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Background: The ComFluCOV trial tested the safety and immunogenicity of COVID-19 and influenza vaccines co-administration. Binding and functional SARS-CoV2 anti-spike responses were measured using assays developed in response to the COVID-19 pandemic. The three assays used to measure the immunogenicity outcomes are reported here and their performance compared to inform future vaccine development., Methods: Adults aged over 18 were vaccinated with a COVID-19 and either an influenza vaccine or saline placebo. Serum sampled one month after vaccination was used to measure SARS-CoV2 anti-spike antibody concentrations using a commercial in-house enzyme-linked immunosorbent assay (ELISA), a commercial fast throughput electrochemiluminescence immunoassay (ECLIA) and a viral neutralisation assay (VNA). Geometric mean ratios were used to compare the response to COVID-19 with or without influenza vaccine with a threshold of 0.67 considered non-inferior. The relationship between the different assays was examined using Kendall rank correlations., Results: The geometric mean ratios exceeded 0.67 using all assays for all COVID-19 and influenza vaccine combinations tested. Moderate rank correlations were found between the three assays., Conclusion: All three assays confirmed that vaccine co-administration did not significantly impact on immunogenicity of any of the vaccines tested., Trial Registration: ISRCTN14391248, registered on 17/03/2021., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rajeka Lazarus reports a relationship with National Institute for Health and Care Research that includes: funding grants. Rajeka Lazarus reports a relationship with University of Bristol Elizabeth Blackwell Institute for Health Research that includes: funding grants. Rajeka Lazarus reports a relationship with AstraZeneca that includes: funding grants. Rajeka Lazarus reports a relationship with Janssen that includes: funding grants. Rajeka Lazarus reports a relationship with Valneva that includes: funding grants. Chris Rogers reports a relationship with National Institute for Health and Care Research that includes: funding grants. Adam Finn reports a relationship with Pfizer that includes: funding grants. Adam Finn reports a relationship with UK Joint Committee for Vaccination and Immunisation that includes: board membership. Adam Finn reports a relationship with WHO SAGE Working Group on COVID-19 vaccines that includes: board membership. Adam Finn reports a relationship with University of Bristol Elizabeth Blackwell Institute for Health Research that includes: funding grants. Adam Finn reports a relationship with Sanofi Pasteur that includes: funding grants. Adam Finn reports a relationship with VBI Vaccines Inc. that includes: funding grants. Adam Finn reports a relationship with Janssen that includes: funding grants. Adam Finn reports a relationship with GSK that includes: funding grants. Adam Finn reports a relationship with MedImmune that includes: funding grants. Adam Finn reports a relationship with Novavax that includes: funding grants. Adam Finn reports a relationship with Valneva that includes: funding grants. Matthew Snape reports a relationship with Moderna that includes: employment. Investigator on studies funded or sponsored by vaccine manufacturers, including AstraZeneca, GSK, Pfizer, Novavax, Pfizer, Janssen, Medimmune, and MCM of behalf of the University of Oxford - MDS If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

The ComFluCOV trial randomized 679 participants to receive an age-appropriate influenza vaccine, or placebo, alongside their second COVID-19 vaccine. Concomitant administration was shown to be safe, and to preserve systemic immune responses to both vaccines. Here we report on a secondary outcome of the trial investigating SARS-CoV-2-specific mucosal antibody responses. Anti-spike IgG and IgA levels in saliva were measured with in-house ELISAs. Concomitant administration of an influenza vaccine did not affect salivary anti-spike IgG positivity rates to Pfizer/BioNTech BNT162b2 (99.1 cf. 95.6%), or AstraZeneca ChAdOx1 (67.8% cf. 64.9%), at 3-weeks post-vaccination relative to placebo. Furthermore, saliva IgG positively correlated with serum titres highlighting the potential utility of saliva for assessing differences in immunogenicity in future vaccine studies. Mucosal IgA was not detected in response to either COVID-19 vaccine, reinforcing the need for novel vaccines capable of inducing sterilising immunity or otherwise reducing transmission. The trial is registered as ISRCTN 14391248., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rajeka Lazarus, Lucy Culliford, Sarah Baos, Rachel Todd, Russell Thirard, Rosie Harris, Alice Halliday, Holly Baum, Elizabeth Oliver, Benjamin Hitchings and Kapil Gupta report that financial support was provided by National Institute for Health Research. Rajeka Lazarus reports a relationship with AstraZeneca that includes: consulting or advisory and travel reimbursement. Rajeka Lazarus reports a relationship with Sanofi Pasteur that includes: consulting or advisory and travel reimbursement. Adam Finn reports a relationship with AstraZeneca that includes: funding grants. Adam Finn reports a relationship with Pfizer that includes: funding grants. Adam Finn reports a relationship with University of Oxford that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier India Pvt Ltd.)

Introduction: Adalimumab is an effective treatment for autoimmune non-infectious uveitis (ANIU), but it is currently only funded for a minority of patients with ANIU in the UK as it is restricted by the National Institute for Health and Care Excellence guidance. Ophthalmologists believe that adalimumab may be effective in a wider range of patients. The Adalimumab vs placebo as add-on to Standard Therapy for autoimmune Uveitis: Tolerability, Effectiveness and cost-effectiveness (ASTUTE) trial will recruit patients with ANIU who do and do not meet funding criteria and will evaluate the effectiveness and cost-effectiveness of adalimumab versus placebo as an add-on therapy to standard care., Methods and Analysis: The ASTUTE trial is a multicentre, parallel-group, placebo-controlled, pragmatic randomised controlled trial with a 16-week treatment run-in (TRI). At the end of the TRI, only responders will be randomised (1:1) to 40 mg adalimumab or placebo (both are the study investigational medicinal product) self-administered fortnightly by subcutaneous injection. The target sample size is 174 randomised participants. The primary outcome is time to treatment failure (TF), a composite of signs indicative of active ANIU. Secondary outcomes include individual TF components, retinal morphology, adverse events, health-related quality of life, patient-reported side effects and visual function, best-corrected visual acuity, employment status and resource use. In the event of TF, open-label drug treatment will be restarted as per TRI for 16 weeks, and if a participant responds again, allocation will be switched without unmasking and treatment with investigational medicinal product restarted., Ethics and Dissemination: The trial received Research Ethics Committee (REC) approval from South Central - Oxford B REC in June 2020. The findings will be presented at international meetings, by peer-reviewed publications and through patient organisations and newsletters to patients, where available., Trial Registration: ISRCTN31474800. Registered 14 April 2020., Competing Interests: Competing interests: CAR received support from the National Institute for Health and Care Research (NIHR) for the project associated with this manuscript, which was paid to the University of Bristol. KP, MH, LC, MPYL, SB and BCR received support from the NIHR for the project associated with this manuscript, which contributed to their salary. SW, TP, SMS, NAVB and AD received support from the NIHR for the project associated with this manuscript, which was paid to their institution. SMS is the chair of the NIHR Uveitis Clinical Study Group. PAK receives support from UK Research and Innovation and Moorfields Eye Charity. PAK reports payment for consulting for Novartis, Boehringer-Ingleheim, Apellis, Abbvie, Roche and Adecco. PAK reports payment or honoraria for educational events for Novartis, Gyroscope, Bayer, Thea, Boehringer-Ingleheim, Apellis, Abbvie and Alimera. PAK participates on an advisory board for RetinAI, Novartis, Boehringer-Ingleheim, Roche and Abbvie. PAK reports patents for Google US10198832B2 (issued) and Google US20220301152A1 (pending). PAK reports stock with Big Picture Medical (stocks) and Bitfount (stock options). NAVB receives support from Wellcome Trust and recently receives support from Indonesian Endowment Fund for Education paid to their institution. NAVB reports payments for consulting for Roche. NAVB reports payment or honoria for educational events for Alimera Sciences. NAVB is a member of the Scientific Committee of the Royal College of Ophthalmologists. AD receives support from NIHR Biomedical Research Centre, Janssen Pharmaceuticals, Macular Society, MRC Cluster Consortium Awards and Arthritis Research UK, which is paid to his institution. AD receives royalties from The Eye Basic Science in Practice (Elsevier). AD reports payment for consulting for Hovartis, Hubble Htz, Active Bio and Gilead. AD participates on an advisory board for Co-THEIA Randomised Controlled Trial in Spain. AD is a non-executive director at Moorfields NHS Foundation Trust. No other conflicts were reported., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In early 2021, the Department of Health and Social Care in the UK called for research on the safety and immunogenicity of concomitant administration of COVID-19 and influenza vaccines. Co-administration of these vaccines would facilitate uptake and reduce the number of healthcare visits required. The ComFluCOV trial was designed to deliver the necessary evidence in time to inform the autumn (September-November) 2021 vaccination policy. This paper presents the statistical methodology applied to help successfully deliver the trial results in 6 months., Methods: ComFluCOV was a parallel-group multicentre randomised controlled trial managed by the Bristol Trials Centre. Two study statisticians, supported by a senior statistician, worked together on all statistical tasks. Tools were developed to aid the pre-screening process. Automated data monitoring reports of clinic data and electronic diaries were produced daily and reviewed by the trial team and feedback provided to sites. Analyses were performed independently in parallel, and derivations and results of all outcomes were compared., Results: Set-up was achieved in less than a month, and 679 participants were recruited over 8 weeks. A total of 537 [at least] daily reports outlining recruitment, protocol adherence, and data quality, and 695 daily reports of participant electronic diaries identifying any missed diary entries and adverse events were produced over a period of 16 weeks. A preliminary primary outcome analysis of validated data was reported to the Department of Health and Social Care in May 2021. The database was locked 6 weeks after the final participant follow-up and final analyses completed 3 weeks later. A pre-print publication was submitted within 14 days of the results being made available. The results were reported 6 months after first discussions about the trial., Conclusion: The statistical methodologies implemented in ComFluCOV helped to deliver the study in the timescale set. Working in a new clinical area to tight timescales was challenging. Having two statisticians working together on the study provided a quality assurance process that enabled analyses to be completed efficiently and ensured data were interpreted correctly. Processes developed could be applied to other studies to maximise quality, reduce the risk of errors, and overall provide enhanced validation methods., Trial Registration: ISRCTN14391248, registered on 30 March 2021., (© 2024. The Author(s).)

Background: In February 2021, the UK Department of Health and Social Care sought evidence on the safety and immunogenicity of COVID-19 and influenza vaccine co-administration to inform the 2021/2022 influenza vaccine policy. Co-administration could support vaccine uptake and reduce healthcare appointments. ComFluCOV was a randomised controlled trial designed to provide this evidence. This report outlines the methods used to deliver the trial in 6 months to answer an urgent public health question as part of the COVID-19 pandemic response., Methods: ComFluCOV was commissioned by the Department of Health and Social Care and was managed by the Bristol Trials Centre, a UK-registered clinical trials unit. It was classed as an Urgent Public Health trial which facilitated fast-track regulatory approvals. Trial materials and databases were developed using in-house templates and those used in other COVID-19 vaccine trials. Participants were recruited by advertising, and via a trial website. Electronic trial systems enabled daily review of participant data. Weekly virtual meetings were held with stakeholders and trial sites., Results: ComFluCOV was delivered within 6 months from inception to reporting, and trial milestones to inform the Department of Health and Social Care policy were met. Set-up was achieved within 1 month. Regulators provided expedited reviews, with feedback ahead of submission. Recruitment took place at 12 sites. Over 380 site staff were trained. Overall, 679 participants were recruited in two months. The final report to the Department of Health and Social Care was submitted in September 2021, following a preliminary safety report in May 2021. Trial results have been published., Conclusion: The rapid delivery of ComFluCOV was resource intensive. It was made possible in part due to a unique set of circumstances created by the pandemic situation including measures put in place to support urgent public health research and public support for COVID-19 vaccine research. Elements of the trial could be adopted to increase efficiency in 'non-pandemic' situations including working with a clinical trials unit to enable immediate mobilisation of a team of experienced researchers, greater sharing of resources between clinical trials units, use of electronic trial systems and virtual meetings., Trial Registration: ISRCTN14391248, submitted on 17/03/2021. Registered on 30/03/2021., (© 2024. The Author(s).)

Introduction: Lung cancer is the most common cause of cancer death worldwide and most patients present with extensive disease. One-year survival is improving but remains low (37%) despite novel systemic anti-cancer treatments forming the current standard of care. Although new therapies improve survival, most patients have residual disease after treatment, and little is known on how best to manage it. Therefore, residual disease management varies across the UK, with some patients receiving only maintenance systemic anti-cancer treatment while others receive local consolidative treatment (LCT), alongside maintenance systemic anti-cancer treatment. LCT can be a combination of surgery, radiotherapy and/or ablation to remove all remaining cancer within the lung and throughout the body. This is intensive, expensive and impacts quality of life, but we do not know if it results in better survival, nor the extent of impact on quality of life and what the cost might be for healthcare providers. The RAMON study (RAdical Management Of Advanced Non-small cell lung cancer) will evaluate the acceptability, effectiveness and cost-effectiveness of LCT versus no LCT after first-line systemic treatment for advanced lung cancer., Methods and Analysis: RAMON is a pragmatic open multicentre, parallel group, superiority randomised controlled trial. We aim to recruit 244 patients aged 18 years and over with advanced non-small-cell lung cancer from 40 UK NHS hospitals. Participants will be randomised in a 1:1 ratio to receive LCT alongside maintenance treatment, or maintenance treatment alone. LCT will be tailored to each patient's specific disease sites. Participants will be followed up for a minimum of 2 years. The primary outcome is overall survival from randomisation., Ethics and Dissemination: The West of Scotland Research Ethics Committee (22/WS/0121) gave ethical approval in August 2022 and the Health Research Authority in September 2022. Participants will provide written informed consent before participating in the study. Findings will be presented at international meetings, in peer-reviewed publications, through patient organisations and notifications to patients., Trial Registration Number: ISRCTN11613852., Competing Interests: Competing interests: All authors received support from the National Institute for Health and Care Research for the project associated with this manuscript, which was paid to their employing institution. EL reports personal fees from Abbott Molecular, AstraZeneca, Glaxo Smith Kline, Pfizer, Norvatis, Covidien, Roche, Lily Oncology, Boehringer Ingelheim, Medela, Ethicon, and AstraZeneca, and grants from ScreenCell, Clearbridge Biomedics, Illumina, and Guardant Health. PDS reports personal fees from Vitae Professionals. JR reports personal and travel fees from NCRI Lung Advanced disease subgroup, ELF lung cancer patient advisory group, BTOG, Clinical expert group lung cancer, WM Cancer Alliance lung cancer and mesothelioma EAG (as a patient representative). TND reports personal fees from AstraZenca, BMS, Boehringer Ingelheim, Lilly, MSD, Otsuka, Roche, Takeda, BMS, Eli-Lilly, Novartis, and Pfizer., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Sarcopenia is a frequent comorbidity of rheumatoid arthritis (RA). Clinical trials have shown that JAK inhibitors (JAKi) produce an asymptomatic increase in serum creatine kinase (CK) in RA, suggesting an impact on muscle. We evaluated the effect of JAKi in muscle remodeling in an experimental RA model. Antigen-induced arthritis (experimental RA, e-RA) was performed in 14 rabbits. Seven rabbits received tofacitinib (TOFA, orally 10 mg/kg/day). Animals were euthanized one day after the last ovalbumin injection, and muscles were prepared for histology, RT-PCR, and WB. C-reactive protein (CRP) and Myostatin (MSTN) serum concentration were determined by ELISA. Creatine and creatine kinase (CK) were analyzed. An increase in body weight as well as tibialis anterior cross-sectional area and diameter was observed in e-RA+TOFA vs. e-RA. e-RA decreased type II fibers and increased the myonuclei number, with all reverted by TOFA. TOFA did not modify CRP levels, neither did MSTN. TOFA significantly reduced IL-6, atrogin-1, and MuRF-1 compared with e-RA. e-RA+TOFA showed higher CK and lower creatine levels compared with e-RA. No differences in PAX-7 were found, while TOFA prevented the increase in MyoD1 in e-RA. Our model reflects the features of rheumatoid sarcopenia in RA. JAKi increased muscle mass through attenuating IL-6/JAK/STAT activation, decreasing atrogenes, and restoring muscle differentiation markers. These data together with an increase in CK support the role of CK as a valuable marker of muscle gain following JAKi treatment.

Objective: The specific effect of Adipose-Derived Mesenchymal Stem Cells (Ad-MSC) on acute joint inflammation, where the response mostly depends on innate immunity activation, remains elusive. The pathogenesis of gouty arthritis, characterized by the deposition of monosodium urate (MSU) crystals in the joints, associated to acute flares, has been associated to NLRP3 inflammasome activation and subsequent amplification of the inflammatory response. Our aim was to study the effect of human Ad-MSC administration in the clinical inflammatory response of rabbits after MSU injection, and the molecular mechanisms involved., Methods: Ad-MSC were administered by intraarterial route shortly after intraarticular MSU crystal injections. Joint and systemic inflammation was sequentially studied, and the mechanisms involved in NLRP3 inflammasome activation, and the synthesis of inflammatory mediators were assessed in the synovial membranes 72h after insult. Ad-MSC and THP-1-derived macrophages stimulated with MSU were co-cultured in transwell system., Results: A single systemic dose of Ad-MSC accelerated the resolution of local and systemic inflammatory response. In the synovial membrane, Ad-MSC promoted alternatively M2 macrophage presence, inhibiting NLRP3 inflammasome and inducing the production of anti-inflammatory cytokines, such as IL-10 or TGF-β, and decreasing nuclear factor-κB activity. Ad-MSC induced a net anti-inflammatory balance in MSU-stimulated THP-1 cells, with a higher increase in IL-10 and IDO expression than that observed for IL-1β and TNF., Conclusion: Our in vivo and in vitro results showed that a single systemic dose of Ad-MSC decrease the intensity and duration of the inflammatory response by an early local COX-2 upregulation and PGE 2 release. Ad-MSCs suppressed NF-kB activity, NLRP3 inflammasome, and promoted the presence of M2 alternative macrophages in the synovium. Therefore, this therapeutic approach could be considered as a pharmacological alternative in patients with comorbidities that preclude conventional treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Medina, Bermejo-Álvarez, Pérez-Baos, Yáñez, Fernández-García, García-Olmo, Mediero, Herrero-Beaumont and Largo.)

Asthma is a complex condition resulting from the interaction of genes and environment. Obesity is a risk factor to develop asthma and contributes to poor response to asthma therapy and severity. The aim of the study was to evaluate the effect of obesity on the expression levels of genes previously associated with severe asthma. Three groups of subjects were studied: non-obese asthmatics (NOA), obese asthma patients (OA), and non-asthmatic obese subjects (O). Previously reported overexpressed ( IL-10 , MSR1 , PHLDA1 , SERPINB2 , and CD86 ) and underexpressed genes ( CHI3L1 , CPA3 , IL-8 , and PI3 ) in severe asthma were analyzed by RT-qPCR in peripheral blood mononuclear cells (PBMCs). In the overexpressed genes, obesity significantly decreased the expression of MSR1 and PHLDA1 and had no effects on CD86 , IL-10 , and SERPINB2 . In underexpressed genes, obesity did not affect PI3 , CHI3L1 , and IL-8 and significantly reduced CPA3 expression. The results of this study show that obesity should be included among the known factors that can contribute toward modifying the expression of genes associated with asthma and, in particular, severe asthma.

Little is known regarding T cell translational regulation. We demonstrate that T follicular helper (TFH) cells use a previously unknown mechanism of selective messenger RNA (mRNA) translation for their differentiation, role in B cell maturation, and in autoimmune pathogenesis. We show that TFH cells have much higher levels of translation factor eIF4E than non-TFH CD4 + T cells, which is essential for translation of TFH cell fate-specification mRNAs. Genome-wide translation studies indicate that modest down-regulation of eIF4E activity by a small-molecule inhibitor or short hairpin RN impairs TFH cell development and function. In mice, down-regulation of eIF4E activity specifically reduces TFH cells among T helper subtypes, germinal centers, B cell recruitment, and antibody production. In experimental autoimmune encephalomyelitis, eIF4E activity down-regulation blocks TFH cell participation in disease pathogenesis while promoting rapid remission and spinal cord remyelination. TFH cell development and its role in autoimmune pathogenesis involve selective mRNA translation that is highly druggable.

Background: Macrophage scavenger receptor 1 (MSR1) has mostly been described in macrophages, but we previously found a significant gene expression increase in peripheral blood mononuclear cells (PBMCs) of asthmatic patients., Objective: To confirm those results and to define its cellular origin in PBMCs., Methods: Four groups of subjects were studied: healthy controls (C), nonallergic asthmatic (NA), allergic asthmatic (AA), and chronic obstructive pulmonary disease (COPD) patients. RNA was extracted from PBMCs. MSR1 gene expression was analyzed by RT-qPCR. The presence of MSR1 on the cellular surface of PBMC cellular subtypes was analyzed by confocal microscopy and flow cytometry., Results: MSR1 gene expression was significantly increased in the three clinical conditions compared to the healthy control group, with substantial variations according to disease type and severity. MSR1 expression on T cells (CD4 + and CD8 + ), B cells, and monocytes was confirmed by confocal microscopy and flow cytometry. In all clinical groups, the four immune cell subtypes studied expressed MSR1, with a greater expression on B lymphocytes and monocytes, exhibiting differences according to disease and severity., Conclusions: This is the first description of MSR1's presence on lymphocytes' surfaces and reinforces the potential role of MSR1 as a player in asthma and COPD.

Background: Concomitant administration of COVID-19 and influenza vaccines could reduce burden on health-care systems. We aimed to assess the safety of concomitant administration of ChAdOx1 or BNT162b2 plus an age-appropriate influenza vaccine., Methods: In this multicentre, randomised, controlled, phase 4 trial, adults in receipt of a single dose of ChAdOx1 or BNT162b2 were enrolled at 12 UK sites and randomly assigned (1:1) to receive concomitant administration of either an age-appropriate influenza vaccine or placebo alongside their second dose of COVID-19 vaccine. 3 weeks later the group who received placebo received the influenza vaccine, and vice versa. Participants were followed up for 6 weeks. The influenza vaccines were three seasonal, inactivated vaccines (trivalent, MF59C adjuvanted or a cellular or recombinant quadrivalent vaccine). Participants and investigators were masked to the allocation. The primary endpoint was one or more participant-reported solicited systemic reactions in the 7 days after first trial vaccination(s), with a difference of less than 25% considered non-inferior. Analyses were done on an intention-to-treat basis. Local and unsolicited systemic reactions and humoral responses were also assessed. The trial is registered with ISRCTN, ISRCTN14391248., Findings: Between April 1 and June 26, 2021, 679 participants were recruited to one of six cohorts, as follows: 129 ChAdOx1 plus cellular quadrivalent influenza vaccine, 139 BNT162b2 plus cellular quadrivalent influenza vaccine, 146 ChAdOx1 plus MF59C adjuvanted, trivalent influenza vaccine, 79 BNT162b2 plus MF59C adjuvanted, trivalent influenza vaccine, 128 ChAdOx1 plus recombinant quadrivalent influenza vaccine, and 58 BNT162b2 plus recombinant quadrivalent influenza vaccine. 340 participants were assigned to concomitant administration of influenza and a second dose of COVID-19 vaccine at day 0 followed by placebo at day 21, and 339 participants were randomly assigned to concomitant administration of placebo and a second dose of COVID-19 vaccine at day 0 followed by influenza vaccine at day 21. Non-inferiority was indicated in four cohorts, as follows: ChAdOx1 plus cellular quadrivalent influenza vaccine (risk difference for influenza vaccine minus placebos -1·29%, 95% CI -14·7 to 12·1), BNT162b2 plus cellular quadrivalent influenza vaccine (6·17%, -6·27 to 18·6), BNT162b2 plus MF59C adjuvanted, trivalent influenza vaccine (-12·9%, -34·2 to 8·37), and ChAdOx1 plus recombinant quadrivalent influenza vaccine (2·53%, -13·3 to 18·3). In the other two cohorts, the upper limit of the 95% CI exceeded the 0·25 non-inferiority margin (ChAdOx1 plus MF59C adjuvanted, trivalent influenza vaccine 10·3%, -5·44 to 26·0; BNT162b2 plus recombinant quadrivalent influenza vaccine 6·75%, -11·8 to 25·3). Most systemic reactions to vaccination were mild or moderate. Rates of local and unsolicited systemic reactions were similar between the randomly assigned groups. One serious adverse event, hospitalisation with severe headache, was considered related to the trial intervention. Immune responses were not adversely affected., Interpretation: Concomitant vaccination with ChAdOx1 or BNT162b2 plus an age-appropriate influenza vaccine raises no safety concerns and preserves antibody responses to both vaccines. Concomitant vaccination with both COVID-19 and influenza vaccines over the next immunisation season should reduce the burden on health-care services for vaccine delivery, allowing for timely vaccine administration and protection from COVID-19 and influenza for those in need., Funding: National Institute for Health Research Policy Research Programme., Competing Interests: Declaration of interests RL reports grants from the National Institute for Health Research (NIHR) during the conduct of the trial, and grants from Elizabeth Blackwell Institute, AstraZeneca, Janssen, and Valneva outside the submitted work. CAR reports grants from NIHR, during the conduct of the trial. JSN-V-T reports that he is seconded to the Department of Health and Social Care, England. AF reports grants from Pfizer during the conduct of the trial, and grants from Elizabeth Blackwell Institute, Sanofi Pasteur, VBI Vaccines, Pfizer, Janssen, GSK, MedImmune, Novavax, and Valneva outside the submitted work. AM reports grants from NIHR during the conduct of the trial, and grants from AstraZeneca, Janssen, and Valneva outside the submitted work. MDS acts on behalf of the University of Oxford as an investigator on studies funded or sponsored by vaccine manufacturers, including AstraZeneca, GSK, Pfizer, Novavax, Pfizer, Janssen, Medimmune, and MCM. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Regulatory T cells (Treg cells) inhibit effector T cells and maintain immune system homeostasis. Treg cell maturation in peripheral sites requires inhibition of protein kinase mTORC1 and TGF-beta-1 (TGF-beta). While Treg cell maturation requires protein synthesis, mTORC1 inhibition downregulates it, leaving unanswered how Treg cells achieve essential mRNA translation for development and immune suppression activity. Using human CD4 + T cells differentiated in culture and genome-wide transcription and translation profiling, here we report that TGF-beta transcriptionally reprograms naive T cells to express Treg cell differentiation and immune suppression mRNAs, while mTORC1 inhibition impairs translation of T cell mRNAs but not those induced by TGF-beta. Rather than canonical mTORC1/eIF4E/eIF4G translation, Treg cell mRNAs utilize the eIF4G homolog DAP5 and initiation factor eIF3d in a non-canonical translation mechanism that requires cap-dependent binding by eIF3d directed by Treg cell mRNA 5' noncoding regions. Silencing DAP5 in isolated human naive CD4 + T cells impairs their differentiation into Treg cells. Treg cell differentiation is mediated by mTORC1 downregulation and TGF-beta transcriptional reprogramming that establishes a DAP5/eIF3d-selective mechanism of mRNA translation., (© 2021. The Author(s).)

Objective: To determine the benefits and harms of pre-admission interventions (prehabilitation) on postoperative outcomes in patients undergoing major elective surgery., Design: Systematic review and meta-analysis of randomised controlled trials (RCTs) (published or unpublished). We searched Medline, Embase, CENTRAL, DARE, HTA and NHS EED, The Cochrane Library, CINAHL, PsychINFO and ISI Web of Science (June 2020)., Setting: Secondary care., Participants: Patients (≥18 years) undergoing major elective surgery (curative or palliative)., Interventions: Any intervention administered in the preoperative period with the aim of improving postoperative outcomes., Outcomes and Measures: Primary outcomes were 30-day mortality, hospital length of stay (LoS) and postoperative complications. Secondary outcomes included LoS in intensive care unit or high dependency unit, perioperative morbidity, hospital readmission, postoperative pain, heath-related quality of life, outcomes specific to the intervention, intervention-specific adverse events and resource use., Review Methods: Two authors independently extracted data from eligible RCTs and assessed risk of bias and the certainty of evidence using Grading of Recommendations, Assessment, Development and Evaluation. Random-effects meta-analyses were used to pool data across trials., Results: 178 RCTs including eight types of intervention were included. Inspiratory muscle training (IMT), immunonutrition and multimodal interventions reduced hospital LoS (mean difference vs usual care: -1.81 days, 95% CI -2.31 to -1.31; -2.11 days, 95% CI -3.07 to -1.15; -1.67 days, 95% CI -2.31 to -1.03, respectively). Immunonutrition reduced infective complications (risk ratio (RR) 0.64 95% CI 0.40 to 1.01) and IMT, and exercise reduced postoperative pulmonary complications (RR 0.55, 95% CI 0.38 to 0.80, and RR 0.54, 95% CI 0.39 to 0.75, respectively). Smoking cessation interventions reduced wound infections (RR 0.28, 95% CI 0.12 to 0.64)., Conclusions: Some prehabilitation interventions may reduce postoperative LoS and complications but the quality of the evidence was low., Prospero Registration Number: CRD42015019191., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Highly prevalent respiratory diseases such as asthma and allergy remain a pressing health challenge. Currently, there is an unmet need for precise diagnostic tools capable of predicting the great heterogeneity of these illnesses. In a previous study of 94 asthma/respiratory allergy biomarker candidates, we defined a group of potential biomarkers to distinguish clinical phenotypes (i.e. nonallergic asthma, allergic asthma, respiratory allergy without asthma) and disease severity. Here, we analyze our experimental results using complex algorithmic approaches that establish holistic disease models (systems biology), combining these insights with information available in specialized databases developed worldwide. With this approach, we aim to prioritize the most relevant biomarkers according to their specificity and mechanistic implication with molecular motifs of the diseases. The Therapeutic Performance Mapping System (Anaxomics' TPMS technology) was used to generate one mathematical model per disease: allergic asthma (AA), non-allergic asthma (NA), and respiratory allergy (RA), defining specific molecular motifs for each. The relationship of our molecular biomarker candidates and each disease was analyzed by artificial neural networks (ANNs) scores. These analyses prioritized molecular biomarkers specific to the diseases and to particular molecular motifs. As a first step, molecular characterization of the pathophysiological processes of AA defined 16 molecular motifs: 2 specific for AA, 2 shared with RA, and 12 shared with NA. Mechanistic analysis showed 17 proteins that were strongly related to AA. Eleven proteins were associated with RA and 16 proteins with NA. Specificity analysis showed that 12 proteins were specific to AA, 7 were specific to RA, and 2 to NA. Finally, a triggering analysis revealed a relevant role for AKT1, STAT1, and MAPK13 in all three conditions and for TLR4 in asthmatic diseases (AA and NA). In conclusion, this study has enabled us to prioritize biomarkers depending on the functionality associated with each disease and with specific molecular motifs, which could improve the definition and usefulness of new molecular biomarkers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cremades-Jimeno, de Pedro, López-Ramos, Sastre, Mínguez, Fernández, Baos and Cárdaba.)

Background To assess differences in platelet inhibition during ticagrelor monotherapy (TIC) or dual therapy with ticagrelor and aspirin (TIC+ASP) in patients after percutaneous coronary intervention using a comprehensive panel of functional tests. Methods and Results In a single-center parallel group, open label, randomized controlled trial, 110 participants were randomized to receive either TIC (n=55) or TIC+ASP (n=55) for 4 weeks. The primary outcome was the platelet aggregation response with 10 μmol/L thrombin receptor activation peptide-6 (TRAP-6). The secondary outcomes were platelet aggregation responses and binding of surface activation markers with a panel of other activators. The mean percentage aggregation for 10 μmol/L TRAP-6 was similar for the TIC and TIC+ASP groups (mean difference+4.29; 95% CI, -0.87 to +9.46). Aggregation was higher in the TIC group compared with the TIC+ASP group with 1 μg/mL (+6.47; +2.04 to +10.90) and 0.5 μg/mL (+14.00; +7.63 to +20.39) collagen related peptide. Aggregation responses with 5 μmol/L TRAP-6, 5 μmol/L or 2.5 μmol/L thromboxane A 2 receptor agonist and surface activation marker binding with 5 μmol/L TRAP-6 or 0.5 μg/mL collagen related peptide were the same between the treatment groups. Conclusions Patients with PCI show similar levels of inhibition of most platelet activation pathways with TIC compared with dual therapy with TIC + ASP. However, the greater aggregation response with collagen related peptide during TIC indicates incomplete inhibition of glycoprotein VI (collagen) receptor-mediated platelet activation. This difference in pharmacodynamic response to anti-platelet medication may contribute to the lower bleeding rates observed with TIC compared with dual antiplatelet therapy in recent clinical trials. Registration Information URL: https://www.isrctn.com; Unique Identifier ISRCTN84335288.

Introduction: Gabapentin is an antiepileptic drug currently licensed to treat epilepsy and neuropathic pain but has been used off-label to treat acute postoperative pain. The GAP study will compare the effectiveness, cost-effectiveness and safety of gabapentin as an adjunct to standard multimodal analgesia versus placebo for the management of pain after major surgery., Methods and Analysis: The GAP study is a multicentre, double-blind, randomised controlled trial in patients aged 18 years and over, undergoing different types of major surgery (cardiac, thoracic or abdominal). Patients will be randomised in a 1:1 ratio to receive either gabapentin (600 mg just before surgery and 600 mg/day for 2 days after surgery) or placebo in addition to usual pain management for each type of surgery. Patients will be followed up daily until hospital discharge and then at 4 weeks and 4 months after surgery. The primary outcome is length of hospital stay following surgery. Secondary outcomes include pain, total opioid use, adverse health events, health related quality of life and costs., Ethics and Dissemination: This study has been approved by the Research Ethics Committee . Findings will be shared with participating hospitals and disseminated to the academic community through peer-reviewed publications and presentation at national and international meetings. Patients will be informed of the results through patient organisations and participant newsletters., Trial Registration Number: ISRCTN63614165., Competing Interests: Competing interests: No competing interests are declared. At the time that the work was carried out, GC was employed by the University Hospitals Bristol NHS Foundation Trust, Bristol, UK. GC is currently the Medical Director Johnson and Johnson Medical Devices UK and Ireland. GC has no competing interests to declare., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Objective: Several studies have linked metabolic syndrome to the development of osteoarthritis (OA) through hypercholesterolemia, one of its components. However, epidemiological studies showed contradictory results, and it is not clear how hypercholesterolemia itself, or oxidized LDL (oxLDL)-a pathological molecule potentially involved in this relationship-could be affecting OA. The objectives of this study were to investigate the effect of hypercholesterolemia induced by high-fat diet (HFD) in cartilage from OA rabbits, and how oxLDL affect human chondrocyte inflammatory and catabolic responses. Design: New Zealand rabbits were fed with HFD for 18 weeks. On week 6, OA was surgically induced. At the end of the study, cartilage damage and IL-1β, IL-6, MCP-1, MMP-13, and COX-2 expression in articular cartilage were evaluated. In addition, cultured human OA articular chondrocytes were treated with oxLDL at concentrations equivalent to those expected in synovial fluid from HFD rabbits, in the presence of IL-1β and TNFα. The effect of oxLDL on cell viability, nitric oxide production and catabolic and pro-inflammatory gene expression was evaluated. Results: HFD intake did not modify cartilage structure or pro-inflammatory and catabolic gene expression and protein presence, both in healthy and OA animals. OxLDL did not affect human chondrocyte viability, ADAMTS5 and liver X receptor (LXR) α gene expression, but decreased the induction of IL-1β, IL-6, MCP-1, MMP-13, iNOS, and COX-2 gene expression and MMP-13 and COX-2 protein presence, evoked by cytokines. Conclusions: Our data suggest that cholesterol intake per se may not be deleterious for articular cartilage. Instead, cholesterol de novo synthesis and altered cholesterol metabolism could be involved in the associations observed in human disease., (Copyright © 2020 Villalvilla, Larrañaga-Vera, Lamuedra, Pérez-Baos, López-Reyes, Herrero-Beaumont and Largo.)

Non-communicable diseases (NCDs) are medical conditions that, by definition, are non-infectious and non-transmissible among people. Much of current NCDs are generally due to genetic, behavioral, and metabolic risk factors that often include excessive alcohol consumption, smoking, obesity, and untreated elevated blood pressure, and share many common signal transduction pathways. Alterations in cell and physiological signaling and transcriptional control pathways have been well studied in several human NCDs, but these same pathways also regulate expression and function of the protein synthetic machinery and mRNA translation which have been less well investigated. Alterations in expression of specific translation factors, and disruption of canonical mRNA translational regulation, both contribute to the pathology of many NCDs. The two most common pathological alterations that contribute to NCDs discussed in this review will be the regulation of eukaryotic initiation factor 2 (eIF2) by the integrated stress response (ISR) and the mammalian target of rapamycin complex 1 (mTORC1) pathways. Both pathways integrally connect mRNA translation activity to external and internal physiological stimuli. Here, we review the role of ISR control of eIF2 activity and mTORC1 control of cap-mediated mRNA translation in some common NCDs, including Alzheimer's disease, Parkinson's disease, stroke, diabetes mellitus, liver cirrhosis, chronic obstructive pulmonary disease (COPD), and cardiac diseases. Our goal is to provide insights that further the understanding as to the important role of translational regulation in the pathogenesis of these diseases.

Olive-pollen allergy is one of the leading causes of respiratory allergy in Mediterranean countries and some areas of North America. Currently, allergen-specific immunotherapy is the only etiophatogenic treatment. However, this approach is not fully optimal, safe, or effective. Thus, efforts continue in the search for novel immunotherapy strategies, being one of the most promising the use of peptides derived from major allergens. This work tries to determine the therapeutic potential and safety of 5 dodecapeptides derived from the main allergen of olive-pollen allergy, Ole e 1. The immunomodulatory capacity of these peptides was studied using peripheral blood mononuclear cells (PBMCs) obtained from 19 olive-pollen-allergic patients and 10 healthy controls. We determined the capacity of these peptides to inhibit the proliferative response toward olive-pollen allergenic extract and to induce the regulatory cytokines, IL-10 and IL-35. To test the safety and absence of allergenicity of the peptides, the basophil activation was analyzed by flow-cytometry, using peripheral blood. The results showed that two of five peptides inhibited near to 30% the proliferative response against the total olive-pollen allergenic extract in olive-pollen-allergic patients. Inhibition increased to nearly 35% when the 5 peptides were used in combination. In both cases, a statistically significant induction of IL-10 and IL-35 secretion was observed in the supernatants of allergic patients PBMCs cultures. None of the 5 peptides induced basophil activation and cross-link inflammatory cell-bound IgE. In conclusion, these results open up new possibilities in the treatment of olive-pollen allergy, which could solve some of the problems facing current therapy approaches.

Osteoarthritis (OA) is a chronic joint disease characterized by cartilage degradation, osteophyte formation, subchondral bone sclerosis, and synovitis. Systemic factors such as obesity and the components of the metabolic syndrome seem to contribute to its progression. Breakdown of cartilage ensues from an altered balance between mechanical overload and its absorption by this tissue. There is in this context a status of persistent local inflammation by means of the chronic activation of innate immunity. A broad variety of danger-associated molecular patterns inside OA joint are able to activate pattern recognition receptors, mainly TLR (toll-like receptor) 2 and 4, which are overexpressed in the OA cartilage. Chronic activation of innate immune responses in chondrocytes results in a robust production of pro-inflammatory cytokines and chemokines, as well as of tissue-destructive enzymes, downstream of NF-κB and MAPK (mitogen activated protein kinase) dependent pathways. Besides, the toxic effects of an excess of glucose and/or fatty acids, which share the same pro-inflammatory intracellular signalling pathways, may add fuel to the fire. Not only high concentrations of glucose can render cells prone to inflammation, but also AGEs (advanced glycation end products) are integrated into the TLR signalling network through their own innate immune receptors. Considering these mechanisms, we argue for the control of both primary inflammation and proteolytic catabolism as a preventive strategy in OA, instead of focusing treatment on the enhancement of anabolic responses. Even though this approach would not return to normal already degraded cartilage, it nonetheless might avoid damage extension to the surrounding tissue., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Asthma is a complex disease comprising various phenotypes and endotypes, all of which still need solid biomarkers for accurate classification. In a previous study, we defined specific genes related to asthma and respiratory allergy by studying the expression of 94 genes in a population composed of 4 groups of subjects: healthy control, nonallergic asthmatic, asthmatic allergic, and nonasthmatic allergic patients. An analysis of differential gene expression between controls and patients revealed a set of statistically relevant genes mainly associated with disease severity, i.e., CHI3L1, IL-8, IL-10, MSR1, PHLDA1, PI3 , and SERPINB2 . Here, we analyzed whether these genes and their proteins could be potential asthma biomarkers to distinguish between nonallergic asthmatic and asthmatic allergic subjects. Protein quantification was determined by ELISA (in serum) or Western blot (in protein extracted from peripheral blood mononuclear cells or PBMCs). Statistical analyses were performed by unpaired t -test using the Graph-Pad program. The sensitivity and specificity of the gene and protein expression of several candidate biomarkers in differentiating the two groups (and the severity subgroups) was performed by receiver operating characteristic (ROC) curve analysis using the R program. The ROC curve analysis determined single genes with good sensitivity and specificity for discriminating some of the phenotypes. However, interesting combinations of two or three protein biomarkers were found to distinguish the asthma disease and disease severity between the different phenotypes of this pathology using reproducible techniques in easy-to-obtain samples. Gene and protein panels formed by single biomarkers and biomarker combinations have been defined in easily obtainable samples and by standardized techniques. These panels could be useful for characterizing phenotypes of asthma, specifically when differentiating asthma severity.

Objective: To compare normothermic (35°C-36°C) versus hypothermic (28°C) cardiopulmonary bypass (CPB) in paediatric patients undergoing open heart surgery to test the hypothesis that normothermic CPB perfusion maintains the functional integrity of major organ systems leading to faster recovery., Methods: Two single-centre, randomised controlled trials (known as Thermic-1 and Thermic-2 , respectively) were carried out to compare the effectiveness and acceptability of normothermic versus hypothermic CPB in children with congenital heart disease undergoing open heart surgery. In both studies, the co-primary clinical outcomes were duration of inotropic support, intubation time and postoperative hospital stay., Results: In total, 200 participants were recruited; 59 to the Thermic-1 study and 141 to the Thermic-2 study. 98 patients received normothermic CPB and 102 patients received hypothermic CPB. There were no significant differences between the treatment groups for any of the co-primary outcomes: inotrope duration HR=1.01, 95% CI (0.72 to 1.41); intubation time HR=1.14, 95% CI (0.86 to 1.51); postoperative hospital stay HR=1.06, 95% CI (0.80 to 1.40). Differences favouring normothermia were found in urea nitrogen at 2 days geometric mean ratio (GMR)=0.86 95% CI (0.77 to 0.97); serum creatinine at 3 days GMR=0.89, 95% CI (0.81 to 0.98); urinary albumin at 48 hours GMR=0.32, 95% CI (0.14 to 0.74) and neutrophil gelatinase-associated lipocalin at 4 hours GMR=0.47, 95% CI (0.22 to 1.02), but not at other postoperative time points., Conclusions: Normothermic CPB is as safe and effective as hypothermic CPB and can be routinely adopted as a perfusion strategy in low-risk infants and children undergoing open heart surgery., Trial Registration Number: ISRCTN93129502., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In order to gain insight into the early effects drawn by JAK inhibitors on intra-joint JAK/STAT-dependent signaling, we sought synovial activation of STATs and their end-products, along with their modification with tofacitinib (TOFA), at flare-up in antigen induced arthritis (AIA). New Zealand rabbits were randomly assigned to four groups -healthy controls, AIA, TOFA-treated AIA, or TOFA-treated controls-. AIA was induced with 4 weekly intra-articular ovalbumin injections in sensitized animals. TOFA (10 mg·kg - 1 ·day - 1 ) was administered for the last 2 weeks. Animals were euthanized 24 h after the last injection., Results: AIA animals showed high-grade synovitis, which was partially improved by TOFA. No effects of the treatment were found on serum C-reactive protein or on the synovial macrophage infiltration at this stage. Synovial MMP-1,-3 and -13 expression levels in treated AIA rabbits were found to drop to those of controls, while a downregulation of IL6, IFNγ and TNF was evident in treated versus untreated AIA rabbits. Concurrently, a reduction in pSTAT1 and SOCS1, but not in pSTAT3, SOCS3 or active NFκB-p65, was noted with TOFA., Conclusions: Studying the mechanism of action of immunomodulatory drugs represents a major challenge in vivo, since drug-dependent decreases in inflammation very likely mask direct effects on disease mechanisms. This study design allowed us to prevent any confounding effect resulting from reductions in the overall inflammatory status, hence assessing the true pharmacological actions of TOFA in a very severe synovitis. Our findings point to pSTAT1 and MMPs as early molecular readouts of response to this JAK inhibitor., Competing Interests: All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All animal care and experimental protocols for this study complied with the Spanish regulations and the Guidelines for the Care and Use of Laboratory Animals drawn up by the National Institutes of Health, USA, and were approved by the Institutional Ethics Committee of the Fundación Jiménez Díaz Hospital, Madrid, Spain (Ref. 2013/10). This article does not contain any studies with human participants performed by any of the authors.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The objective of this study was to validate musculoskeletal ultrasound (US) in a rabbit model of acute gout. Acute gout was induced by intra-articular injection of monosodium urate (MSU) crystals in 10 rabbits; the 3 controls received vehicle. Rabbit knees were assessed by B-mode and power Doppler (PD) US 24 and 72 h after injections. After 72 h, all rabbits were euthanized. US discriminated between the MSU-injected and control groups with respect to the different inflammatory findings at both at 24 and 72 h and for MSU crystal-related findings after 24 h of injection. US synovial thickening, intra-synovial power Doppler signal and global joint distension significantly correlated with the synovial global histopathological score (r = 0.47, p = 0.0188), tissue vascularization measured by CD31 immunohistochemical-positive staining (r = 0.46, p = 0.0172) and tissue levels of interleukin-1β (r = 0.53, p = 0.0078), respectively. US is a valid method for assessment of synovial inflammation in experimental gouty arthritis in rabbits., (Copyright © 2018 World Federation for Ultrasound in Medicine and Biology. Published by Elsevier Inc. All rights reserved.)

Asthma is a complex and heterogeneous respiratory disorder characterized by chronic airway inflammation. It has generally been associated with allergic mechanisms related to type 2 airway inflammation. Nevertheless, between 10 and 33% of asthmatic individuals have nonallergic asthma (NA). Several targeted treatments are in clinical development for patients with Th2 immune response, but few biomarkers are been defined for low or non-Th2-mediated inflammation asthma. We have recently defined by gene expression a set of genes as potential biomarkers of NA, mainly associated with disease severity: IL10, MSR1, PHLDA1, SERPINB2, CHI3L1, IL8, and PI3. Here, we analyzed their protein expression and specificity using sera and isolated peripheral blood mononuclear cells (PBMCs). First, protein quantification was carried out using ELISA (in sera) or Western blot (proteins extracted from PBMCs by Trizol procedure), depending on the biomarker in 30 healthy controls (C) subjects and 30 NA patients. A receiver operating characteristic curve analysis was performed by using the R program to study the specificity and sensitivity of the candidate biomarkers at a gene- and protein expression level. Four kinds of comparisons were performed: total NA group vs C group, severe NA patients vs C, moderate-mild NA patients vs C, and severe NA patients vs moderate-mild NA patients. We found that all the single genes showed good sensitivity vs specificity for some phenotypic discrimination, with CHI3L1 and PI3 exhibiting the best results for C vs NA: CHI3L1 area under the curve (AUC) (CI 95%): 0.95 (0.84-1.00) and PI3 AUC: 0.99 (0.98-1.00); C vs severe NA: PI3 AUC: 1 (0.99-1.00); and C vs moderate-mild NA: CHI3L1 AUC: 1 (0.99-1.00) and PI3 AUC: 0.99 (0.96-1.00). However, the results for discriminating asthma disease and severity with protein expression were better when two or three biomarkers were combined. In conclusion, individual genes and combinations of proteins have been evaluated as reliable biomarkers for classifying NA subjects and their severity. These new panels could be good diagnostic tests.

Besides its primary function in locomotion, skeletal muscle (SKM), which represents up to half of human's weight, also plays a fundamental homeostatic role. Through the secretion of soluble peptides, or myokines, SKM interacts with major organs involved in metabolic processes. In turn, metabolic cues from these organs are received by muscle cells, which adapt their response accordingly. This is done through an intricate intracellular signaling network characterized by the cross-talking between anabolic and catabolic pathways. A fine regulation of the network is required to protect the organism from an excessive energy expenditure. Systemic inflammation evokes a catabolic reaction in SKM known as sarcopenia. In turn this response comprises several mechanisms, which vary depending on the nature of the insult and its magnitude. In this regard, aging, chronic inflammatory systemic diseases, osteoarthritis and idiopathic inflammatory myopathies can lead to muscle loss. Interestingly, sarcopenia may persist despite remission of chronic inflammation, an issue which warrants further research. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) system stands as a major participant in muscle loss during systemic inflammation, while it is also a well-recognized orchestrator of muscle cell turnover. Herein we summarize current knowledge about models of sarcopenia, their triggers and major mediators and their effect on both protein and cell growth yields. Also, the dual action of the JAK/STAT pathway in muscle mass changes is discussed. We highlight the need to unravel the precise contribution of this system to sarcopenia in order to design targeted therapeutic strategies.

Background: Paediatric chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a relatively common and disabling condition. The National Institute for Health and Clinical Excellence (NICE) recommends Cognitive Behavioural Therapy (CBT) as a treatment option for paediatric CFS/ME because there is good evidence that it is effective. Despite this, most young people in the UK are unable to access local specialist CBT for CFS/ME. A randomised controlled trial (RCT) showed FITNET was effective in the Netherlands but we do not know if it is effective in the National Health Service (NHS) or if it is cost-effective. This trial will investigate whether FITNET-NHS is clinically effective and cost-effective in the NHS., Methods: Seven hundred and thirty-four paediatric patients (aged 11-17 years) with CFS/ ME will be randomised (1:1) to receive either FITNET-NHS (online CBT) or Activity Management (delivered via video call). The internal pilot study will use integrated qualitative methods to examine the feasibility of recruitment and the acceptability of treatment. The full trial will assess whether FITNET-NHS is clinically effective and cost-effective. The primary outcome is disability at 6 months, measured using the SF-36-PFS (Physical Function Scale) questionnaire. Cost-effectiveness is measured via cost-utility analysis from an NHS perspective. Secondary subgroup analysis will investigate the effectiveness of FITNET-NHS in those with co-morbid mood disorders., Discussion: If FITNET-NHS is found to be feasible and acceptable (internal pilot) and effective and cost-effective (full trial), its provision by the NHS has the potential to deliver substantial health gains for the large number of young people suffering from CFS/ME but unable to access treatment because there is no local specialist service. This trial will provide further evidence evaluating the delivery of online CBT to young people with chronic conditions., Trial Registration: ISRCTN registry, registration number: ISRCTN18020851 . Registered on 4 August 2016.

Background: Nowadays, allergen-specific immunotherapy (AIT) is the only treatment able to modulate the course of allergic diseases. Although it has been applied for the last 100 years, treatment with whole allergen extracts is not without its drawbacks: AIT can cause local and systemic adverse events and may produce new IgE sensitization against other allergens present in the extract. Furthermore, the lengthy treatment duration (3-5 years), frequent administration, and high cost of treatment are other disadvantages. For these reasons, there is a need for safer and more effective AIT strategies. One promising approach is the use of synthetic peptides representing the B- or T-cell epitopes of allergens., Objective: This review summarizes the main advances in peptide immunotherapy, from preclinical models to early clinical trials, focusing on house dust mite, bee venom, cat allergy, and Oleaceae pollinosis., Results: Following an extensive review of the relevant literature, we summarize how peptide therapies may change the course of allergic diseases and promote allergen tolerance, thereby ameliorating the main disadvantages of AIT. Although the molecular mechanisms involved are not yet fully defined, they seem to depend on structure, length, peptide sequence, and route of administration. This novel immunotherapy has been demonstrated to modulate the immune system, promoting regulatory T-cell induction and Th2 inhibition. This tolerance-inducing potential has led this therapy to be termed SPIRE (synthetic peptide immuno-regulatory epitopes)., Conclusion: Experimental models and clinical trials have demonstrated the usefulness of SPIRE treatment to cure these diseases, opening a new era in allergen therapeutics., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Metabolic syndrome (MetS) may be associated with knee osteoarthritis (OA), but the association between the individual components and OA are not well-understood. We aimed to study the effect of hypercholesterolemia on synovial inflammation in knee OA., Methods: OA was surgically induced in rabbits fed with standard diet (OA group, n = 10) or in rabbits fed with high fat diet (OA-HFD, n = 10). Healthy rabbits receiving standard diet (Control, n = 10) or fed with HFD (HFD, n = 6) were also monitored. Twelve weeks after OA induction, synovial membranes were isolated and processed for studies., Results: Animals fed HFD showed higher levels of total serum cholesterol, triglycerides and C-reactive protein than control rabbits. Twelve weeks after OA induction, synovial membrane inflammation and macrophage infiltration were increased in rabbits with OA, particularly in the OA-HFD group. Extensive decrease of synovial adipose tissue area, adipocyte size and perilipin-1A synthesis were observed in the OA-HFD group in comparison to the OA and control groups. The HFD further increased the proinflammatory mediators IL-1β, IL-6 and TNF in the OA synovium. However, the synovial gene expression of adipokines, such as leptin and adiponectin, were markedly decreased in the rabbits with OA, especially in the OA-HFD group, in correlation with adipose tissue loss. However, circulating leptin was upregulated in the HFD and OA-HFD groups., Conclusion: Our results indicate that a HFD is an aggravating factor worsening synovial membrane inflammation during OA, guided by increased infiltration of macrophages and removal of the adipose tissue, together with a remarkable presence of proinflammatory factors. Synovial adipocytes and dyslipemia could probably play pivotal roles in OA joint deterioration in patients with MetS, supporting that the link between obesity and OA transcends mechanical loading.

Background: Dual antiplatelet therapy (DAPT) with aspirin (ASP) and a P2Y 12 blocker is currently standard care after percutaneous coronary intervention (PCI) with stent insertion, and aims to inhibit platelet function in order to prevent stent thrombosis. The P2Y 12 blocker ticagrelor (TIC) has greater antiplatelet effect than the previously used members of this class, such as clopidogrel. In healthy volunteers, TIC is sufficient to cause strong platelet inhibition, with little additional effect from ASP. Omission of ASP may improve the safety of antiplatelet regimes by reducing bleeding. However, the effect of single antiplatelet treatment with TIC, compared to DAPT with TIC + ASP, has not been studied in detail in patients with coronary artery disease., Methods: To compare TIC with TIC + ASP, we have initiated a single centre, open-label randomised controlled trial (TEMPLATE study) in adults receiving DAPT following PCI with a sample size of 110 patients. Patients are invited to join the study when, as part of standard care, they are due to switch from DAPT (ASP + any P2Y 12 blocker) to single antiplatelet treatment with ASP alone after 6-12 months. Patients are randomised to receive either TIC or TIC + ASP for 4 weeks. All patients then revert to standard care with ASP alone. Blood samples and clinical data are collected at three study visits: at baseline during treatment with ASP + any P2Y 12 blocker (visit 1); approximately 4 weeks after visit 1 during treatment with either TIC or TIC + ASP (visit 2); and approximately 8 weeks after visit 1 when treatment has reverted to ASP alone (visit 3). The primary outcome is the extent of platelet inhibition, measured by light transmission aggregation, flow cytometry, flow chamber and plasma biomarker tests. The primary analysis will compare the extent of platelet inhibition between the TIC and TIC + ASP groups at visit 2, adjusted for baseline platelet reactivity. Secondary analyses will compare the extent of platelet inhibition at visit 2 with that at visit 3., Discussion: This is the first study to compare in detail the extent of platelet inhibition in patients who are receiving TIC compared with TIC + ASP. The study findings will complement larger-scale trials of the clinical efficacy and safety of TIC compared to TIC + ASP., Trial Registration: ISRCTN registry, identifier ISRCTN84335288 . Registered on 23 June 2014.

Inflammatory activity in rheumatoid arthritis may alter the regulation of muscle mass leading to a secondary sarcopenia, commonly termed rheumatoid cachexia (RC). We characterized alterations to muscle structure and various pro-inflammatory, catabolic and regenerative markers in an animal model of RC. Antigen induced arthritis (AiA) was performed in 20 male adult rabbits. AiA animals exhibited significantly less weight gain, a markedly elevated serum C-reactive protein (CRP), lighter muscles with shorter cross-sectional diameter and increased myonuclei when compared to controls. Atrogin-1 and MuRF-1 were up-regulated alongside an increase in IL-1β, active NF-κB and a higher ratio of phosphorylated to inactive p38 MAPK. CCL-2 and TNF levels were reduced and IL-6 was unchanged between groups. We observed decreased pSTAT3, unchanged pSTAT1 and Myf5, but increased Pax7, MyoD and myogenin. AiA rabbits had a reduction in myostatin from gastrocnemii and synovium with a congruent decrease in serum myostatin compared to controls. Chronic arthritis induced an RC-like secondary sarcopenia with increased muscle protein breakdown. Elevated IL-1β may trigger proteolysis via elevated NF-κB and p38 MAPK signaling with a compensatory anabolic response suggested by myonuclear expansion, increased Pax7, MyoD and myogenin, reduced pSTAT3 as well as reduced serum, synovial and muscular myostatin.

Asthma is a complex, chronic respiratory disease with a wide clinical spectrum. Use of high-throughput technologies has generated a great deal of data that require validation. In this work the objective was to validate molecular biomarkers related to asthmatic disease types in peripheral blood samples and define their relationship with disease severity. With this purpose, ninety-four previously described genes were analyzed by qRT-PCR in 30 healthy control (HC) subjects, 30 patients with nonallergic asthma (NA), 30 with allergic asthma (AA), and 14 patients with allergy (rhinitis) but without asthma (AR). RNA was extracted from peripheral blood mononuclear cells (PBMCs) using the TRIzol method. After data normalization, principal component analysis (PCA) was performed, and multiple approaches were used to test for differential gene expression. Relevance was defined by RQ (relative quantification) and corrected P value (<0.05). Protein levels of IL-8 and MSR1 were determined by ELISA and Western blot, respectively. PCA showed 4 gene expression clusters that correlated with the 4 clinical phenotypes. Analysis of differential gene expression between clinical groups and HCs revealed 26 statistically relevant genes in NA and 69 in AA. Protein interaction analysis revealed IL-8 to be a central protein. Average levels of IL-8 were higher in the asthma patients' sera (NA: 452.28±357.72, AA: 327.46±377pg/ml) than in HCs (286.09±179.10), but without reaching statistical significance. Nine genes, especially MSR1, were strongly associated with severe NA. In conclusion, several molecular biomarkers of asthma have been defined, some of which could be useful for the diagnosis or prognosis of disease severity., (Copyright © 2016 Elsevier Ltd. All rights reserved.)