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The concept of source-sink dynamics as a potentially important component of metapopulation dynamics was introduced in the 1980s. The objective of the present review was to review the considerable body of work that has been developed, to consider its theoretical implications as well as to understand how source-sink dynamics may manifest under field conditions in the specific case of nontarget arthropods in the agricultural environment. Our review concludes that metapopulation dynamics based on field observations are often far more complex than existing theoretical source-sink models would indicate, because they are dependent on numerous population processes and influencing factors. The difficulty in identifying and measuring these factors likely explains why empirical studies assessing source-sink dynamics are scarce. Furthermore, we highlight the importance of considering the spatial and temporal heterogeneity of agricultural landscapes when assessing the population dynamics of nontarget arthropods in the context of the risk from the use of plant protection products. A need is identified to further develop and thoroughly validate predictive population models, which can incorporate all factors relevant to a specific system. Once reliable predictive models for a number of representative nontarget arthropod species are available, they could provide a meaningful tool for refined risk evaluations (higher tier level risk assessment), addressing specific concerns identified at the initial evaluation stages (lower tier level risk assessment). Environ Toxicol Chem 2021;40:2667-2679. © 2021 ERM, FMC, Syngenta, Bayer AG, BASF SE, Corteva agriscience. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

With the accelerated growth of the esports industry over the last few years, there has been a corresponding increase in the number of esports athletes. Yet there is limited research examining these...

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., Graphical abstract, The exact mechanism by which metformin exerts its anti-inflammatory effects is still not known. Xian et al. shows that metformin’s inhibition of ETCCI blocks ATP-dependent mtDNA synthesis, cytoplasmic ox-mtDNA generation and NLRP3 inflammasome activation in macrophages, independent of AMPK and NF-κB. By limiting IL-1β production, metformin blunts pulmonary inflammation.

The concept of fame has been associated with celebrities, wealth, attractiveness, and social recognition. Nevertheless, people have admiration for the famous who may not be celebrities. Admiration is regarded as one of the emotions of appreciation, or moral emotions, triggered by positive appraisals of excellence. It is present when seeing extraordinary displays of skills talent or achievement. However, theoretical and empirical research on admiration and its psychological effects on people are scarce. In this article, we discuss a qualitative study that explores a collection of experiences of admiration for the famous. Based on 26 in-depth interviews with residents in southern England, we explored why people admire famous individuals and how the experience may produce positive attitudes and behaviors. We found that through admiring famous individuals who are perceived to share similar interests and attributes, people may develop positive thinking about their own lives and may be more active in seeking new opportunities or engaging in self-growth. We also discuss the potential problems of admiration. This exploratory research contributes to the literature of positive psychology and has implications for furthering the understanding of people’s well-being.

Allergic asthma is a chronic inflammatory disease characterized by airway hyperreactivity (AHR) and type-2 immune response. Type-2 innate lymphoid cells (ILC2s) mimic T helper 2 (Th2) cells in cytokine secretion and are among the first pulmonary immune responders to the allergen-induced alarmins. Programmed cell death protein-1 (PD-1) is known as an immune checkpoint equipped with tyrosine-based inhibitory motifs in the cytoplasmic tail. Since PD-1 is associated with immune regulation in many inflammatory diseases, the objective of this study was to investigate the role of PD-1 in the initiation and development of AHR. Lung function tests, RNA sequencing, flow cytometry, targeted metabolomic assays, and adoptive transfer experiments were principally used to explore the role of PD-1 in AHR mouse models and in human ILC2s. Using IL-33 and Alternaria alternata models, we have demonstrated that PD-1 knockout mice develop a higher AHR and lung inflammation as compared to control wild-type mice. In particular, PD-1 is highly inducible on lung ILC2s and downregulates their effector functions. Moreover, PD-1 controls glycolysis and methionine catabolism, limiting, therefore, the proliferation of activated pulmonary ILC2s. In line with mice data, PD-1 is inducible and functional in human ILC2s in response to IL-33. To confirm the translational relevance of our findings, we tested a novel human PD-1 agonist in vitro and in a humanized mouse model of AHR. Interestingly, the PD-1 agonist decreases human ILC2 activation and is able to dampen AHR and lung inflammation. Altogether this study reveals the protective role of PD-1 as regulators of ILC2s and highlights for the first time the therapeutic potential of PD-1 agonists in allergic asthma. Supported by grants from NIH: R01 ES025786, R01 ES021801, R01 HL144790, and R21 AI109059 (O.A.)

Background Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is characterized by type 2 inflammation with high levels of Th2 cytokines. Although T helper cytokines are released from T cells, innate lymphoid cells (ILC) are also known to produce high levels of the same cytokines. However, the presence of various types of ILC in CRS is poorly understood. Objective The objective of this study was to fully characterize the presence of all ILC subsets in CRS and to identify phenotypical differences of group 2 ILC (ILC2) in CRSwNP compared to ILC2 from non-type 2 inflamed areas. Methods We investigated the presence of ILC subsets in peripheral blood mononuclear cells (PBMC) from healthy subjects, tonsil tissue, ethmoid tissue from control subjects and patients with non-polypoid CRS (CRSsNP) and CRSwNP, as well as nasal polyp (NP) tissue from CRSwNP by flow cytometry. Sorted ILC2 were cultured in the presence and absence of IL-33 and production of IL-5 and IL-13 was assessed by Luminex. Results We found that all ILC subsets were present in NP but ILC2 were dominant and significantly elevated compared to PBMC, tonsil, CRSsNP, and normal sinus tissue. We also found that inducible T-cell co-stimulator (ICOS) and side scatter were increased and CD127 was down-regulated in ILC2 from NP compared to blood or tonsil ILC2. Thymic stromal lymphopoietin, IL-7, and IL-33 were able to down-regulate expression of CD127 and increase side scatter in blood ILC2. Furthermore, sorted NP ILC2 but not blood ILC2 spontaneously released type 2 cytokines including IL-5 and IL-13. Conclusions and Clinical Relevance These results suggest that ILC2 are not only elevated but also activated in CRSwNP in vivo and that ILC2 may play important roles in the type 2 inflammation in CRSwNP.

Acute respiratory distress syndrome (ARDS) is a leading cause of COVID-19 death. Long-term metformin usage decreases COVID-19 mortality through an obscure mechanism unrelated to glycemic control. It is unclear whether and how short-term metformin-based intervention can block acute inflammation. We show that metformin inhibits IL-6 and IL-1β secretion from LPS or SARS-CoV-2 Spike protein primed macrophages undergoing NLRP3 inflammasome activation, a key to ARDS initiation. Reduced IL-6 production correlates with blunted NFAT and C/EBPβ/NFIL-6 activation, whereas inhibition of IL-1β secretion reflects interference with NLRP3 inflammasome activation. By targeting electron transfer chain complex 1, but independently of AMPK and mitophagy, metformin inhibits ATP-dependent mitochondrial DNA synthesis and blocks generation of oxidized mitochondrial DNA, a trigger of inflammasome assembly. Correspondingly, short-term metformin treatment abrogates LPS-induced ARDS, lung macrophage recruitment, damage and mortality. We suggest that metformin, a cheap and safe drug, can be used to prevent ARDS onset in COVID-19 patients. Funding: The UCSD Tissue Technology Shared Resource supported by a National Cancer Institute Cancer Center Support Grant (CCSG P30CA23100). M.A. was supported by NIH (R01AI072726). E.S-L. was supported by NIAMS (K01AR077111). Research was supported by NIH grant awards to M.K. and M.A. (U54CA260591), and M.K. (R01A1043477, P42ES010337), who is an American Cancer Research Society Professor and holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases. Conflict of Interest: M.K. is a founder of Elgia Pharmaceuticals and receives research support from Gossamer Bio and Jansen Pharmaceuticals. All other authors declare no competing interests. Ethical Approval: All mouse studies were conducted in accordance with UCSD and NIH guidelines and regulations for the housing and treatment of laboratory animals using protocols approved by the UCSD Institutional Animal Care and Use Committee.

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 (ILC210s). Objective Our aim was to characterize the effector functions of ILC210s in the development and pathology of allergic asthma. Methods IL-4–stimulated ILC210s were isolated to evaluate cytokine secretion, transcription factor signaling, metabolic dependence, and effector functions in vitro. ILC210s 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 ILC210s. Strikingly, our results demonstrate that ILC210s 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, ILC210s 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 ILC210s 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.

Innate lymphoid cell (ILC) cytokine signatures mirror those of T helper subsets, but ILCs differ substantially as far as biological role. Tissue-resident and antigen-independent, ILCs mediate induction and resolution of inflammation, tissue homeostasis, and barrier maintenance. Although extensively character-ized in periphery, ILCs were newly identified as resident in central nervous system (CNS) meninges, and are less well-understood within this novel context. Here we show that ILC-deficient mice exhibit enhanced microglial reactivity, amplified neuroinflammatory responses and blood-brain barrier (BBB) permeability. Accordingly, transcriptomic and functional examination revealed meningeal ILC2s as vigorous interleukin (IL)-10 producers. Mechanistic relevance was demonstrated by amelioration of neuroinflammation following meningeal engraftment of adoptively-transferred wild type — but not IL-10-deficient — ILC2s. Notably, ILC2s from murine bone marrow and human blood also showed IL-10 competency, suggesting a previously-unappreciated immunoregulatory role for canonical ILC2s. Collectively, these findings reveal meningeal ILC2s as suppressors of neuroinflammation — suggesting potential for ILC2-based cell therapies in CNS pathology.

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., Type-2 innate lymphoid cells (ILC2s) are an immune population secreting Th2 cytokines playing a role in the regulation of adipose metabolic homeostasis. Here the authors show that engagement of GITR, a member of the TNF superfamily, in activated ILC2s is protective against insulin resistance in both a preventive and a therapeutic manner in the context of obesity.

New stable isotope data from organic carbon (δ13Corg) and inorganic elemental geochemistry data have been generated from Upper Ordovician to Silurian strata in two boreholes in the Lublin Basin of Poland: Grabowiec-6 and Zwierzyniec-1. They have been integrated here with biostratigraphical data from graptolites, acritarchs, and chitinozoans. Faunal assemblages from Grabowiec-6 indicate that it spans from the Katian (clingani graptolite Biozone) to the Gorstian (scanicus graptolite Biozone); δ13Corg values from this section record the Sheinwoodian Ireviken Excursion, the Homerian Mulde Excursion, and a minor positive shift associated with the lower Ludfordian leintwardinensis Biozone. The second section, Zwierzyniec-1, spans the Sandbian through Gorstian (nilssoni Biozone); δ13Corg values record the Hirnantian carbon isotope excursion (HICE) and the Ireviken Excursion as well.Elemental geochemistry data is used to recognize subtle changes in provenance and lithology. Significant increases in the abundance of V and Mo are recognized in strata deposited above the Ireviken Excursion. The enrichment of these redox sensitive elements suggests that persistent regional anoxia and euxinia may be associated with the aftermath of these oceanographic disturbances. Some of these same trace elements, along with Fe2O3, and Pb are also abundant in strata coeval with, or just below the Ireviken and HICE excursions. This may have a causal link with malformed palynomorphs observed at these intervals by some workers, which are thought to reflect toxic levels of dissolved heavy metals in the world's oceans.

BACKGROUND: Allergic asthma is a chronic inflammatory disorder that is characterized with airway hyperreactivity (AHR) and driven by Th2 cytokine production. Group 2 innate lymphoid cells (ILC2s) secrete high amount of Th2 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 them challenged with IL-33 and assessed for airway hyperreactivity 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 Atg5 resulted in decreased cytokine secretion and increased apoptosis. Moreover, lack of autophagy among ILC2s impaired their ability to utilize 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 Th2 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.

Vascular Ultrasound for AFA 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.

Background Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is characterized by type 2 inflammation with high levels of Th2 cytokines. Although T helper cytokines are released from T cells, innate lymphoid cells (ILC) are also known to produce high levels of the same cytokines. However, the presence of various types of ILC in CRS is poorly understood. Objective The objective of this study was to fully characterize the presence of all ILC subsets in CRS and to identify phenotypical differences of group 2 ILC (ILC2) in CRSwNP compared to ILC2 from non‐type 2 inflamed areas. Methods We investigated the presence of ILC subsets in peripheral blood mononuclear cells (PBMC) from healthy subjects, tonsil tissue, ethmoid tissue from control subjects and patients with non‐polypoid CRS (CRSsNP) and CRSwNP, as well as nasal polyp (NP) tissue from CRSwNP by flow cytometry. Sorted ILC2 were cultured in the presence and absence of IL‐33 and production of IL‐5 and IL‐13 was assessed by Luminex. Results We found that all ILC subsets were present in NP but ILC2 were dominant and significantly elevated compared to PBMC, tonsil, CRSsNP, and normal sinus tissue. We also found that inducible T‐cell co‐stimulator (ICOS) and side scatter were increased and CD127 was down‐regulated in ILC2 from NP compared to blood or tonsil ILC2. Thymic stromal lymphopoietin, IL‐7, and IL‐33 were able to down‐regulate expression of CD127 and increase side scatter in blood ILC2. Furthermore, sorted NP ILC2 but not blood ILC2 spontaneously released type 2 cytokines including IL‐5 and IL‐13. Conclusions and Clinical Relevance These results suggest that ILC2 are not only elevated but also activated in CRSwNP in vivo and that ILC2 may play important roles in the type 2 inflammation in CRSwNP.

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.

About 15 years have passed since the implementation of Directive 91/414/EEC and the regulatory framework with regard to pesticide use and environmental protection aims, as well as the plant protection techniques involving pesticides, have evolved over this period. In the case of honey bees, further developments and updates with regards to larval testing have been undertaken. Experimental protocols for semi-field and field testing have been reviewed in detail. Finally, a dedicated risk assessment scheme has been developed for seed coating and soil applications that involve systemic compounds. A revision of the original EPPO Standards: the Risk Assessment Scheme PP 3/10(2) Honeybees and the test guidelines PP1/170 (3) Side-effects on honeybees has thus been undertaken in order to benefit from these improvements. This paper aims to provide the details of the reasoning on which the revised risk assessment scheme relies as well as providing the necessary references to the data which have been reviewed in the context of this revision.

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 + IFNα) 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 £7474, £8621, £10,732, and £8551, respectively. Sensitivity analyses indicated that rituximab plus chemotherapy was a cost-effective treatment option, with incremental cost-effectiveness ratios below a threshold of £30,000 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.

Global declines of bumble bees and other pollinator populations are of concern because of their critical role for crop production and maintenance of wild plant biodiversity. Although the consensus among scientists is that the interaction of many factors, including habitat loss, forage scarcity, diseases, parasites, and pesticides, potentially plays a role in causing these declines, pesticides have received considerable attention and scrutiny. In response, regulatory agencies have introduced more stringent pollinator testing requirements for registration and reregistration of pesticides, to ensure that the risks to pollinators are minimized. In this context, guidelines for testing bumble bees (Bombus spp.) in regulatory studies are not yet available, and a pressing need exists to develop suitable protocols for routine higher-tier studies with these non-Apis sp., social bees. To meet this need, Bayer CropScience LP, Syngenta Crop Protection LLC US, and Valent U.S.A. Corporation organized a workshop bringing together a group of global experts on bumble bee behavior, ecology, and ecotoxicology to discuss and develop draft protocols for both semi-field (Tier II) and field (Tier III) studies. The workshop was held May 8-9, 2014, at the Bayer Bee Care Center, North Carolina, USA. The participants represented academic, consulting, and industry scientists from Europe, Canada, the United States, and Brazil. The workshop identified a clear protection goal and generated proposals for basic experimental designs, relevant measurements, and endpoints for both semi-field (tunnel) and field tests. These initial recommendations are intended to form the basis of discussions to help advance the development of appropriate protocol guidelines

Well‐calibrated seismic interpretation in the Halten Terrace of Mid‐Norway demonstrates the important role that structural feedback between normal fault growth and evaporite mobility has for depocentre development during syn‐rift deposition of the Jurassic–Early Cretaceous Viking and Fangst Groups. While the main rift phase reactivated pre‐existing structural trends, and initiated new extensional structures, a Triassic evaporite interval decouples the supra‐salt cover strata from the underlying basement, causing the development of two separate fault populations, one in the cover and the other confined to the pre‐salt basement. Detailed displacement–length analyses of both cover and basement fault arrays, combined with mapping of the component parts of the syn‐rift interval, have been used to reveal the spatial and temporal evolution of normal fault segments and sediment depocentres within the Halten Terrace area. Significantly, the results highlight important differences with traditional models of normal fault‐controlled subsidence, including those from parts of the North Sea where salt is absent. It can now be shown that evaporite mobility is intimately linked to the along‐strike displacement variations of these cover and basement faults. The evaporites passively move beneath the cover in response to the extension, such that the evaporite thickness becomes greatest adjacent to regions of high fault displacement. The consequent evaporite swells can become large enough to have pronounced palaeobathymetric relief in hangingwall locations, associated with fault displacement maxima– the exact opposite situation to that predicted by traditional models of normal fault growth. Evaporite movement from previous extension also affects the displacement–length relationships of subsequently nucleated or reactivated faults. Evaporite withdrawal, on the other hand, tends to be a later‐stage feature associated with the high stress regions around the propagating tips of normal faults or their coeval hangingwall release faults. The results indicate the important effect of, and structural feedback caused by, syn‐rift evaporite mobility in heavily modifying subsidence patterns produced by normal fault array evolution. Despite their departure from published models, the results provide a new, generic framework within which to interpret extensional fault and depocentre development and evolution in areas in which mobile evaporites exist.

The Tertiary development of the Norwegian continental margin was dominated by the opening of the Arctic–North Atlantic Ocean. The correct identification of magnetic anomalies and their ages and the analysis of spreading rates during the formation of this ocean are important in understanding the development of the region and specifically the history of its passive margins. Three ocean domains, the AEgir, Reykjanes and Mohns regions, were investigated in an effort to understand the lateral changes in structural development of the passive margin after continental break-up. Spreading rates generally slowed down from 2 cm a −1 after Early Eocene initiation of sea-floor spreading, to values around 0.5 cm a −1 in Oligocene time. An increase in spreading rates to around 1 cm a −1 coincided with the positioning of the Iceland hotspot under the North Atlantic mid-ocean ridge. At the same time, the European plate changed its absolute plate motion from a north-directed drift to a motion more towards the east. The location of inversion structures in the Voring and Faeroes Basin rather than in the More Basin is related to differences in spreading rates. The Mohns and the Reykjanes Ridges produced more ocean floor than the AEgir–Kolbeinsey Ridges. Asymmetric ocean-floor formation in the AEgir Ridge led to differential stress at the base of the lithosphere, which probably explains the absence of inversion features in the More Basin (less mantle drag). Furthermore, upper plate margins such as the Voring Basin and possibly the Faeroe Basin have a lower compressional strength than lower plate margins such as the More Basin, and therefore preferentially developed inversion structures. Along the transform boundaries separating the domains, additional stress probably built up along extension of the transform zones into the extended continental crust. This additional stress probably also assisted initiation of the inversion structures in the Voring Basin and the Faeroes area. The amplification of the inversion structures in the Voring Basin and the Faeroes Basin was subsequently caused by a variety of processes related to sedimentation and uplift–erosion.

Type 2 innate lymphoid cells (ILC2s) are newly identified subset of immune cells that play important roles in the pathogenesis of allergic diseases and asthma. The regulatory mechanisms that control the function and homeostasis of ILC2s are incompletely understood. Plasmacytoid dendritic cells (pDCs) have been previously associated with maintaining respiratory tolerance. To identify a novel mechanism for alleviating ILC2-mediated asthma we investigated impact of pDCs on ILC2s and ILC2-mediated airway hyperreactivity and inflammation. We investigated human and murine ILC2s and used clinically relevant allergen, Alternaria Alternata, as well as IL-33, to activate ILC2s in several mouse models including BDCA-2-DTR transgenic and Interferon alpha receptor-1 deficient mice. We found that activation of pDCS by a Toll-like receptor-7 agonist, R848, suppresses ILC2-mediated AHR and airway inflammation and that depletion of pDCs reverses this suppression. Moreover, we found that pDCs suppress cytokine production and proliferation of ILC2s through the production of interferon alpha. Transcriptome analysis of both human and murine ILC2s confirms the activation of regulatory pathways in ILC2s by interferon alpha. In addition, activation of pDCs alleviates airway hyperreactivity and inflammation by suppressing ILC2’s function and survival. Our findings reveal a novel regulatory pathway in ILC2-mediated pulmonary inflammation with important clinical implications.

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.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.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).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.

In the face of austerity cuts to state infrastructure provision, the British Broadcasting Corporation has recently generated something of a moral panic about the future of public sector broadcasting—mobilizing both its own news channel and its friends in the corporate media around the issue. Yet in the midst of this ongoing existential crisis, few have asked: What is it we are being asked to defend?… As in car manufacturing, what is provided is a limitedly resourced primary product, altered for different consumption demands, by add-on and take-off parts.Click here to purchase a PDF version of this article at the Monthly Review website.

Background There is little published evidence regarding intraoperative and postoperative complications in patients with ventriculoperitoneal shunts who undergo cholecystectomy. Methods Nationwide Department of Veterans Affairs databases were searched to identify patients with International Classification of Diseases, 9th revision, Clinical Modification codes for a VP shunt who later had a cholecystectomy during fiscal years 1994 to 2003. Charts on these patients were obtained and reviewed. Results Twenty-three patients were deemed evaluable. Of these, 8 had laparoscopic converted to open cholecystectomies. All conversions were owing to dense adhesions. There were 2 cases of postoperative shunt infection that required shunt removal and replacement. Conclusions The rate of conversion from laparoscopic to open cholecystectomy was 57% in this study, significantly higher than the reported rate of conversion for patients without shunts in Department of Veterans Affairs Medical Centers (5%). Cholecystectomy in adult patients with a preexisting ventriculoperitoneal shunt appears to result in a shunt infection rate similar to that reported after shunt insertion or revision.

Background: The risk of graft failure is the pivotal measure of effectiveness when evaluating immunosuppressive regimens for renal transplantation. However, to date most randomized trials of immunosuppressive therapy have had acute rejection as the primary endpoint for treatment comparisons. The objective here was to review the evidence relating acute rejection to renal graft function and graft survival. Methods: A systematic review of the published literature was undertaken. Studies were reviewed if they included the following: study populations of adults undergoing renal transplantation, endpoints of graft loss or survival, and quantitative data on the associations between acute rejection and graft function and survival. Results: Overall, 31 observational studies were included. The definition of acute rejection varied, and there was substantial heterogeneity in study design and methodology. In all but two studies, acute rejection was associated with an increased risk of graft loss-risk ratios ranged from 1.2 (no definition reported) to 10.5 (confirmed by biopsy and grade I Banff criteria). In addition, there was fairly strong evidence linking timing of acute rejection and graft survival and weaker evidence linking the number of episodes and graft survival. The heterogeneity between studies invalidated pooling of quantitative studies. Conclusions. The weight of the evidence indicates that occurrence, timing, and number of acute rejection episodes are associated with increased risk of graft loss. Less is known about the severity of rejection, which is important because many immunosuppressive regimens lessen severity. Quantifying these relationships is a priority if acute rejection continues to be a surrogate trial endpoint.

Triclosan (2,4,4'-trichloro-2'-hydroxydiphenyl ether) is a broad-spectrum bactericide used throughout North America and Europe for a variety of antimicrobial functions. This paper addresses the risk to terrestrial organisms from several potential exposure pathways: Exposure experienced by earthworms, terrestrial plants, and soil microorganisms as the result of the use of sewage sludge containing triclosan as an agricultural soil amendment; secondary exposure by birds and mammals from consumption of earthworms that have been exposed to triclosan in soil; and secondary exposure by birds and mammals from consumption of fish exposed to triclosan as the result of wastewater treatment discharges. The assessment found satisfactory margins of safety for plants, earthworms, birds, fish, mammals, and soil microorganisms. The lowest margins of safety were for nontarget plants (100 for the typical scenario and 8 for the upper-bound scenario). However, these margins of safety are still above the European Union (EU) recommended fivefold assessment value for nontarget plants and are based on cucumber results from a vegetative vigor study conducted in quartz sand that is of limited relevance for risk assessment. In a pre-emergence study conducted in a more relevant soil (sandy loam), cucumbers showed no response to triclosan at the highest dose tested (1,000 microg/kg). A recent study provides limited field measurements of soil and earthworm concentrations. While that study finds higher soil and earthworm concentrations than were estimated in the present study, even these higher concentrations do not indicate significant risks.

The Eastern Kentucky Coalfield contains Pennsylvanian aged strata deposited into the Central Appalachian Basin, eastern USA. These strata are deltaic to shallow marine facies and represent prograding sediment accumulated into a foreland basin, from an emergent and uplifting Appalachian landmass to the east. The sediments are predominantly unfaulted away from the Appalachian thrust front; however, spectacular examples of metre to decimetre-scale syn-sedimentary growth faulting are observed. The growth faulting was caused by sedimentary differential loading of underlying mobile shale units. For this reason these fault systems develop soon after deposition while the sediments are semi- to unconsolidated. The fault systems are comprised of listric to planar, down to the basin (regional) and landward (counter-regional) faults as observed in modern deltaic environments such as offshore Texas, Gulf of Mexico and the Niger Delta. Observations made on the structure and architecture within the fault zones identify three critical deformation styles that will affect predicting the fluid flow characteristics of fault systems formed in this environment. These deformation styles are as follows. (1) Faults formed whilst the sediments are unconsolidated show evidence of sands being sheared down the fault plane forming disaggregation bands parallel to the fault plane. (2) Faults propagating through an inter-bedded sequence of sands and shales experience a large strength contrast at the sand-shale interfaces leading to fault plane refraction. Further fault development tends to ‘smooth’ the fault's surface producing slivers (riders) of sandstone, which are incorporated into the fault zone. (3) Fault motion during soft sediment deformation can lead to sands injected along the fault plane and along planes of weakness in the footwall to increase sand connectivity. Traditional fault seal analysis techniques such as the Shale Gouge Ratio (SGR) assumes the percentage of shale in the fault zone, its petrophysical properties and hence its sealing potential is controlled by the ratio of sand to shale passing a point on the fault. The incorporation or injection of sand into the fault plane is not accounted for. Thus use of the SGR method for assessing intra-reservoir faulting formed by syn-sedimentary processes can overestimate the sealing potential of the system.

Introduction The most frequent complications of AF Ablation (AFA) are related to vascular access but there is little published evidence as to how these can be minimised. In 2012 the European Society of Cardiology clearly stated in their updated guidelines that “improving safety of catheter ablation should be a primary goal in the further development of this therapy”. Methods In this prospective study, consecutive patients undergoing AFA received either standard femoral vascular access, guided by a landmark technique (Group S), or routine ultrasound-guided vascular access (Group U). Vascular complications were assessed before hospital discharge, and by means of bespoke postal questionnaire one month later. Outcome measures were actionable (BARC2+) bleeding complications, groin pain that required analgesics, and prolonged bruising lasting >2 weeks. Results Patients in Groups S (n = 146) and U (n = 163) were well matched at baseline. Follow up questionnaires were received from 92.6% of patients. Uninterrupted warfarin therapy was used in 65% of cases. There was no difference between the groups in mean INR levels, peak ACT levels or in the use of protamine post-procedure. Procedures in Group U were significantly shorter than those in Group S (184 ± 53 min v. 167 ± 4 min, p = 0.04). Inadvertent femoral arterial puncture, as recognised by the operator, was less common in Group U (10, 6.1%) than in Group S (19,13.0%), p = 0.04. Patients in Group U were significantly less likely to have a BARC 2+ bleed (10.4% v. 19.9% p = 0.02), were less likely to suffer groin pain after discharge (27.1% v. 42.8%, p = 0.006) and were less likely to experience prolonged local bruising (21.5% v. 40.4% p = 0.001). 2 patients in Group S and 1 patient in Group U had major (BARC 3) bleeding requiring blood transfusion (p = NS). Multivariable logistic regression analysis revealed a significant association of vascular complications with non-ultrasound 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). The number needed to treat with ultrasound to prevent one bleeding complication was 11. Discussion Previous work has shown that physician-reported complication rates following AFA miss the majority of vascular events considered important to patients. For this reason we assessed patient reported outcome measures post-discharge, and chose a broad definition of bleeding complications rather than restricting ourselves to life-threatening complications. Accordingly our complication rates seem high at first glance, but we believe they better represent the true patient experience. To our knowledge, this is the first study to show the benefit of adopting a policy of using vascular ultrasound for AFA. Conclusion Routine use of ultrasound guided vascular access for AFA is associated with a significant reduction in bleeding complications, post procedural groin pain and prolonged local bruising when compared to standard vascular access.

Persistent viruses create a profound immunosuppressive environment that is conserved in mice and humans. While several pathways suppressing CD8 T cell responses have been identified, much less is known about the immune regulatory molecules restricting the number and helper function of CD4 T cells. By using Lymphocytic Choriomeningitis Virus (LCMV) infection in mice, we observed enhanced signaling of the immunosuppressive cytokine Transforming Growth Factor-β (TGF-β) in virus-specific T cells during chronic infection. Importantly, genetic ablation of TGF-β receptor (R) resulted in rapid mortality upon chronic, but not acute, LCMV infection. While TGF-βR deficient mice showed comparable CD8 T cell responses, CD4 T cell proliferation, terminal differentiation and a cytotoxic program characterized by Granzyme B, Perforin and EOMES expression were significantly enhanced in the absence of TGF-βR signaling. Importantly, EOMES overexpression recapitulated the phenotype of TGF-βR deficient CD4 T cells while EOMES inhibition suppressed it. Finally, preliminary experiments showed TGF-β signaling also suppressed cytotoxic molecules and EOMES in human CD4 T cells. Together these data uncover a novel TGF-βR-dependent axis that restricts EOMES-driven differentiation and cytotoxicity in murine and human CD4 T cells while highlighting a critical role for TGF-βR in limiting anti-viral CD4 T cell responses and mortality upon chronic viral infection.

Chronic viral infections such as human immunodeficiency virus 1 and hepatitis C virus represent a significant global health burden. Virus specific CD4+ T cell number and function are critical in determining the outcome of these chronic viral infections, but little is known about the signals that can promote their survival or helper functions in this environment. By studying both acute and chronic variants of lymphocytic choriomeningitis virus infection of mice we found that the IL-6 cytokine family signal transduction molecule gp130 expression on CD4+ T cells was essential for long term viral control in chronic, but not acute infection. It was critical for virus specific CD4+ T cell survival, differentiation and the production of IL-21, factors which are critical in the control of chronic infections. Dissection of the individual IL-6 family of cytokines revealed that IL-6 was critical for the upregulation of the transcriptional regulator Bcl6 and subsequent escalation in T follicular helper cell responses and development of antiviral antibody. Contrastingly IL-27 was uniquely required in the survival of these virus specific CD4+ T cells at late stages of chronic infection. Use of Il6ra-/-;Il27ra-/- ¬mice showed however that IL-6 and IL-27 had an overlapping role in the production of IL-21. Our data situates the IL-6 cytokine family as central orchestrators of anti-viral CD4+ T cell responses and subsequent immune responses vital during established chronic viral infections.

Introduction Catheter ablation (CA) is increasingly seen as an effective treatment for symptomatic atrial fibrillation (AF), particularly when antiarrhythmic drug therapy has failed. To perform CA several large-bore sheaths must be placed percutaneously into central veins. To prevent thromboembolism patients receive intravenous heparin±systemic anticoagulation with warfarin or an alternative agent. Perhaps unsurprisingly, the most commonly encountered complications from CA are vascular, with published rates of 2–5%. It is feared that some access complications may occur after hospital discharge, and so the overall incidence may be higher. There are no studies with systematic screening to include the post-discharge period. Methods We prospectively studied consecutive cases undergoing CA at a single high-volume centre in the UK using a dedicated proforma to record vascular complications at the time of the CA and at hospital discharge. This was followed up 1 month later with a bespoke postal questionnaire. Results 143 consecutive patients underwent CA for AF over 5 months. An anatomical approach was used as standard. Where possible all sheaths were placed into a single, usually right femoral, vein. All patients received intra-procedural heparin to maintain an ACT of >300 s and 70% were performed on uninterrupted warfarin (with most of the rest receiving post-op dabigatran). Bleeding complications were classified according to BARC criteria (See table) and the time of reporting (Pre or post discharge). In hospital data was collected on all patients and questionnaire was returned by 77%. 32% of patients had vascular access complications, including 19 (13%) with minor (BARC 1) bleeding, 30 (21%) with a BARC 2 complication requiring further medical intervention, and 2 (1.4%) patients with BARC 3 bleeds. A further 11 (8%) patients suffered arterial puncture without sequelae and/or prolonged groin pain. 22 of the 51 bleeding complications (43%) were only detected on post-discharge screening. There were no fatal bleeds (BARC 5) or BARC 4 (CABG-related) bleeds. Most (26) oif the BARC 2 bleeds were managed with additional haemostasis although 2 required further imaging or resulted in repeat hospitalisation. Discussion The incidence of vascular access complications following CA for AF is much higher than has been previously reported although major complications are thankfully rare. Physicians should consider techniques that may reduce this risk, such as vascular ultrasound and we are currently evaluating this in the next phase of this study. Patients should be counselled about the true risks as part of the informed consent process. Trials must comprehensively screen for bleeding complications if they are to avoid under-reporting.