Search

The author proposes that the Labour Party in Great Britain should pursue a managed immigration policy that welcomes asylum-seekers fleeing persecution and civil war in their home countries but at the same time discourages cheap immigrant labor brought in by multinational corporations for the purpose of keeping working-class wage levels down from entering the country. However, he adds that anti-cheap labor policies must be balanced with measures to prevent the scapegoating of immigrant groups.

The article assesses the performance of British Labour Party leader Ed Miliband. The failure of Labour to reemerge as a democratic organisation following the leadership election is mentioned. The author points out the tendency of continuity with former New Labour elite to undermine the credibility of Miliband as demonstrated in the Living Wage Campaign. He notes the failure of Miliband to discipline politician Jack Straw for complaining about the threat posed by Pakistani men to white girls.

A response by Gavin Lewis to a letter to the editor about his article "The New Imperialism or the Return of the White Man's Burden," in the Number 246 issue is presented.

A response by Gavin Lewis to the article by Dave Lister that criticizes Lewis' article that provides a short history of Imperialism is presented.

Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1β production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration., Competing Interests: Declaration of interests M.K. is a founder of Elgia Pharmaceuticals and receives research support from Gossamer Bio, Jansen Pharmaceuticals and Merck. G.R.A.-M., G.L., and P.S. are employees of Jansen Pharmaceuticals. The University of California San Diego is in the process of applying for a patent covering the generation and use of novel anti-inflammatory therapy for ARDS listing H.X., E.S.-L., and M.K. as inventors. All other authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Heart failure with preserved ejection fraction (HFpEF) does not exist as a singular clinical or pathological entity but as a syndrome encompassing a wide range of clinical and biological phenotypes. There is an urgent need to progress from the unsuccessful 'one-size-fits-all' approach to more precise disease classification, in order to develop targeted therapies, personalise risk stratification and guide future research. In this regard, this review discusses the current and emerging roles of cardiovascular imaging for the diagnosis of HFpEF, for distilling HFpEF into distinct disease entities according to underlying pathobiology and for risk stratification.

Background: Group 2 innate lymphoid cells (ILC2s) are the dominant innate lymphoid cell population in the lungs at steady state, and their release of type 2 cytokines is a central driver in responding eosinophil infiltration and increased airway hyperreactivity. Our laboratory has identified a unique subset of ILC2s in the lungs that actively produce IL-10 (ILC2 10 s)., Objective: Our aim was to characterize the effector functions of ILC2 10 s in the development and pathology of allergic asthma., Methods: IL-4-stimulated ILC2 10 s were isolated to evaluate cytokine secretion, transcription factor signaling, metabolic dependence, and effector functions in vitro. ILC2 10 s were also adoptively transferred into Rag2 -/- γc -/- mice, which were then challenged with IL-33 and assessed for airway hyperreactivity and lung inflammation., Results: We have determined that the transcription factors cMaf and Blimp-1 regulate IL-10 expression in ILC2 10 s. Strikingly, our results demonstrate that ILC2 10 s can utilize both autocrine and paracrine signaling to suppress proinflammatory ILC2 effector functions in vitro. Further, this subset dampens airway hyperreactivity and significantly reduces lung inflammation in vivo. Interestingly, ILC2 10 s demonstrated a metabolic dependency on the glycolytic pathway for IL-10 production, shifting from the fatty acid oxidation pathway conventionally utilized for proinflammatory effector functions., Conclusion: These findings provide an important and previously unrecognized role of ILC2 10 s in diseases associated with ILC2s such as allergic lung inflammation and asthma. They also provide new insights into the metabolism dependency of proinflammatory and anti-inflammatory ILC2 phenotypes., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Disturbances in glucose homeostasis and low-grade chronic inflammation culminate into metabolic syndrome that increase the risk for the development of type 2 diabetes mellitus (T2DM). The recently discovered group 2 innate lymphoid cells (ILC2s) are capable of secreting copious amounts of type 2 cytokines to modulate metabolic homeostasis in adipose tissue. In this study, we have established that expression of Death Receptor 3 (DR3), a member of the TNF superfamily, on visceral adipose tissue (VAT)-derived murine and peripheral blood human ILC2s is inducible by IL-33. We demonstrate that DR3 engages the canonical and/or non-canonical NF-κB pathways, and thus stimulates naïve and co-stimulates IL-33-activated ILC2s. Importantly, DR3 engagement on ILC2s significantly ameliorates glucose tolerance, protects against insulin-resistance onset and remarkably reverses already established insulin-resistance. Taken together, these results convey the potent role of DR3 as an ILC2 regulator and introduce DR3 agonistic treatment as a novel therapeutic avenue for treating T2DM.

Allergic asthma is a leading chronic disease associated with airway hyperreactivity (AHR). Type-2 innate lymphoid cells (ILC2s) are a potent source of T-helper 2 (Th2) cytokines that promote AHR and lung inflammation. As the programmed cell death protein-1 (PD-1) inhibitory axis regulates a variety of immune responses, here we investigate PD-1 function in pulmonary ILC2s during IL-33-induced airway inflammation. PD-1 limits the viability of ILC2s and downregulates their effector functions. Additionally, PD-1 deficiency shifts ILC2 metabolism toward glycolysis, glutaminolysis and methionine catabolism. PD-1 thus acts as a metabolic checkpoint in ILC2s, affecting cellular activation and proliferation. As the blockade of PD-1 exacerbates AHR, we also develop a human PD-1 agonist and show that it can ameliorate AHR and suppresses lung inflammation in a humanized mouse model. Together, these results highlight the importance of PD-1 agonistic treatment in allergic asthma and underscore its therapeutic potential.

Background: Allergic asthma is a chronic inflammatory disorder characterized by airway hyperreactivity (AHR) and driven by T H 2 cytokine production. Group 2 innate lymphoid cells (ILC2s) secrete high amounts of T H 2 cytokines and contribute to the development of AHR. Autophagy is a cellular degradation pathway that recycles cytoplasmic content. However, the role of autophagy in ILC2s remains to be fully elucidated., Objective: We characterized the effects of autophagy deficiency on ILC2 effector functions and metabolic balance., Methods: ILC2s from autophagy-deficient mice were isolated to evaluate proliferation, apoptosis, cytokine secretion, gene expression and cell metabolism. Also, autophagy-deficient ILC2s were adoptively transferred into Rag -/- GC -/- mice, which were then challenged with IL-33 and assessed for AHR and lung inflammation., Results: We demonstrate that autophagy is extensively used by activated ILC2s to maintain their homeostasis and effector functions. Deletion of the critical autophagy gene autophagy-related 5 (Atg5) resulted in decreased cytokine secretion and increased apoptosis. Moreover, lack of autophagy among ILC2s impaired their ability to use fatty acid oxidation and strikingly promoted glycolysis, as evidenced by our transcriptomic and metabolite analyses. This shift of fuel dependency led to impaired homeostasis and T H 2 cytokine production, thus inhibiting the development of ILC2-mediated AHR. Notably, this metabolic reprogramming was also associated with an accumulation of dysfunctional mitochondria, producing excessive reactive oxygen species., Conclusion: These findings provide new insights into the metabolic profile of ILC2s and suggest that modulation of fuel dependency by autophagy is a potentially new therapeutic approach to target ILC2-dependent inflammation., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The myocardial interstitium has emerged as a potential therapeutic target and as a biological entity to improve risk stratification and better guide existing interventions. Clinical trials focusing on the myocardial interstitium are required to establish causality and improve patient outcomes. This review will discuss issues around clinical trials targeting the myocardial interstitium, including antifibrotic therapies, efficacy outcome measurements, mechanistic outcome measurements and mediation analysis, sample size, trial duration, considerations for multicenter trials, stratifying trial recruitment according to the interstitium, and approaches to enrich recruitment, using examples of ongoing clinical trials., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The PIROUETTE (PIRfenidOne in patients with heart failUre and preserved lEfT venTricular Ejection fraction) trial is designed to evaluate the efficacy and safety of the anti-fibrotic pirfenidone in patients with chronic heart failure and preserved ejection fraction (HFpEF) and myocardial fibrosis. HFpEF is a diverse syndrome associated with substantial morbidity and mortality. Myocardial fibrosis is a key pathophysiological mechanism of HFpEF and myocardial fibrotic burden is strongly and independently associated with adverse outcome. Pirfenidone is an oral anti-fibrotic agent, without haemodynamic effect, that leads to regression of myocardial fibrosis in preclinical models. It has proven clinical effectiveness in pulmonary fibrosis., Methods: The PIROUETTE trial is a randomised, double-blind, placebo-controlled phase II trial evaluating the efficacy and safety of 52 weeks of treatment with pirfenidone in patients with chronic HFpEF (symptoms and signs of heart failure, left ventricular ejection fraction ≥ 45%, elevated natriuretic peptides [BNP ≥ 100 pg/ml or NT-proBNP ≥ 300 pg/ml; or BNP ≥ 300 pg/ml or NT-proBNP ≥ 900 pg/ml if in atrial fibrillation]) and myocardial fibrosis (extracellular matrix (ECM) volume ≥ 27% measured using cardiovascular magnetic resonance). The primary outcome measure is change in myocardial ECM volume. A sub-study will investigate the relationship between myocardial fibrosis and myocardial energetics, and the impact of pirfenidone, using 31 phosphorus magnetic resonance spectroscopy., Discussion: PIROUETTE will determine whether pirfenidone is superior to placebo in relation to regression of myocardial fibrosis and improvement in myocardial energetics in patients with HFpEF and myocardial fibrosis (NCT02932566)., Clinical Trial Registration: clinicaltrials.gov (NCT02932566) https://clinicaltrials.gov/ct2/show/NCT02932566.

Metabolic syndrome is characterized by disturbances in glucose homeostasis and the development of low-grade systemic inflammation, which increase the risk to develop type 2 diabetes mellitus (T2DM). Type-2 innate lymphoid cells (ILC2s) are a recently discovered immune population secreting Th2 cytokines. While previous studies show how ILC2s can play a critical role in the regulation of metabolic homeostasis in the adipose tissue, a therapeutic target capable of modulating ILC2 activation has yet to be identified. Here, we show that GITR, a member of the TNF superfamily, is expressed on both murine and human ILC2s. Strikingly, we demonstrate that GITR engagement of activated, but not naïve, ILC2s improves glucose homeostasis, resulting in both protection against insulin resistance onset and amelioration of established insulin- resistance. Together, these results highlight the critical role of GITR as a novel therapeutic molecule against T2DM and its fundamental role as an immune checkpoint for activated ILC2s.

Background: Allergic asthma is a prevalent inflammatory disease of the airways caused by dysregulated immune balance in the lungs with incompletely understood pathogenesis. The recently identified type 2 innate lymphoid cells (ILC2s) play significant roles in the pathogenesis of asthma. Although ILC2-activating factors have been identified, the mechanisms that suppress ILC2s remain largely unknown. Plasmacytoid dendritic cells (pDCs) are important in antiviral immunity and in maintaining tolerance to inert antigens., Objective: We sought to address the role of pDCs in regulating ILC2 function and ILC2-mediated airway hyperreactivity (AHR) and lung inflammation., Methods: We used several murine models, including BDCA-2-diphtheria toxin receptor (DTR) transgenic and IFN-α receptor 1-deficient mice, as well as purified primary ILC2s, to reach our objective. We extended and validated our findings to human ILC2s., Results: We show that activation of pDCs through Toll-like receptor 7/8 suppresses ILC2-mediated AHR and airway inflammation and that depletion of pDCs reverses this suppression. We further show that pDCs suppress cytokine production and the proliferation rate while increasing the apoptosis rate of ILC2s through IFN-α production. Transcriptomic analysis of both human and murine ILC2s confirms the activation of regulatory pathways in ILC2s by IFN-α., Conclusion: Activation of pDCs alleviates AHR and airway inflammation by suppressing ILC2 function and survival. Our findings reveal a novel regulatory pathway in ILC2-mediated pulmonary inflammation with important clinical implications., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Aims: Investigators have proposed that cardiovascular magnetic resonance (CMR) should have restrictions similar to those of ionizing imaging techniques. We aimed to investigate the acute effect of 1.5 T CMR on leucocyte DNA integrity, cell counts, and function in vitro, and in a large cohort of patients in vivo., Methods and Results: In vitro study: peripheral blood mononuclear cells (PBMCs) were isolated from healthy volunteers, and histone H2AX phosphorylation (γ-H2AX) expression, leucocyte counts, and functional parameters were quantified using flow cytometry under the following conditions: (i) immediately following PBMC isolation, (ii) after standing on the benchside as a temperature and time control, (iii) after a standard CMR scan. In vivo study: blood samples were taken from 64 consecutive consenting patients immediately before and after a standard clinical scan. Samples were analysed for γ-H2AX expression and leucocyte counts. CMR was not associated with a significant change in γ-H2AX expression in vitro or in vivo, although there were significant inter-patient variations. In vitro cell integrity and function did not change with CMR. There was a significant reduction in circulating T cells in vivo following CMR., Conclusion: 1.5 T CMR was not associated with DNA damage in vitro or in vivo. Histone H2AX phosphorylation expression varied markedly between individuals; therefore, small studies using γ-H2AX as a marker of DNA damage should be interpreted with caution. Cardiovascular magnetic resonance was not associated with loss of leucocyte viability or function in vitro. Cardiovascular magnetic resonance was associated with a statistically significant reduction in viable leucocytes in vivo., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

The nitro-substituted neonicotinoid insecticides, which include imidacloprid, thiamethoxam and clothianidin, are widely used to control a range of important agricultural pests both by foliar applications and also as seed dressings and by soil application. Since they exhibit systemic properties, exposure of bees may occur as a result of residues present in the nectar and/or pollen of seed- or soil-treated crop plants and so they have been the subject of much debate about whether they cause adverse effects in pollinating insects under field conditions. Due to these perceived concerns, the use of the three neonicotinoids imidacloprid, clothianidin and thiamethoxam has been temporarily suspended in the European Union for seed treatment, soil application and foliar treatment in crops attractive to bees. Monitoring data from a number of countries are available to assess the presence of neonicotinoid residues in honey bee samples and possible impacts at the colony level and these are reviewed here together with a number of field studies which have looked at the impact of clothiandin on honey bees in relation to specific crop use and in particular with oilseed rape. Currently there is considerable uncertainty with regards to the regulatory testing requirements for field studies. Accordingly, a testing protocol was developed to address any acute and chronic risks from oilseed rape seeds containing a coating with 10 g clothianidin and 2 g beta-cyfluthrin per kg seeds (Elado ® ) for managed honey bee (Apis mellifera) colonies, commercially bred bumble bee (Bombus terrestris) colonies and red mason bees (Osmia bicornis) as a representative solitary bee species. This is described here together with a summary of the results obtained as an introduction to the study details given in the following papers in this issue., Competing Interests: Richard Schmuck works for the company Bayer CropScience AG that manufactures and sells neonicotinoid-containing products. Gavin Lewis has delivered his contribution under contractual agreement with Bayer CropScience AG. Ethical approval This article does not contain any studies with human participants performed by any of the authors. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Suppression of CD8 and CD4 T cells is a hallmark in chronic viral infections, including hepatitis C and HIV. While multiple pathways are known to inhibit CD8 T cells, the host molecules that restrict CD4 T cell responses are less understood. Here, we used inducible and CD4 T cell-specific deletion of the gene encoding the TGF-β receptor during chronic lymphocytic choriomeningitis virus infection in mice, and determined that TGF-β signaling restricted proliferation and terminal differentiation of antiviral CD4 T cells. TGF-β signaling also inhibited a cytotoxic program that includes granzymes and perforin expression at both early and late stages of infection in vivo and repressed the transcription factor eomesodermin. Overexpression of eomesodermin was sufficient to recapitulate in great part the phenotype of TGF-β receptor-deficient CD4 T cells, while SMAD4 was necessary for CD4 T cell accumulation and differentiation. TGF-β signaling also restricted accumulation and differentiation of CD4 T cells and reduced the expression of cytotoxic molecules in mice and humans infected with other persistent viruses. These data uncovered an eomesodermin-driven CD4 T cell program that is continuously suppressed by TGF-β signaling. During chronic viral infection, this program limits CD4 T cell responses while maintaining CD4 T helper cell identity.

Introduction: The most frequent complications of AF ablation (AFA) are related to vascular access, but there is little evidence as to how these can be minimized., Methods: Consecutive patients undergoing AFA at a high-volume center received either standard care (Group S) or routine ultrasound-guided vascular access (Group U). Vascular complications were assessed before hospital discharge and by means of postal questionnaire 1 month later. Outcome measures were BARC 2+ bleeding complications, postprocedural pain, and prolonged bruising., Results: Patients in Group S (n = 146) and U (n = 163) were well matched at baseline. Follow-up questionnaires were received from 92.6%. Patients in Group U were significantly less likely to have a BARC 2+ bleed, 10.4% versus 19.9% P = 0.02, were less likely to suffer groin pain after discharge (27.1% vs. 42.8%; P = 0.006) and were less likely to experience prolonged local bruising (21.5% vs. 40.4%; P = 0.001). Multivariable logistic regression analysis revealed a significant association of vascular complications with nonultrasound guided access (OR 3.12 95%CI 1.54-5.34; P = 0.003) and increasing age (OR 1.05 95%CI 1.01-1.09; P = 0.02)., Conclusion: Routine use of ultrasound-guided vascular access for AFA is associated with a significant reduction in bleeding complications, postprocedural pain, and prolonged bruising when compared to standard care., (© 2014 Wiley Periodicals, Inc.)

Multiple inhibitory molecules create a profoundly immunuosuppressive environment during chronic viral infections in humans and mice. Therefore, eliciting effective immunity in this context represents a challenge. Here, we report that during a murine chronic viral infection, interleukin-6 (IL-6) was produced by irradiation-resistant cells in a biphasic manner, with late IL-6 being absolutely essential for viral control. The underlying mechanism involved IL-6 signaling on virus-specific CD4 T cells that caused up-regulation of the transcription factor Bcl6 and enhanced T follicular helper cell responses at late, but not early, stages of chronic viral infection. This resulted in escalation of germinal center reactions and improved antibody responses. Our results uncover an antiviral strategy that helps to safely resolve a persistent infection in vivo.

Objectives: In this study, the cost-effectiveness of rituximab was evaluated in comparison with commonly used chemotherapy regimens for patients with advanced follicular lymphoma (FL), from the perspective of the UK National Health Service (NHS)., Methods: Results from four randomized controlled trials comparing the addition of rituximab to chemotherapy regimens: mitoxantrone, chlorambucil, and prednisolone (MCP); cyclophosphamide, vincristine, and prednisolone (CVP); cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP); or cyclophosphamide, etoposide, doxorubicin, prednisolone, and interferon alpha (CHVP + IFNalpha) versus chemotherapy alone were used to develop a Markov model. The rates of disease progression and the duration of treatment effect were obtained from the trial data. Treatments were compared in two ways: 1) an individual comparison of rituximab + chemotherapy versus chemotherapy and 2) a multiple treatment comparison using league tables. Economic and clinical outcomes (quality-adjusted life-years (QALYs)) were estimated over patient lifetimes and discounted at 3.5% per annum., Results: In the individual comparison, the addition of rituximab increased QALYs by (mean, 95% confidence interval) 1.174 (1.02-1.30), 0.909 (0.79-1.01), 0.823 (0.71-0.91), and 0.453 (0.40-0.50) for MCP, CVP, CHOP, and CHVP, respectively, compared with chemotherapy alone. The incremental costs per QALY gained were pound7474, pound8621, pound10,732, and pound8551, respectively. Sensitivity analyses indicated that rituximab plus chemotherapy was a cost-effective treatment option, with incremental cost-effectiveness ratios below a threshold of pound30,000 per QALY gained. When compared across the chemotherapy regimens, rituximab plus MCP appeared to be the single most cost-effective treatment option, but further randomized trials are required to substantiate this., Conclusions: The addition of rituximab to chemotherapy in advanced FL was found to be highly cost-effective in the UK.

Background: Oral ibandronate is a single-nitrogen bisphosphonate whose efficacy is similar to that of IV ibandronate for the treatment of bone metastases., Objective: The aim of this study was to compare the cost-effectiveness of oral ibandronate with zoledronic acid and generic pamidronate (both administered by IV) for the treatment of bone metastases in patients with breast cancer receiving oral hormonal therapy in the United Kingdom., Methods: A global economic model was adapted to the UK National Health Service. Patients were assumed to receive oral hormonal therapy for 50% of their projected 14.3-month survival. The primary outcome was incremental cost per quality-adjusted life-year (QALY). Bisphosphonate efficacy data for relative risk reduction of skeletal-related events (SREs) were obtained from clinical trials. Resource use data and costs associated with IV bisphosphonate infusions were derived from published studies and a unit cost database; monthly drug acquisition costs were obtained from the British National Formulary. Utility scores were applied to time with or without an SRE to adjust survival for quality of life. Therefore, differences in QALYs were driven by utility weights rather than survival time. Model design and inputs were validated through expert UK clinician review. The absence of comparative efficacy and safety data from clinical trials for the different bisphosphonates was a model limitation that we addressed by supporting our assumptions with UK expert clinician opinion and with expert clinician opinion outside of the United Kingdom, and by conducting sensitivity analyses., Results: The projected total cost per patient was pound307 less with oral ibandronate compared with zoledronic acid, and pound158 less compared with the use of generic pamidronate (due to a reduction in staff time for infusions, avoidance of renal safety monitoring visits, and, in the case of IV generic pamidronate, a reduction in the number of SREs). Oral ibandronate was estimated to lead to a gain of 0.02 QALY, making it the economically dominant treatment option., Conclusions: In this study, we found that oral ibandronate was cost-effective for the management of bone metastases from breast cancer among patients receiving oral hormonal therapy in the United Kingdom. Oral ibandronate provided effective SRE and bone-pain management while avoiding resource use and costs associated with regular IV bisphosphonate infusions. Due to uncertainty surrounding the model assumptions, it would be valuable to repeat the analyses using data from comparative bisphosphonate trials, once they become available.