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AdultAcartiacongeners,A.bifilosa,A.clausi,A.discaudataandA.tonsa, have distinct seasonal and spatial distribution patterns in Southampton Water (UK), reflecting patterns of temperature and salinity, respectively. The effect of these factors on other life stages, hatch success and naupliar survival was investigated by exposing the congeners to a range of salinity (15.5-33.3) and of temperature (5-20°C).A.clausiis known to prefer more saline waters, and showed highest hatch success at 33.3 salinity.A.tonsais most tolerant to dilution, and at 15.5 salinity it had the highest hatch success of all the congeners. Hatch success in bothA.bifilosaandA.discaudatawas similar over the range of salinities investigated, confirming that they are intermediate species in terms of spatial distribution. The nauplii of all species survived well at the higher salinities and best at 33.3, which allows for differential transport of the poorly swimming nauplii to the mouth of the estuary until size and swimming ability increase, after which they can then return to regions of preferred salinity. The summer species,A.clausiandA.tonsashowed higher hatch success at 20°C, whereasA.discaudata, which is present in the water column all year round, showed no significant temperature-related differences in hatch success.A.bifilosa, which diapauses over summer, showed significantly higher hatch success at 10°C than at 20°C. The physiological relationship between temperature and development time was clear; naupliar survival of all species was highest at 20°C and all congeners reached the first copepodite stage (CI) significantly faster at 20°C. However, no consistent pattern was seen for salinity. It would appear that the adult Acartidae in Southampton Water remain in regions of their preferred salinity and lay eggs there which hatch well. However, because the nauplii are not good swimmers, they are swept towards the mouth of the estuary and into areas of higher salinity, where they remain and develop into more advanced stages before moving back up the estuary to take up their adult distribution pattern. [ABSTRACT FROM AUTHOR]

Introduction: Acne is one of the most common inflammatory skin diseases worldwide and can have significant psychosocial impact and cause permanent scarring. Spironolactone, a potassium-sparing diuretic, has antiandrogenic properties, potentially reducing sebum production and hyperkeratinisation in acne-prone follicles. Dermatologists have prescribed spironolactone for acne in women for over 30 years, but robust clinical study data are lacking. This study seeks to evaluate whether spironolactone is clinically effective and cost-effective in treating acne in women., Methods and Analysis: Women (≥18 years) with persistent facial acne requiring systemic therapy are randomised to receive one tablet per day of 50 mg spironolactone or a matched placebo until week 6, increasing to up to two tablets per day (total of 100 mg spironolactone or matched placebo) until week 24, along with usual topical therapy if desired. Study treatment stops at week 24; participants are informed of their treatment allocation and enter an unblinded observational follow-up period for up to 6 months (up to week 52 after baseline). Primary outcome is the Acne-specific Quality of Life (Acne-QoL) symptom subscale score at week 12. Secondary outcomes include Acne-QoL total and subscales; participant acne self-assessment recorded on a 6-point Likert scale at 6, 12, 24 weeks and up to 52 weeks; Investigator's Global Assessment at weeks 6 and 12; cost and cost effectiveness are assessed over 24 weeks. Aiming to detect a group difference of 2 points on the Acne-QoL symptom subscale (SD 5.8, effect size 0.35), allowing for 20% loss to follow-up, gives a sample size of 398 participants., Ethics and Dissemination: This protocol was approved by Wales Research Ethics Committee (18/WA/0420). Follow-up to be completed in early 2022. Findings will be disseminated to participants, peer-reviewed journals, networks and patient groups, on social media, on the study website and the Southampton Clinical Trials Unit website to maximise impact., Trial Registration Number: ISRCTN12892056;Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Over 13,000 new cases of non-Hodgkin's lymphoma (NHL) are diagnosed in the UK, with approximately 4,900 attributable deaths each year. Diffuse Large B-cell Lymphoma (DLBCL) is the most common NHL comprising one third of adult NHL cases. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) is accepted as the international standard first-line regimen, but improvement in first line treatment is needed. Dysregulated B-cell receptor (BCR) signalling has been identified as a feature of DLBCL. Inhibition of Bruton's tyrosine kinase (Btk), downstream of the BCR has proven efficacious in other B-cell malignancies and in combination with R-CHOP. The second generation Btk inhibitor, acalabrutinib, may have improved target potency and specificity, and therefore better efficacy and tolerability. Methods: ACCEPT is an open-label non-randomised Phase Ib/II trial testing the addition of acalabrutinib to conventional R-CHOP therapy. ACCEPT incorporates an initial 6+6 modified Phase I design of up to 24 participants followed by 15 participant single arm Phase II expansion cohort in treatment naive patients with histologically confirmed DLBCL expressing CD20. Participants are recruited from UK secondary care sites. Phase I will establish the recommended Phase II dose (RP2D, primary endpoint) of acalabrutinib in combination with R-CHOP. Phase II will gain additional information on safety and efficacy on the RP2D. The primary endpoints of Phase II are overall response rate and toxicity profile. Secondary endpoints include duration of response (progression-free survival and overall survival OS) in relation to cell of origin. Analyses are not powered for formal statistical comparisons; descriptive statistics will describe rates of toxicity, efficacy and translational endpoints. Discussion:  ACCEPT will provide evidence for whether acalabrutinib in combination with R-CHOP is safe and biologically effective prior to future Phase II/III trials in patients with previously untreated CD20 positive DLBCL. Trial registration: EudraCT Number: 2015-003213-18 (issued 16 July 2015); ISRCTN 13626902 (registered 07 March 2017)., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Davies A et al.)

Objectives: Innovations resulting from research have both national and global impact, so selecting the most promising research studies to fund is crucial. Peer review of research funding applications is part of the selection process, and requires considerable resources. This study aimed to elicit stakeholder opinions about which factors contribute to and influence effective peer review of funding applications to the UK National Institute for Health Research (NIHR), and to identify possible minor improvements to current processes and any major changes or potential innovations to achieve a more efficient peer review process., Design: Qualitative interviews with 30 stakeholders involved in the peer review process., Participants: Participants were drawn from three NIHR coordinating centres and represented four types of stakeholders: board members with responsibility for making funding decisions, applicants, external peer reviewers and NIHR staff., Methods: All interviews were conducted by telephone apart from three that were face to face with NIHR staff. Data were analysed using a thematic template method., Results: The responses from NIHR staff, board members and reviewers differed from those received from applicants. The first three groups focused on how well the process of peer review did or did not function. The applicants mentioned these points but in addition often reflected on how their personal application was assessed. Process improvements suggested included: developing a more proportionate review process; providing greater guidance, feedback, training, acknowledgement or incentives for peer reviewers; reducing the time commitment and amount of paperwork; and asking reviewers to comment on the importance, strengths and weaknesses of applications and flaws which are potentially 'fixable'., Conclusions: Overall, participants were supportive of the need for peer review in evaluating applications for research funding. This study revealed which parts of the process are working well and are valued, and barriers, difficulties and potential areas for improvement and development., Competing Interests: Competing interests: All of the authors were employed by the University of Southampton to work at least part time for the NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC) at the time when the study was conducted., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: HTA Programme funding is governed by the need for evidence and scientific quality, reflecting funding of the National Institute for Health Research (NIHR) by the NHS. The need criterion incorporates covering the spectrum of diseases, but also taking account of research supported by other funders. This study compared the NIHR HTA Programme portfolio of research with the UK burden of disease as measured by Disability-adjusted Life Years (DALYs)., Methods: A retrospective cross-sectional study using a cohort of all funded primary research and evidence syntheses projects received by the HTA Programme from April 2011 to March 2016 (n = 363); to determine the proportion of spend by disease compared with burden of disease in the UK calculated using 2015 UK DALY data., Results: The programme costing just under £44 million broadly reflected UK DALY burden by disease. Spend was lower than disease burden for cancer, cardiovascular and musculoskeletal diseases, which may reflect the importance of other funders, notably medical charities, which concentrate on these diseases., Conclusion: The HTA Programme spend, adjusted for other relevant funders, broadly matches disease burden in the UK; no diseases are being neglected.

Objective: To assess the time to publication of primary research and evidence syntheses funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme published as a monograph in Health Technology Assessment and as a journal article in the wider biomedical literature., Study Design: Retrospective cohort study., Setting: Primary research and evidence synthesis projects funded by the HTA Programme were included in the cohort if they were registered in the NIHR research programmes database and was planned to submit the draft final report for publication in Health Technology Assessment on or before 9 December 2011., Main Outcome Measures: The median time to publication and publication at 30 months in Health Technology Assessment and in an external journal were determined by searching the NIHR research programmes database and HTA Programme website., Results: Of 458 included projects, 184 (40.2%) were primary research projects and 274 (59.8%) were evidence syntheses. A total of 155 primary research projects had a completion date; the median time to publication was 23 months (26.5 and 35.5 months to publish a monograph and to publish in an external journal, respectively) and 69% were published within 30 months. The median time to publication of HTA-funded trials (n=126) was 24 months and 67.5% were published within 30 months. Among the evidence syntheses with a protocol online date (n=223), the median time to publication was 25.5 months (28 months to publication as a monograph), but only 44.4% of evidence synthesis projects were published in an external journal. 65% of evidence synthesis studies had been published within 30.0 months., Conclusions: Research funded by the HTA Programme publishes promptly. The importance of Health Technology Assessment was highlighted as the median time to publication was 9 months shorter for a monograph than an external journal article.

Natural killer (NK) cells play a critical role in antitumor immunity, their activation being regulated through NK cell receptors. Although the endogenous ligands for these receptors are largely unknown, viral ligands have been identified. We investigated the ability of an activating NK receptor ligand derived from the mumps virus, haemagglutinin-neuraminidase (HN) to enhance NK activation against tumor cells. HN-expressing B16.OVA tumor cells induced stronger activation of NK cells compared with B16.OVA cells and also promoted dendritic cell (DC) activation toward a DC1 phenotype, in vitro. Moreover, incubation of DCs, NK cells and HN-expressing B16-OVA cells further enhanced NK cell activation through the NK-DC crosstalk, in a cell-to-cell contact- and IL-12-dependent fashion. Immunization of mice with HN-expressing B16-OVA cells resulted in > 85% survival rate after subsequent challenge with parental B16 or B16.OVA tumor cells. Tumor rejection was dependent on both NK and CD8+ T cells but not on CD4+ T cells, demonstrating induction of an effective adaptive immune response through innate immune cell activation. Our data indicate the potential of using robust NK cell activation, which through the NK-DC crosstalk stimulates effective antitumor responses, providing an alternate vaccine strategy.

Cross-presentation is the presentation by MHC class I of antigenic peptides from exogenous proteins that have been internalized and processed by professional antigen-presenting cells, e.g. dendritic cells. We have investigated the influence of particle size and antigen load on cross-presentation following antigen delivery on microspheres (MS). Cross-presentation from small particles (0·8-μm) is sensitive to proteasome inhibition and the blockade of endoplasmic reticulum-resident MHC class I complex export, whereas cross-presentation from larger particles (aggregated clumps of 0·8-μm MS) is resistant to these antagonists. This observation may have been overlooked previously, because of the heterogeneity of particle size and MS uptake in unsorted dendritic cell populations. Larger particles carry more antigen, but we show that antigen load does not influence the cross-presentation pathway used. Whereas early endosome autoantigen 1 (EEA1) could be observed in all phagosomes, we observed endoplasmic reticulum SNARE of molecular weight 24 000 (ERS24) and cathepsin S in association with 3·0-μm and aggregated 0·8-μm MS, but not individual 0·8-μm MS. A potential mechanism underlying our observations may be the activation of β-catenin by disruption of E-cadherin-mediated adhesion. Activated β-catenin was detected in the cytoplasm of cells after phagocytosis of MS (highest levels for the largest particles). We propose that particle size can direct the use of different pathways for the cross-presentation of an identical antigen. Furthermore, these pathways have differing yields of MHC class I-peptide complexes, which is an important variable in designing vaccination strategies for maximal antigen expression and CD8(+) T-cell priming., (© 2012 The Authors. Immunology © 2012 Blackwell Publishing Ltd.)