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Innate sensing of viruses by cytosolic nucleic acid sensors is a key feature of anti-viral immunity against these pathogens. The DNA sensing pathway through the sensor cyclic GMP–AMP ...synthase (cGAS) and its downstream effector stimulator of interferon genes (STING) has emerged in recent years as a key, front-line means of driving interferons and pro-inflammatory cytokines in response to DNA virus infection in vertebrates. Unsurprisingly, many DNA viruses have evolved effective inhibitors of this signalling system which target at a wide variety of points from sensing all the way down to the activation of Interferon Regulatory Factor (IRF)-family and Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-family transcription factors which drive a program of pro-inflammatory and anti-viral gene expression. Here we review DNA viruses that have been shown to inhibit this pathway and the inhibitors they have evolved to do it.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Since the publication of the EULAR recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in 2016, several randomised clinical trials have been ...published that have the potential to change clinical care and support the need for an update.
Using EULAR standardised operating procedures, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 16 countries. We modified existing recommendations and created new recommendations.
Four overarching principles and 17 recommendations were formulated. We recommend biopsies and ANCA testing to assist in establishing a diagnosis of AAV. For remission induction in life-threatening or organ-threatening AAV, we recommend a combination of high-dose glucocorticoids (GCs) in combination with either rituximab or cyclophosphamide. We recommend tapering of the GC dose to a target of 5 mg prednisolone equivalent/day within 4-5 months. Avacopan may be considered as part of a strategy to reduce exposure to GC in granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Plasma exchange may be considered in patients with rapidly progressive glomerulonephritis. For remission maintenance of GPA/MPA, we recommend rituximab. In patients with relapsing or refractory eosinophilic GPA, we recommend the use of mepolizumab. Azathioprine and methotrexate are alternatives to biologics for remission maintenance in AAV.
In the light of recent advancements, these recommendations provide updated guidance on AAV management. As substantial data gaps still exist, informed decision-making between physicians and patients remains of key relevance.
Approximately 500 monogenic causes of chronic kidney disease (CKD) have been identified, mainly in pediatric populations. The frequency of monogenic causes among adults with CKD has been less ...extensively studied. To determine the likelihood of detecting monogenic causes of CKD in adults presenting to nephrology services in Ireland, we conducted whole exome sequencing (WES) in a multi-centre cohort of 114 families including 138 affected individuals with CKD. Affected adults were recruited from 78 families with a positive family history, 16 families with extra-renal features, and 20 families with neither a family history nor extra-renal features. We detected a pathogenic mutation in a known CKD gene in 42 of 114 families (37%). A monogenic cause was identified in 36% of affected families with a positive family history of CKD, 69% of those with extra-renal features, and only 15% of those without a family history or extra-renal features. There was no difference in the rate of genetic diagnosis in individuals with childhood versus adult onset CKD. Among the 42 families in whom a monogenic cause was identified, WES confirmed the clinical diagnosis in 17 (40%), corrected the clinical diagnosis in 9 (22%), and established a diagnosis for the first time in 16 families referred with CKD of unknown etiology (38%). In this multi-centre study of adults with CKD, a molecular genetic diagnosis was established in over one-third of families. In the evolving era of precision medicine, WES may be an important tool to identify the cause of CKD in adults.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
High‐intensity interval training (HIT) induces skeletal muscle metabolic and performance adaptations that resemble traditional endurance training despite a low total exercise volume. Most HIT studies ...have employed ‘all out’, variable‐load exercise interventions (e.g. repeated Wingate tests) that may not be safe, practical and/or well tolerated by certain individuals. Our purpose was to determine the performance, metabolic and molecular adaptations to a more practical model of low‐volume HIT. Seven men (21 ± 0.4 years, ml kg−1 min−1) performed six training sessions over 2 weeks. Each session consisted of 8–12 × 60 s intervals at ∼100% of peak power output elicited during a ramp peak test (355 ± 10 W) separated by 75 s of recovery. Training increased exercise capacity, as assessed by significant improvements on both 50 kJ and 750 kJ cycling time trials (P < 0.05 for both). Skeletal muscle (vastus lateralis) biopsy samples obtained before and after training revealed increased maximal activity of citrate synthase (CS) and cytochrome c oxidase (COX) as well as total protein content of CS, COX subunits II and IV, and the mitochondrial transcription factor A (Tfam) (P < 0.05 for all). Nuclear abundance of peroxisome proliferator‐activated receptor γ co‐activator 1α (PGC‐1α) was ∼25% higher after training (P < 0.05), but total PGC‐1α protein content remained unchanged. Total SIRT1 content, a proposed activator of PGC‐1α and mitochondrial biogenesis, was increased by ∼56% following training (P < 0.05). Training also increased resting muscle glycogen and total GLUT4 protein content (both P < 0.05). This study demonstrates that a practical model of low volume HIT is a potent stimulus for increasing skeletal muscle mitochondrial capacity and improving exercise performance. The results also suggest that increases in SIRT1, nuclear PGC‐1α, and Tfam may be involved in coordinating mitochondrial adaptations in response to HIT in human skeletal muscle.
Muscles respond to exercise training by developing physiological changes that improve their performance. It has been found that the changes brought about by traditional endurance training can also be produced by high‐intensity interval training. Here a practical form of such training is outlined and shown to be effective (as indicated by changes in mitochondrial capacity and exercise performance). It involves spending 20–30 min, three days a week in cycling that consists of ten 60‐second periods of high‐intensity exercise with 75‐second recovery periods in between. Such a regime may appeal to people who are reluctant to spend more time exercising, and future research will examine whether it can bring health benefits to people who are overweight or have metabolic diseases.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
High-intensity interval training (HIT) increases skeletal muscle oxidative capacity similar to traditional endurance training, despite a low total exercise volume. Much of this work has focused on ...young active individuals, and it is unclear whether the results are applicable to older less active populations. In addition, many studies have used "all-out" variable-load exercise interventions (e.g., repeated Wingate tests) that may not be practical for all individuals. We therefore examined the effect of a more practical low-volume submaximal constant-load HIT protocol on skeletal muscle oxidative capacity and insulin sensitivity in middle-aged adults, who may be at a higher risk for inactivity-related disorders.
Seven sedentary but otherwise healthy individuals (three women) with a mean ± SD age, body mass index, and peak oxygen uptake (VO(2peak)) of 45 ± 5 yr, 27 ± 5 kg·m(-2), and 30 ± 3 mL·kg(-1)·min(-1) performed six training sessions during 2 wk. Each session involved 10 × 1-min cycling at ∼60% of peak power achieved during a ramp VO(2peak) test (eliciting ∼80%-95% of HR reserve) with 1 min of recovery between intervals. Needle biopsy samples (vastus lateralis) were obtained before training and ∼72 h after the final training session.
Muscle oxidative capacity, as reflected by the protein content of citrate synthase and cytochrome c oxidase subunit IV, increased by ∼35% after training. The transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α was increased by ∼56% after training, but the transcriptional corepressor receptor-interacting protein 140 remained unchanged. Glucose transporter protein content increased ∼260%, and insulin sensitivity, on the basis of the insulin sensitivity index homeostasis model assessment, improved by ∼35% after training.
Constant-load low-volume HIT may be a practical time-efficient strategy to induce metabolic adaptations that reduce the risk for inactivity-related disorders in previously sedentary middle-aged adults.
Background Readmission rates are used as a quality metric in medical and surgical specialties; however, little is known about obstetrics readmissions. Objective Our goals for this study were to ...describe the trends in postpartum readmissions over time; to characterize the common indications and associated diagnoses for readmissions; and to determine maternal, delivery, and hospital characteristics that may be associated with readmission. Study Design Postpartum readmissions occurring within the first 6 weeks after delivery in California, Florida, and New York were identified between 2004 and 2011 in State Inpatient Databases. Of the 5,949,739 eligible deliveries identified, 114,748 women were readmitted over the 8-year period. We calculated the rates of readmissions and their indications by state and over time. The characteristics of the readmission stay, including day readmitted, length of readmission, and charge for readmission, were compared among the diagnoses. Odds ratios were calculated using a multivariate logistic regression to determine the predictors of readmission. Results The readmission rate increased from 1.72% in 2004 to 2.16% in 2011. Readmitted patients were more likely to be publicly insured (54.3% vs 42.0%, P < .001), to be black (18.7% vs 13.5%, P < .001), to have comorbidities such as hypertension (15.3% vs 2.4%, P < 0.001) and diabetes (13.1% vs 6.8%, P < .001), and to have had a cesarean delivery (37.2% vs 32.9%, P < .001). The most common indications for readmission were infection (15.5%), hypertension (9.3%), and psychiatric illness (7.7%). Patients were readmitted, on average, 7 days after discharge, but readmission day varied by diagnosis: day 3 for hypertension, day 5 for infection, and day 9 for psychiatric disease. Maternal comorbidities were the strongest predictors of postpartum readmissions: psychiatric disease, substance use, seizure disorder, hypertension, and tobacco use. Conclusion Postpartum readmission rates have risen over the last 8 years. Understanding the risk factors, etiologies, and cause-specific timing for postpartum readmissions may aid in the development of new quality metrics in obstetrics and targeted strategies to curb the rising rate of postpartum readmissions in the United States.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a rare multi-system autoimmune disease, characterised by a pauci-immune necrotising small-vessel vasculitis, with a relapsing ...and remitting course. Like many autoimmune diseases, the exact aetiology of AAV, and the factors that influence relapse are unknown. Evidence suggests a complex interaction of polygenic genetic susceptibility, epigenetic influences and environmental triggers. This systematic mapping review focuses on the environmental risk factors associated with AAV. The aim was to identify gaps in the literature, thus informing further research.
Articles that examined any environmental risk factor in AAV disease activity (new onset disease or relapse) were included. Studies had to make explicit reference to AAV, which includes the 3 clinico-pathological phenotypes (GPA, MPA and EGPA), rather than isolated ANCA-positivity. All articles identified were English-language, full manuscripts involving adult humans (>16 years). There was no restriction on publication date and all study designs, except single case reports, were included. The systematic search was performed on 9th December 2019, using the following databases: EMBASE, Medline (Ovid), Cochrane Library, CINAHL and Web of Science.
The search yielded a total of 2375 articles. 307 duplicates were removed, resulting in the title and abstract of 2068 articles for screening. Of these, 1809 were excluded. Thus, 259 remained for full-text review, of which 181 were excluded. 78 articles were included in this review. The most notable findings support the role of various pollutants - primarily silica and other environmental antigens released during natural disasters and through farming. Assorted geoepidemiological triggers were also identified including seasonality and latitude-dependent factors such as UV radiation. Finally, infection was tightly associated, but the exact microorganism(s) is not clear - Staphylococcus aureus is the most presently convincing.
The precise aetiology of AAV has yet to be elucidated. It is likely that different triggers, and the degree to which they influence disease activity, vary by subgroup (e.g. ANCA subtype, geographic region). There is a need for more interoperable disease registries to facilitate international collaboration and hence large-scale epidemiological studies, with novel analytical techniques.
•The aetiology of AAV involves an interplay of environmental and epigenetic factors, in a genetically susceptible individual.•Environmental factors include: pollutants, geoepidemiological triggers and notable infections (e.g. Staphylococcus aureus).•Different triggers and the degree to which they influence disease activity likely vary by subgroup (e.g. ANCA subtype).•Validated exposure biomarkers and interoperable disease registries are critical to enable large-scale epidemiological studies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Molluscum contagiosum virus (MCV) is a human-adapted poxvirus that causes a common and persistent yet mild infection characterized by distinct, contagious, papular skin lesions. These lesions are ...notable for having little or no inflammation associated with them and can persist for long periods without an effective clearance response from the host. Like all poxviruses, MCV encodes potent immunosuppressive proteins that perturb innate immune pathways involved in virus sensing, the interferon response, and inflammation, which collectively orchestrate antiviral immunity and clearance, with several of these pathways converging at common signaling nodes. One such node is the regulator of canonical nuclear factor kappa B (NF-κB) activation, NF-κB essential modulator (NEMO). Here, we report that the MCV protein MC008 specifically inhibits NF-κB through its interaction with NEMO, disrupting its early ubiquitin-mediated activation and subsequent downstream signaling. MC008 is the third NEMO-targeting inhibitor to be described in MCV to date, with each inhibiting NEMO activation in distinct ways, highlighting strong selective pressure to evolve multiple ways of disabling this key signaling protein.
Inflammation lies at the heart of most human diseases. Understanding the pathways that drive this response is the key to new anti-inflammatory therapies. Viruses evolve to target inflammation; thus, understanding how they do this reveals how inflammation is controlled and, potentially, how to disable it when it drives disease. Molluscum contagiosum virus (MCV) has specifically evolved to infect humans and displays an unprecedented ability to suppress inflammation in our tissue. We have identified a novel inhibitor of human innate signaling from MCV, MC008, which targets NEMO, a core regulator of proinflammatory signaling. Furthermore, MC008 appears to inhibit early ubiquitination, thus interrupting later events in NEMO activation, thereby validating current models of IκB kinase (IKK) complex regulation.
Abstract
ANCA-associated vasculitis (AAV) is a severe systemic autoimmune disease. A key feature of AAV is the presence of Anti-Neutrophil Cytoplasmic Antibodies (ANCA) directed against ...myeloperoxidase (MPO) or proteinase-3 (PR3). ANCA are key to the pathogenesis of AAV, where they activate innate immune cells to drive inflammation. Pre-activation or ‘priming’ of immune cells appears to be important for complete cellular activation in AAV. The burgeoning field of immunometabolism has illuminated the governance of immune cell function by distinct metabolic pathways. There is ample evidence that the priming events synonymous with AAV alter immune cell metabolism. In this review we discuss the pathogenesis of AAV and its intersection with recent insights into immune cell metabolism.
Immunometabolism examines the links between immune cell function and metabolism. Dysregulation of immune cell metabolism is now an established feature of innate immune cell activation. Advances in ...liquid chromatography mass spectrometry (LC-MS) technologies have allowed discovery of unique insights into cellular metabolomics. Here we have studied and compared different sample preparation techniques and data normalisation methods described in the literature when applied to metabolomic profiling of human monocytes.
Primary monocytes stimulated with lipopolysaccharide (LPS) for four hours was used as a study model. Monocytes (n=24) were freshly isolated from whole blood and stimulated for four hours with lipopolysaccharide (LPS). A methanol-based extraction protocol was developed and metabolomic profiling carried out using a Hydrophilic Interaction Liquid Chromatography (HILIC) LC-MS method. Data analysis pipelines used both targeted and untargeted approaches, and over 40 different data normalisation techniques to account for technical and biological variation were examined. Cytokine levels in supernatants were measured by ELISA.
This method provided broad coverage of the monocyte metabolome. The most efficient and consistent normalisation method was measurement of residual protein in the metabolite fraction, which was further validated and optimised using a commercial kit. Alterations to the monocyte metabolome in response to LPS can be detected as early as four hours post stimulation. Broad and profound changes in monocyte metabolism were seen, in line with increased cytokine production. Elevated levels of amino acids and Krebs cycle metabolites were noted and decreases in aspartate and β-alanine are also reported for the first time. In the untargeted analysis, 154 metabolite entities were significantly altered compared to unstimulated cells. Pathway analysis revealed the most prominent changes occurred to (phospho-) inositol metabolism, glycolysis, and the pentose phosphate pathway.
These data report the emergent changes to monocyte metabolism in response to LPS, in line with reports from later time points. A number of these metabolites are reported to alter inflammatory gene expression, which may facilitate the increases in cytokine production. Further validation is needed to confirm the link between metabolic activation and upregulation of inflammatory responses.
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