specificity was variable between animals and we found no clear evidence for a post-boost epitope spreading. In conclusion, the protection associated with boosting BCG with Ad5-85A is linked with increased frequencies of Ag85A-specific CD4+ T cells without increasing avidity or widening of the Ag85A-specific CD4+ T cell repertoire.

Increased pulmonary ceramide levels are suggested to play a causative role in lung diseases including COPD. Neutral sphingomyelinase-2 (nSMase-2) and acid SMase (aSMase), which hydrolyze sphingomyelin to produce ceramide, are activated by a range of cellular stresses, including inflammatory cytokines and pathogens, but notably cigarette smoke appears to only activate nSMase-2. Our primary objective was to investigate nSMase-2 and aSMase protein localization and quantification in lung tissue from nonsmokers (NS), smokers (S), and COPD patients. In addition, various ceramide species (C16, C18, and C20) were measured in alveolar macrophages from COPD patients versus controls. Patients undergoing surgical resection for suspected or confirmed lung cancer were recruited, and nSMase-2 and aSMase protein was investigated in different areas of lung tissue (small airways, alveolar walls, subepithelium, and alveolar macrophages) by immunohistochemistry. Ceramide species were measured in alveolar macrophages from COPD patients and controls by mass spectrometry. nSMase-2 and aSMase were detected in the majority of small airways. There was a significant increase in nSMase-2 immunoreactivity in alveolar macrophages from COPD patients (54%) compared with NS (31.7%) ( <0.05), and in aSMase immunoreactivity in COPD (68.2%) and S (69.5%) alveolar macrophages compared with NS (52.4%) ( <0.05). aSMase labeling was also increased in the subepithelium and alveolar walls of S compared with NS. Ceramide (C20) was significantly increased in alveolar macrophages from COPD patients compared with controls. nSMase-2 and aSMase are both increased in COPD alveolar macrophages at the protein level; this may contribute toward the elevated ceramide (C20) detected in alveolar macrophages from COPD patients.

Despite significant clinical progress, checkpoint blockade remains limited by variable response rates, resistance, and toxicity. Activating costimulatory receptors offers a promising alternative to enhance anti-tumor immunity. However, there is insufficient understanding of how to mimic physiological membrane-anchored costimulatory ligands. Here, we describe a strategy for developing effective agonists of the costimulatory receptor CD27 by increasing both antibody valency and FcγRIIB engagement. Engineered anti-CD27 antibodies capable of tetravalent binding to CD27 and selective FcγRIIB association exhibit potent T cell stimulatory activity and anti-tumor efficacy in pre-clinical models, compared to bivalent counterparts. The anti-tumor effects of the tetravalent antibody are mediated through CD8⁺ T cell activation without evidence of regulatory T cell depletion. Mechanistically, whereas the increase in avidity drives more efficient CD27 clustering, FcγRIIB engagement triggers polarization of receptor clusters to the cell-cell interface and reduces receptor internalization. This work provides a framework for developing more effective agonist-based T cell stimulatory therapies.

Introduction United Kingdom surgical training consists of a two-year core surgical training (CST) followed by a six-year higher speciality training (ST). There is a significant step up in responsibility and operative skills when transitioning from core to higher training. One-way trainees can bridge this gap is to \"act up\" to registrar level \"CST-R.\" The CST \"steps up\" to the role of ST typically in the latter part of their core training and gains exposure at being the \"reg of the week,\" primary assistant in theatre, managing MDTs, and taking speciality referrals. This can be an excellent training opportunity. This study aims to demonstrate a quantitative improvement in trainee operation as a result of stepping up. Methods This study compares the operative experience of one vascular surgery-themed trainee during six months as a CST and six months acting up as a CST-R. The trainee's eLogbook was searched for all operations between August 3, 2022, and January 31, 2023, and between February 1, 2023, and August 1, 2023. The number of cases performed and the role played in each were analyzed. The number of low complexity cases conducted in each block was used as a baseline to ensure the progression seen was because of increasingly complex ST operating rather than the increase in CST level operating expected throughout CST. An abscess incision and drainage were used as the reference low-complexity case. Results The number of cases the trainee performed independently increased from 13% to 25%, while the number where they were simply assisting decreased from 43% to 35%. The number of cases where the trainer remained scrubbed decreased nonsignificantly from 43% to 39%. The number of low-complexity cases performed remained unchanged for each six-month block. Conclusion As a CST-R, the trainee played a more prominent operative role in a greater number of cases. The CST-R does require a supportive department and consultant body. It also enables other STs to gain more surgical exposure because of their reduced frequency of being the \"reg of the week.\" If a trainee can remain in a post for two six-month blocks, then there is much to be gained from a formalised acting-up program, and consideration should be given to formally incorporating this into core surgical programs.

IntroductionHepatitis C virus (HCV) is the second largest contributor to liver disease in the UK, with injecting drug use as the main risk factor among the estimated 200 000 people currently infected. Despite effective prevention interventions, chronic HCV prevalence remains around 40% among people who inject drugs (PWID). New direct-acting antiviral (DAA) HCV therapies combine high cure rates (>90%) and short treatment duration (8 to 12 weeks). Theoretical mathematical modelling evidence suggests HCV treatment scale-up can prevent transmission and substantially reduce HCV prevalence/incidence among PWID. Our primary aim is to generate empirical evidence on the effectiveness of HCV ‘Treatment as Prevention’ (TasP) in PWID.Methods and analysisWe plan to establish a natural experiment with Tayside, Scotland, as a single intervention site where HCV care pathways are being expanded (including specialist drug treatment clinics, needle and syringe programmes (NSPs), pharmacies and prison) and HCV treatment for PWID is being rapidly scaled-up. Other sites in Scotland and England will act as potential controls. Over 2 years from 2017/2018, at least 500 PWID will be treated in Tayside, which simulation studies project will reduce chronic HCV prevalence among PWID by 62% (from 26% to 10%) and HCV incidence will fall by approximately 2/3 (from 4.2 per 100 person-years (p100py) to 1.4 p100py). Treatment response and re-infection rates will be monitored. We will conduct focus groups and interviews with service providers and patients that accept and decline treatment to identify barriers and facilitators in implementing TasP. We will conduct longitudinal interviews with up to 40 PWID to assess whether successful HCV treatment alters their perspectives on and engagement with drug treatment and recovery. Trained peer researchers will be involved in data collection and dissemination. The primary outcome – chronic HCV prevalence in PWID – is measured using information from the Needle Exchange Surveillance Initiative survey in Scotland and the Unlinked Anonymous Monitoring Programme in England, conducted at least four times before and three times during and after the intervention. We will adapt Bayesian synthetic control methods (specifically the Causal Impact Method) to generate the cumulative impact of the intervention on chronic HCV prevalence and incidence. We will use a dynamic HCV transmission and economic model to evaluate the cost-effectiveness of the HCV TasP intervention, and to estimate the contribution of the scale-up in HCV treatment to observe changes in HCV prevalence. Through the qualitative data we will systematically explore key mechanisms of TasP real world implementation from provider and patient perspectives to develop a manual for scaling up HCV treatment in other settings. We will compare qualitative accounts of drug treatment and recovery with a ‘virtual cohort’ of PWID linking information on HCV treatment with Scottish Drug treatment databases to test whether DAA treatment improves drug treatment outcomes.Ethics and disseminationExtending HCV community care pathways is covered by ethics (ERADICATE C, ISRCTN27564683, Super DOT C Trial clinicaltrials.gov: NCT02706223). Ethical approval for extra data collection from patients including health utilities and qualitative interviews has been granted (REC ref: 18/ES/0128) and ISCRCTN registration has been completed (ISRCTN72038467). Our findings will have direct National Health Service and patient relevance; informing prioritisation given to early HCV treatment for PWID. We will present findings to practitioners and policymakers, and support design of an evaluation of HCV TasP in England.

Williams–Beuren syndrome (WBS) is a developmental disorder with characteristic physical, cognitive and behavioural traits caused by a microdeletion of ∼1.5 Mb on chromosome 7q11.23. In total, 24 genes have been described within the deleted region to date. We have isolated and characterised a novel human gene, GTF2IRD2 , mapping to the WBS critical region thought to harbour genes important for the cognitive aspects of the disorder. GTF2IRD2 is the third member of the novel TFII-I family of genes clustered on 7q11.23. The GTF2IRD2 protein contains two putative helix-loop-helix regions (I-repeats) and an unusual C-terminal CHARLIE8 transposon-like domain, thought to have arisen as a consequence of the random insertion of a transposable element generating a functional fusion gene. The retention of a number of conserved transposase-associated motifs within the protein suggests that the CHARLIE8-like region may still have some degree of transposase functionality that could influence the stability of the region in a mechanism similar to that proposed for Charcot–Marie–Tooth neuropathy type 1A. GTF2IRD2 is highly conserved in mammals and the mouse ortholgue ( Gtf2ird2 ) has also been isolated and maps to the syntenic WBS region on mouse chromosome 5G. Deletion mapping studies using somatic cell hybrids show that some WBS patients are hemizygous for this gene, suggesting that it could play a role in the pathogenesis of the disorder.

Most previous efforts to calibrate how rotation and magnetic activity depend on stellar age and mass have relied on observations of clusters, where isochrones from stellar evolution models are used to determine the properties of the ensemble. Asteroseismology employs similar models to measure the properties of an individual star by matching its normal modes of oscillation, yielding the stellar age and mass with high precision. We use 27 days of photometry from the Transiting Exoplanet Survey Satellite to characterize solar-like oscillations in the G8 subgiant of the 94 Aqr triple system. The resulting stellar properties, when combined with a reanalysis of 35 yr of activity measurements from the Mount Wilson HK project, allow us to probe the evolution of rotation and magnetic activity in the system. The asteroseismic age of the subgiant agrees with a stellar isochrone fit, but the rotation period is much shorter than expected from standard models of angular momentum evolution. We conclude that weakened magnetic braking may be needed to reproduce the stellar properties, and that evolved subgiants in the hydrogen shell-burning phase can reinvigorate large-scale dynamo action and briefly sustain magnetic activity cycles before ascending the red giant branch.