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Atrial fibrillation (AF) is the most common significant cardiac rhythm disorder and is a powerful common risk factor for stroke. Randomized trials have demonstrated that anticoagulation can reduce the risk of stroke in patients with AF. Yet, there continues to be widespread underutilization of this therapy. To address this practice gap locally and improve efforts to reduce the risk of stroke for patients with AF in our health system, we have designed a study to implement and evaluate the effectiveness of an Atrial Fibrillation Decision Support Tool (AFDST) embedded within our electronic health record.Our intervention is provider-facing and focused on decision support. The clinical setting is ambulatory patients being seen by primary care physicians. Patients include those with both incident and prevalent AF. This randomized, prospective trial will enroll 800 patients in our University of Cincinnati Health System who are currently receiving less than optimal anticoagulation therapy as determined by the AFDST. Patients will be randomized to one of two arms - 1) usual care, in which the AFDST is available for use; 2) addition of a best practice advisory (BPA) to the AFDST notifying the clinician that their patient stands to gain a significant benefit from a change in their current thromboprophylactic therapy.The primary outcome is effectiveness of the BPA measured by change to "appropriate thromboprophylaxis" based on the AFDST recommendation at 3 months post randomization. Secondary endpoints include Reach and Adoption, from the RE-AIM framework for implementation studies. Sample size is based upon an improvement from inappropriate to appropriate anticoagulation therapy estimated at 4% in the usual care arm and ≥10% in the experimental arm.Our goal is to examine whether addition of a BPA to an AFDST focused on primary care physicians in an ambulatory care setting will improve "appropriate thromboprophylaxis" compared with usual care. Results will be examined at 3 months post randomization and at the end of the study to evaluate durability of changes. We expect to complete patient enrollment by the end of June 2022.Clinicaltrials.gov NCT04099485.

Objective In response to COVID-19, the informatics community united to aggregate as much clinical data as possible to characterize this new disease and reduce its impact through collaborative analytics. The National COVID Cohort Collaborative (N3C) is now the largest publicly available HIPAA limited dataset in US history with over 6.4 million patients and is a testament to a partnership of over 100 organizations. Materials and Methods We developed a pipeline for ingesting, harmonizing, and centralizing data from 56 contributing data partners using 4 federated Common Data Models. N3C data quality (DQ) review involves both automated and manual procedures. In the process, several DQ heuristics were discovered in our centralized context, both within the pipeline and during downstream project-based analysis. Feedback to the sites led to many local and centralized DQ improvements. Results Beyond well-recognized DQ findings, we discovered 15 heuristics relating to source Common Data Model conformance, demographics, COVID tests, conditions, encounters, measurements, observations, coding completeness, and fitness for use. Of 56 sites, 37 sites (66%) demonstrated issues through these heuristics. These 37 sites demonstrated improvement after receiving feedback. Discussion We encountered site-to-site differences in DQ which would have been challenging to discover using federated checks alone. We have demonstrated that centralized DQ benchmarking reveals unique opportunities for DQ improvement that will support improved research analytics locally and in aggregate. Conclusion By combining rapid, continual assessment of DQ with a large volume of multisite data, it is possible to support more nuanced scientific questions with the scale and rigor that they require.

The immunomodulatory property of some parasitic helminths is well documented. The glycoprotein ES-62 from the nematode, acanthocheilonema viteae has been found to possess immunomodulatory properties. Two small molecule analogues (SMA’s) of ES-62 (S3 and S5) were found to mimic its immunomodulatory properties in vivo and were active in animal models of allergic, inflammatory and autoimmune diseases. In this work, new efforts were made to further optimise the activities of compound S3 by making small but directed structural changes. A variety of analogues based on the S3 prototype were simulated by making variations at one position and then screened in silico. The best compounds were selected based on predicted physiochemical properties and medicinal chemistry indices and synthesised. Structural elucidation was done via HNMR, LCMS, FTIR and HRESIMS. The predicted properties were evaluated by HPLC method. A total of 11 novel molecules were synthesised and characterised. Significant correlation was obtained between the predicted physicochemical properties and their HPLC retention times (RT) for eight of our novel compounds. This suggests that these compounds may behave in a physiological environment as closely as computationally predicted. This entails, lesser host toxicity while maintaining good or better activities compared to the earlier prototype. They hence provide a good opportunity for development of drugs for immune conditions such as asthma, inflammation and autoimmune diseases.

The guanine nucleotide exchange factor cytohesin-2 (ARNO) is a major activator of the small GTPase ARF6, and has been shown to play an important role(s) in cell adhesion, migration and cytoskeleton reorganization in various cell types and models of disease. Interestingly, dysregulated cell migration, in tandem with hyper-inflammatory responses, is one of the hallmarks associated with activated synovial fibroblasts (SFs) during chronic inflammatory joint diseases, like rheumatoid arthritis. The role of ARNO in this process was unknown but we hypothesized that the pro-inflammatory milieu of inflamed joints induces local activation of ARNO-mediated pathways in SFs, promoting an invasive cell phenotype that ultimately leads to bone and cartilage damage. Thus, we used small interference RNA to investigate the impact of ARNO on the pathological migration and inflammatory responses of murine SFs, revealing a fully functional ARNO-ARF6 pathway in SFs, which can be rapidly activated by IL-1β. Such activation promotes cell migration and formation of focal adhesions. Unexpectedly, ARNO was also shown to modulate SF-inflammatory responses, dictating the precise cytokine and chemokine expression profile. Our results uncover a novel role for ARNO in SF-dependent inflammation, that potentially links pathogenic migration with initiation of local joint inflammation, offering new approaches for targeting the fibroblast compartment in chronic arthritis and joint disease.

This article describes a multifaceted approach to delivering results from current research in astrobiology to visitors at Pacific Science Center, along with the evaluated results of the impact of the work. Content was delivered by (1) training scientists to communicate effectively with the public, (2) providing the trained scientists with venues to engage with the public, and (3) creating two Science on Sphere shows that highlight key tenant scientists are investigating, a hands-on activity to facilitate interactive learning, and a temporary exhibit that highlights current research on the topic. Evaluation of visitors who engaged with each element demonstrates that the content had a large impact on both the increase in knowledge of the visitors and the increase of interest in the topic.

Aims ES‐62 is a well‐studied anti‐inflammatory molecule secreted by L4‐adult stage Acanthocheilonema viteae. We maintain the life cycle of A viteae using Meriones libycus as the definitive host. Here, we investigated whether the full life cycle could be maintained, and functional ES‐62 produced, in a related jird species—Meriones shawi. Methods and Results Adult worms were produced in comparable numbers in the two species, but very few microfilariae (MF) were observed in the M shawi bloodstream. M shawi ES‐62 produced ex vivo was functional and protective in a mouse model of arthritis. Myeloid‐derived cells from naïve and infected jirds of both species were compared with respect to ROS production and osteoclast generation, and some differences between the two species in both the absence and presence of infection were observed. Conclusions The life cycle of A viteae cannot be successfully completed in M shawi jirds but L3 stage worms develop to adulthood and produce functional ES‐62. Preliminary investigation into jird immune responses suggests that infection can differentially modulate myeloid responses in the two species. However, species‐specific reagents are required to understand the complex interplay between A viteae and its host and to explain the lack of circulating MF in infected M shawi jirds.

The parasitic worm product, ES-62 protects against collagen-induced arthritis, a mouse model of rheumatoid arthritis (RA) by suppressing the synovial fibroblast (SF) responses perpetuating inflammation and driving joint destruction. Such SF responses are shaped during disease progression by the inflammatory microenvironment of the joint that promotes remodelling of their epigenetic landscape, inducing an “aggressive” pathogenic SF phenotype. Critically, exposure to ES-62 in vivo induces a stably imprinted “safe” phenotype that exhibits responses more typical of healthy SFs. Surprisingly however, DNA methylome analysis reveals that rather than simply preventing the pathogenic rewiring of SFs, ES-62 induces further epigenetic remodelling, including targeting genes associated with ciliogenesis and differentiation, to program a distinct “protective” phenotype. Such unique behaviour signposts potential DNA methylation signatures predictive of pathogenesis and its resolution and hence, candidate mechanisms by which novel therapeutic interventions could prevent SFs from perpetuating joint inflammation and destruction in RA.

The five largest planets all have strong intrinsic magnetic fields that interact with their satellites, many of which contain electrically conducting materials on global scales. Conducting bodies exposed to time-varying magnetic fields induce secondary magnetic fields from movement of eddy currents. In the case of spherically symmetric conducting bodies, matching magnetic solutions at the boundary results in relatively simple relations between the excitation field and the induced field. In this work, we determine the more complicated induced magnetic field from a near-spherical conductor, where the outer boundary is expanded in spherical harmonics. Under the approximations that the excitation field is uniform at a single frequency, the product of wavenumber and radius for the body is large, and the average radius of the body is large compared to the perturbation from spherical symmetry, we find that each spherical harmonic in the shape expansion induces discrete magnetic moments that are independent from the other harmonics in the expansion. That is, simple superposition applies to the magnetic moments induced by each perturbation harmonic. We present a table of the magnetic moments induced by each spherical harmonic up to degree 2 in the perturbed shape. We also present a simple formula by which the induced magnetic field may be evaluated for any arbitrary shape described by expanding the radius of the conducting body in spherical harmonics. Unlike the Earth, many moons in the Solar System are tidally locked to their parent bodies, and many also contain saline, subsurface oceans. Conductive material in these moons is therefore expected to be non-spherical. Accounting for the boundary shape of Europa’s ocean will be critical for interpretation of Europa Clipper magnetic measurements near the moon, where the effects of quadrupole-and-higher magnetic moments will be most apparent. The results of this work permit magnetic studies considering non-spherical oceans of satellites for the first time.

Improvements in hygiene and health management have driven significant increases in human lifespan over the last 50 years. Frustratingly however, this extension of lifespan has not been matched by equivalent improvements in late-life health, not least due to the global pandemic in type-2 diabetes, obesity and cardiovascular disease, all ageing-associated conditions exacerbated and accelerated by widespread adoption of the high calorie Western diet (HCD). Recently, evidence has begun to emerge that parasitic worm infection might protect against such ageing-associated co-morbidities, as a serendipitous side-effect of their evolution of pro-survival, anti-inflammatory mechanisms. As a novel therapeutic strategy, we have therefore investigated the potential of ES-62, an anti-inflammatory secreted product of the filarial nematode Acanthocheilonema viteae, to improve healthspan (the period of life before diseases of ageing appear) by targeting the chronic inflammation that drives metabolic dysregulation underpinning ageing-induced ill-health. We administered ES-62 subcutaneously (at a dose of 1 μg/week) to C57BL/6J mice undergoing HCD-accelerated ageing throughout their lifespan, while subjecting the animals to analysis of 120 immunometabolic responses at various time-points. ES-62 improved a number of inflammatory parameters, but markedly, a range of pathophysiological, metabolic and microbiome parameters of ageing were also successfully targeted. Notably, ES-62-mediated promotion of healthspan in male and female HCD-mice was associated with different mechanisms and reflecting this, machine learning modelling identified sex-specific signatures predictive of ES-62 action against HCD-accelerated ageing. Remarkably, ES-62 substantially increased the median survival of male HCD-mice. This was not the case with female animals and unexpectedly, this difference between the two sexes could not be explained in terms of suppression of the chronic inflammation driving ageing, as ES-62 tended to be more effective in reducing this in female mice. Rather, the difference appeared to be associated with ES-62’s additional ability to preferentially promote a healthier gut-metabolic tissue axis in male animals., Author summary Infection with parasitic worms is increasingly considered to protect against chronic inflammatory disorders, including obesity, type-2 diabetes and cardiovascular disease. Although previously associated with old age, these ailments are ever more prevalent even in young people, due to the global adoption of the “Western” lifestyle and high calorie diet (HCD; high sugar and high fat). Rather than developing live worm therapies, our approach focuses on the potential of ES-62, a molecule secreted by the parasitic worm Acanthocheilonema viteae that we have previously shown to protect against inflammatory conditions like allergic asthma and arthritis in mice. We found that a small weekly dose of ES-62 promoted late-life wellbeing in HCD-fed mice of both sexes and substantially extended the life of obese male mice (by over 70 days; >10%). Machine learning modelling of its impact on the complex immunometabolic networks underpinning obesity showed that health-promoting effects of ES-62 could not simply be explained by its anti-inflammatory actions but encompassed protection against adipose, liver and gut pathology. The target signatures identified may thus represent a starting point for developing novel ES-62-based approaches to improving health during ageing and increasing lifespan in humans.

Appropriate thromboprophylaxis for patients with atrial fibrillation or atrial flutter (AF) remains a national challenge.We hypothesized that a shared decision-making interaction facilitated by an Atrial Fibrillation Shared Decision Making Tool (AFSDM) would improve patient knowledge about atrial fibrillation, and the risks and benefits of various treatment options for stroke prevention; increase satisfaction with the decision-making process; improve the therapeutic alliance between patient and the clinical care team; and increase medication adherence. Using a pre- and post-visit study design, we enrolled 76 patients and completed 2 office visits and 1-month telephone follow-up for 65 patients being seen in our Arrhythmia Clinic over the 1-year period (July 2016 through June 2017). Our primary outcome measure was change in decisional conflict between the first and second clinical visit.Decisional conflict decreased from an average of 31 to 9. Mean change was 22.3 (95% CI, 25.7 - 37.1), corresponding to an effect size of 0.94 standard deviations. Satisfaction with decision increased from 4.0 to 4.5, measures of therapeutic alliance with the care team (Kim Alliance scale) increased from 100.1 to 103.1, and satisfaction with provider increased from 4.2 to 4.5 (P.0001 for all measures). AF knowledge assessment scores increased from 8.4 to 9.1, and knowledge about personal stroke and bleeding risk increased from 1 to 1.5 (P.0001). Finally, medication adherence improved as reflected by an increase in the Morisky Medication Adherence scale from 5.9 to 6.4 (P.0001).A shared decision-making interaction, facilitated by an AFSDM can significantly improve multiple measures of decision-making quality, leading to improved medication adherence and patient satisfaction.

There has been increasing recognition that the alarming surge in allergy and autoimmunity in the industrialised and developing worlds shadows the rapid eradication of pathogens, such as parasitic helminths. Appreciation of this has fuelled an explosion in research investigating the therapeutic potential of these worms. This review considers the current state-of-play with a particular focus on exciting recent advances in the identification of potential novel targets for immunomodulation that can be exploited therapeutically. Furthermore, we contemplate the prospects for designing worm-derived immunotherapies for an ever-widening range of inflammatory diseases, including, for example, obesity, cardiovascular disease, and ageing as well as neurodevelopmental disorders like autism.

One of the most rapidly increasing human public health problems is obesity, whose sequelae like type-2 diabetes, represent continuously worsening, life-long conditions. Over the last 15 years, data have begun to emerge from human and more frequently, mouse studies, that support the idea that parasitic worm infection can protect against this condition. We have therefore investigated the potential of two synthetic small molecule analogues (SMAs) of the anti-inflammatory Acanthocheilonema viteae product ES-62, to protect against metabolic dysfunction in a C57BL/6 J mouse model of high calorie diet-induced obesity. We found weekly subcutaneous administration of the SMAs in combination (1 μg of each), starting one week before continuous exposure to high calorie diet (HCD), decreased fasting glucose levels and reversed the impaired glucose clearance observed in male mice, when measured at approximately 7 and 13 weeks after exposure to HCD. Fasting glucose levels were also-reduced in male mice fed a HCD for some 38 weeks when given SMA-treatment 13 weeks after the start of HCD, indicating an SMA-therapeutic potential. For the most part, protective effects were not observed in female mice. SMA treatment also conferred protection against each of reduced ileum villus length and liver fibrosis, but more prominently in female mice. Previous studies in mice indicate that protection against metabolic dysfunction is usually associated with polarisation of the immune system towards a type-2/anti-inflammatory direction but our attempts to correlate improved metabolic parameters with such changes were unsuccessful. Further analysis will therefore be required to define mechanism of action. Nevertheless, overall our data clearly show the potential of the drug-like SMAs as a preventative or treatment for metabolic dysregulation associated with obesity.

The recent extension of human lifespan has not been matched by equivalent improvements in late-life health due to the global pandemic in type-2 diabetes, obesity and cardiovascular disease, ageing-associated conditions exacerbated by widespread adoption of the high calorie Western diet (HCD). As a novel therapeutic strategy, we have investigated the potential of ES-62, an immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, to improve healthspan by targeting the chronic inflammation that drives metabolic dysregulation underpinning ageing-induced ill-health. We found that ES-62 improves a range of inflammatory but also pathophysiological, metabolic and microbiome parameters, when administered subcutaneously at only 1 µg/week throughout the lifespan of HCD-fed mice. Strikingly, ES-62 induced sex-specific healthspan signatures and indeed, it substantially increased the median survival of male, but not female, HCD-mice. Modelling of 113 responses contributing to these differential signatures by machine learning approaches now signposts candidate parameters key to promoting both healthspan and lifespan.

Background Appropriate thromboprophylaxis for patients with atrial fibrillation (AF) remains a national challenge. Methods We hypothesized that provision of decision support in the form of an Atrial Fibrillation Decision Support Tool (AFDST) would improve thromboprophylaxis for AF patients. We conducted a cluster randomized trial involving 15 primary care practices and 1,493 adults with nonvalvular AF in an integrated health care system between April 2014 and February 2015. Physicians in the intervention group received patient-level treatment recommendations made by the AFDST. Our primary outcome was the proportion of patients with antithrombotic therapy that was discordant from AFDST recommendation. Results Treatment was discordant in 42% of 801 patients in the intervention group. Physicians reviewed reports for 240 patients. Among these patients, thromboprophylaxis was discordant in 63%, decreasing to 59% 1 year later ( P = .02). In nonstratified analyses, changes in discordant care were not significantly different between the intervention group and control groups. In multivariate regression models, assignment to the intervention group resulted in a nonsignificant trend toward decreased discordance ( P = .29), and being a patient of a resident physician ( P = .02) and a higher HAS-BLED score predicted decreased discordance ( P = .03), whereas female gender ( P = .01) and a higher CHADSVASc score ( P = .10) predicted increased discordance. Conclusions Among patients whose physicians reviewed recommendations of the decision support tool discordant therapy decreased significantly over 1 year. However, in nonstratified analyses, the intervention did not result in significant improvements in discordant antithrombotic therapy.

Objectives To assess the appropriateness of oral anticoagulant therapy (OAT) in women and elderly adults, looking for patterns of undertreatment or unnecessary treatment. Design Retrospective cohort study. Setting Primary care practices of an academic healthcare system. Participants Adults (aged 28–93) with nonvalvular atrial fibrillation (AF) seen between March 2013 and February 2014 (N = 1,585). Measurements Treatment recommendations were made using an AF decision support tool (AFDST) based on projections of quality-adjusted life expectancy calculated using a decision analytical model that integrates individual-specific risk factors for stroke and hemorrhage. Results Treatment was discordant from AFDST-recommended treatment in 45% (326/725) of women and 39% (338/860) of men (P = .02). Although current treatment was discordant from recommended in 35% (89/258) of participants aged 85 and older and in 43% (575/1,328) of those younger than 85 (P = .01), many undertreated elderly adults were receiving aspirin as the sole antithrombotic agent. Conclusion Physicians should understand that female sex is a significant risk factor for AF-related stroke and incorporate this into decision-making about thromboprophylaxis. Treating older adults with aspirin instead of OAT exposes them to significant risk of bleeding with little to no reduction in AF-related stroke risk.

The human immune system has evolved in the context of our colonisation by bacteria, viruses, fungi and parasitic helminths. Reflecting this, the rapid eradication of pathogens appears to have resulted in reduced microbiome diversity and generation of chronically activated immune systems, presaging the recent rise of allergic, autoimmune and metabolic disorders. Certainly, gastrointestinal helminths can protect against gut and lung mucosa inflammatory conditions by modulating the microbiome and suppressing the chronic inflammation associated with dysbiosis. Here, we employ ES-62, an immunomodulator secreted by tissue-dwelling Acanthocheilonema viteae to show that modulation of the gut microbiome does not require live infection with gastrointestinal-based helminths nor is protection restricted to mucosal diseases. Specifically, subcutaneous administration of this defined parasitic worm product affords protection against joint disease in collagen-induced arthritis, a mouse model of rheumatoid arthritis, which is associated with normalisation of gut microbiota and prevention of loss of intestinal barrier integrity.

Parasitic worms are receiving much attention as a potential new therapeutic approach to treating autoimmune and allergic conditions but concerns remain regarding their safety. As an alternative strategy, we have focused on the use of defined parasitic worm products and recently taken this one step further by designing drug-like small molecule analogues of one such product, ES-62, which is anti-inflammatory by virtue of covalently attached phosphorylcholine moieties. Previously, we have shown that ES-62 mimics are efficacious in protecting against disease in mouse models of rheumatoid arthritis, systemic lupus erythematosus and skin and lung allergy. Given the potential role of chronic inflammation in fibrosis, in the present study we have focused our attention on lung fibrosis, a debilitating condition for which there is no cure and which in spite of treatment slowly gets worse over time. Two mouse models of fibrosis - bleomycin-induced and LPS-induced - in which roles for inflammation have been implicated were adopted. Four ES-62 analogues were tested - 11a and 12b, previously shown to be active in mouse models of allergic and autoimmune disease and 16b and AIK-29/62 both of which are structurally related to 11a. All four compounds were found to significantly reduce disease development in both fibrosis models, as shown by histopathological analysis of lung tissue, indicating their potential as treatments for this condition.

Highlights • Small molecule analogues (SMAs) of the immunomodulator, ES-62, have been produced. • Two SMAs protect against oxazolone-induced skin inflammation in mouse ears. • Protection is associated with reduced cellular infiltration and collagen deposition. • Protection is associated with decreased IFNγ mRNA in the ears., Graphical Abstract, ES-62 is the major secreted protein of the rodent filarial nematode Acanthocheilonema viteae. The molecule contains covalently attached phosphorylcholine (PC) residues, which confer anti-inflammatory properties on ES-62, underpinning the idea that drugs based on this active moiety may have therapeutic potential in human diseases associated with aberrant inflammation. Here we demonstrate that two synthetic small molecule analogues (SMAs) of ES-62 termed SMA 11a and SMA 12b are protective in the oxazolone-induced acute allergic contact dermatitis mouse model of skin inflammation, as measured by a significant reduction in ear inflammation following their administration before oxazolone sensitisation and before oxazolone challenge. Furthermore, it was found that when tested, 12b was effective at reducing ear swelling even when first administered before challenge. Histological analysis of the ears showed elevated cellular infiltration and collagen deposition in oxazolone-treated mice both of which were reduced by treatment with the two SMAs. Likewise, the oxazolone-induced increase in IFNγ mRNA in the ears was reduced but no effect on other cytokines investigated was observed. Finally, no influence on the mast cell populations in the ear was observed.

Rheumatoid arthritis (RA) remains a debilitating autoimmune condition as many patients are refractory to existing conventional and biologic therapies, and hence successful development of novel treatments remains a critical requirement. Towards this, we now describe a synthetic drug-like small molecule analogue, SMA-12b, of an immunomodulatory parasitic worm product, ES-62, which acts both prophylactically and therapeutically against collagen-induced arthritis (CIA) in mice. Mechanistic analysis revealed that SMA-12b modifies the expression of a number of inflammatory response genes, particularly those associated with the inflammasome in mouse bone marrow-derived macrophages and indeed IL-1β was the most down-regulated gene. Consistent with this, IL-1β was significantly reduced in the joints of mice with CIA treated with SMA-12b. SMA-12b also increased the expression of a number of genes associated with anti-oxidant responses that are controlled by the transcription factor NRF2 and critically, was unable to inhibit expression of IL-1β by macrophages derived from the bone marrow of NRF2−/− mice. Collectively, these data suggest that SMA-12b could provide the basis of an entirely novel approach to fulfilling the urgent need for new treatments for RA., Graphical abstract, Highlights • SMA-12b is a mimetic of the active PC-moiety of the helminth immunomodulator, ES-62. • SMA-12b effectively protects mice against collagen-induced arthritis (CIA). • SMA-12b downregulates IL-1β and inflammasome genes via activation of NRF2. • SMA-12b reduces IL-1β in the joints of mice with CIA.

Evidence from human studies suggests that parasitic worm infection can protect humans against rheumatoid arthritis (RA) and this idea is strengthened by data generated in model systems. Although therapeutic use of parasitic worms is currently being explored, there are obvious benefits in pursuing drug development through identification and isolation of the ‘active ingredients’. ES-62 is a secreted glycoprotein of the filarial nematode Acanthocheilonema viteae, which we have found to protect against the development of collagen-induced arthritis (CIA) in mice. ES-62 activity is dependent on the inflammatory phenotype of the local environment and protection arises via inhibition of Th17- and γδT cell-dependent IL-17 production. At the same time, NK and NK T cell IL-17 production is left intact, and such selectivity suggests that ES-62 might make a particularly attractive therapeutic for RA. However, as a potentially immunogenic protein, ES-62 is unsuitable for development as a drug. Nevertheless, ES-62 activity is dependent on covalently attached phosphorylcholine (PC) residues and we have therefore produced a library of PC-based drug-like ES-62 small-molecule analogues (SMAs) as an alternative therapeutic strategy. Screening this library, we have found an ES-62 SMA that mirrors ES-62 in protecting against CIA and by the same IL-17-dependent mechanism of action.

ES-62 is an anti-inflammatory phosphorylcholine-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae. Accelerated atherosclerosis frequently occurs in systemic lupus erythematosus, resulting in substantial cardiovascular morbidity and mortality. We examined the effects of ES-62 in the gld.apoE(-/-) mouse model of this condition. Treatment with ES-62 did not substantially modulate renal pathology but caused decreased anti-nuclear autoantibody levels. Moreover, a striking 60% reduction in aortic atherosclerotic lesions was observed, with an associated decrease in macrophages and fibrosis. We believe that these latter findings constitute the first example of a defined parasitic worm product with therapeutic potential in atherosclerosis: ES-62-based drugs may represent a novel approach to control accelerated atherosclerosis in systemic lupus erythematosus.

ES-62 is a secreted parasitic worm-derived immunomodulator that exhibits therapeutic potential in allergy by downregulating aberrant MyD88 signalling to normalise the inflammatory phenotype and mast cell responses. IL-33 plays an important role in driving mast cell responses and promoting type-2 allergic inflammation, particularly with respect to asthma, via MyD88-integrated crosstalk amongst the IL-33 receptor (ST2), TLR4 and FcεRI. We have now investigated whether ES-62 targets this pathogenic network by subverting ST2-signalling, specifically by characterising how the functional outcomes of crosstalk amongst ST2, TLR4 and FcεRI are modulated by the worm product in wild type and ST2-deficient mast cells. This analysis showed that whilst ES-62 inhibits IL-33/ST2 signalling, the precise functional modulation observed varies with receptor usage and/or mast cell phenotype. Thus, whilst ES-62’s harnessing of the capacity of ST2 to sequester MyD88 appears sufficient to mediate its inhibitory effects in peritoneal-derived serosal mast cells, downregulation of MyD88 expression appears to be required to dampen the higher levels of cytokine production typically released by bone marrow-derived mucosal mast cells.

The immunomodulatory actions of parasitic helminth excretory-secretory (ES) products that serendipitously protect against development of chronic inflammatory disorders are well established: however, knowledge of the interaction between ES products and the host musculoskeletal system in such diseases is limited. In this study, we have focused on ES-62, a glycoprotein secreted by the rodent filarial nematode Acanthocheilonema viteae that is immunomodulatory by virtue of covalently attached phosphorylcholine (PC) moieties, and also two synthetic drug-like PC-based small molecule analogues (SMAs) that mimic ES-62’s immunomodulatory activity. We have previously shown that each of these molecules prevents development of pathology in collagen-induced arthritis (CIA), a model of the musculoskeletal disease rheumatoid arthritis (RA) and reflecting this, we now report that ES-62 and its SMAs, modify bone remodeling by altering bone marrow progenitors and thus impacting on osteoclastogenesis. Consistent with this, we find that these molecules inhibit functional osteoclast differentiation in vitro. Furthermore, this appears to be achieved by induction of anti-oxidant response gene expression, thereby resulting in reduction of the reactive oxygen species production that is necessary for the increased osteoclastogenesis witnessed in musculoskeletal diseases like RA.

Background Appropriate thromboprophylaxis for patients with atrial fibrillation or atrial flutter (AF) remains a national challenge. The recent availability of direct oral anticoagulants (DOACs) with comparable efficacy and improved safety compared with warfarin alters the balance between risk factors for stroke and benefit of anticoagulation. Our objective was to examine the impact of DOACs as an alternative to warfarin on the net benefit of oral anticoagulant therapy (OAT) in a real-world population of AF patients. Methods This is a retrospective cohort study of patients with paroxysmal or persistent nonvalvular AF. We updated an A trial F ibrillation D ecision S upport T ool (AFDST) to include DOACs as treatment options. The tool generates patient-specific recommendations based upon individual patient risk factor profiles for stroke and major bleeding using quality-adjusted life-years (QALYs) calculated for each treatment strategy by a decision analytic model. The setting included inpatient and ambulatory sites in an academic health center in the midwestern United States. The study involved 5,121 adults with nonvalvular AF seen for any ambulatory visit or inpatient hospitalization over the 1-year period (January through December 2016). Outcome measure was net clinical benefit in QALYs. Results When DOACs are a therapeutic option, the AFDST recommends OAT for 4,134 (81%) patients and no antithrombotic therapy or aspirin for 489 (9%). A strong recommendation for OAT could not be made in 498 (10%) patients. When warfarin is the only option, OAT is recommended for 3,228 (63%) patients and no antithrombotic therapy or aspirin for 973 (19%). A strong recommendation for OAT could not be made in 920 (18%) patients. In total, 1,508 QALYs could be gained if treatment were changed to that recommended by the AFDST. Conclusions Availability of DOACs increases the proportion of patients for whom oral anticoagulation therapy is recommended in a real-world cohort of AF patients and increased projected QALYs by more than 1,500 when all patients are receiving thromboprophylaxis as recommended by the AFDST compared with current treatment.

Apicomplexan parasites are responsible for a number of important human pathologies. Obviously, as Eukaryotes they share a number of cellular features and pathways with their respective host cells. One of them is autophagy, a process involved in the degradation of the cell's own components. These intracellular parasites nonetheless seem to present a number of original features compared to their very evolutionarily distant host cells. In mammals and other metazoans, autophagy has been identified as an important contributor to the defence against microbial pathogens. Thus, host autophagy also likely plays a key role in the control of apicomplexan parasites, although its potential manipulation and subversion by intracellular parasites creates a complex interplay in the regulation of host and parasite autophagy. In this mini-review, we summarise current knowledge on autophagy in both parasites and their host cells, in the context of infection by three Apicomplexa: Plasmodium, Toxoplasma, and Theileria. [Abstract copyright: Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.]

Background— Guidelines for anticoagulant therapy in patients with atrial fibrillation are based on stroke risk as calculated by either the CHADS 2 or the CHA 2 DS 2 VASc scores and do not integrate bleeding risk in an explicit, quantitative manner. Our objective was to quantify the net clinical benefit resulting from improved decision making about antithrombotic therapy. Methods and Results— This study is a retrospective cohort study of 1876 adults with nonvalvular atrial fibrillation or flutter seen in primary care settings of an integrated healthcare delivery system between December 2012 and January 2014. Projections for quality-adjusted life expectancy reported as quality-adjusted life-years were calculated by a decision analytic model that integrates patient-specific risk factors for stroke and hemorrhage and examines strategies of no antithrombotic therapy, aspirin, or oral anticoagulation with warfarin. Net clinical benefit was defined by the gain or loss in quality-adjusted life expectancy between current treatment and treatment recommended by an Atrial Fibrillation Decision Support Tool. Current treatment was discordant from treatment recommended by the Atrial Fibrillation Decision Support Tool in 931 patients. A clinically significant gain in quality-adjusted life expectancy (defined as ≥0.1 quality-adjusted life-years) was projected in 832 patients. Subgroups were examined. For example, oral anticoagulant therapy was recommended for 188 who currently were receiving no antithrombotic therapy. For the entire cohort, a total of 736 quality-adjusted life-years could be gained were treatment changed to that recommended by the Atrial Fibrillation Decision Support Tool. Conclusions— Use of a decision support tool that integrates patient-specific stroke and bleeding risk could result in significant gains in quality-adjusted life expectancy for a primary care population of patients with atrial fibrillation.