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ABSTRACTObjective Direct oral anticoagulants (DOACs) are first-line therapy for stroke prevention for 1.4 million atrial fibrillation (AF) patients in the UK. However, the rates of DOAC dosing below evidence-based recommendations are estimated between 9% and 22%. This study explores specific patient and physician factors associated with prescribing inappropriate DOAC underdoses.Methods DOAC-prescribing physicians within the UK completed both a clinical vignette survey, which contained 12 hypothetical patient profiles designed to replicate DOAC prescribing scenarios, and a physician survey to capture sociodemographic, clinical experience, and prescriber-related beliefs and motivations related to DOAC prescribing. Eight patient factors based on a literature search and an expert consultation process were varied within the vignettes. Associations between the prescribers’ dosing choices and patient factors were explored via multilevel logistic regression. The analysis is focused on the most frequently selected DOACs, apixaban and rivaroxaban, both of which have different dosing guidelines.Results In all, 336 prescribers (69% male; 233/336) completed the survey, mostly general physicians (GPs) (45%) or cardiology specialists (36%) with a mean of 17.9 years’ experience. Most prescribers (73%; 244/336) inappropriately underdosed at least once; rates between GPs and specialists were nearly identical. Patient factors most strongly associated with apixaban inappropriate underdosing included a history of major bleeding and falls. For rivaroxaban, these were major bleeding and severe frailty. Only 32% (106/335) of prescribers reported DOAC dosing guidelines as the sole influence on their prescribing behaviour. Among prescribers who did not inappropriately underdose, greater prescribing confidence was aligned to increased perception of inappropriate underdose risk.Conclusions Overall, patient factors such as major bleeding and severe frailty were found to be associated with inappropriate underdosing of apixaban and rivaroxaban. Furthermore, prescribers who were more confident in DOAC prescribing, and were more worried about the risk of stroke, were significantly less likely to inappropriately underdose. These findings suggest that all prescribers, regardless of speciality, may benefit from education and training to raise awareness of the risks associated with inappropriate DOAC underdosing.

Abstract Background Black and minority ethnic women and those with social risk factors such as deprivation, refugee and asylum seeker status, homelessness, mental health issues and domestic violence are at a disproportionate risk of poor birth outcomes. Language barriers further exacerbate this risk, with women struggling to access, engage with maternity services and communicate concerns to healthcare professionals. To address the language barrier, many UK maternity services offer telephone interpreter services. This study explores whether or not women with social risk factors find these interpreter services acceptable, accessible and safe, and to suggest solutions to address challenges. Methods Realist methodology was used to refine previously constructed programme theories about how women with language barriers access and experience interpreter services during their maternity care. Twenty-one longitudinal interviews were undertaken during pregnancy and the postnatal period with eight non-English speaking women and their family members. Interviews were analysed using thematic framework analysis to confirm, refute or refine the programme theories and identify specific contexts, mechanisms and outcomes relating to interpreter services. Results Women with language barriers described difficulties accessing maternity services, a lack of choice of interpreter, suspicion around the level of confidentiality interpreter services provide, and questioned how well professional interpreters were able to interpret what they were trying to relay to the healthcare professional during appointments. This resulted in many women preferring to use a known and trusted family member or friend to interpret for them where possible. Their insights provide detailed insight into how poor-quality interpreter services impact on their ability to disclose risk factors and communicate concerns effectively with their healthcare providers. A refined programme theory puts forward mechanisms to improve their experiences and safety such as regulated, high-quality interpreter services throughout their maternity care, in which women have choice, trust and confidence. Conclusions The findings of this study contribute to concerns highlighted in previous literature around interpreter services in the wider healthcare arena, particularly around the lack of regulation and access to high-quality interpretation. This is thought to have a significant effect on pregnant women who are living socially complex lives as they are not able to communicate their concerns and access support. This not only impacts on their safety and pregnancy outcomes, but also their wider holistic needs. The refined program theory developed in this study offers insights into the mechanisms of equitable access to appropriate interpreter services for pregnant women with language barriers.

The innate immune response to viruses is critical for the correct establishment of protective adaptive immunity. Amongst the many pathways involved, the NLRP3 [nucleotide-binding oligomerisation domain (NOD)-like receptor protein 3 (NLRP3)] inflammasome has received considerable attention, particularly in the context of immunity and pathogenesis during infection with influenza A (IAV) and SARS-CoV-2, the causative agent of COVID-19. Activation of the NLRP3 inflammasome results in the secretion of the proinflammatory cytokines IL-1β and IL-18, commonly coupled with pyroptotic cell death. While this mechanism is protective and key to host defense, aberrant NLRP3 inflammasome activation causes a hyperinflammatory response and excessive release of cytokines, both locally and systemically. Here, we discuss key molecules in the NLRP3 pathway that have also been shown to have significant roles in innate and adaptive immunity to viruses, including DEAD box helicase X-linked (DDX3X), vimentin and macrophage migration inhibitory factor (MIF). We also discuss the clinical opportunities to suppress NLRP3-mediated inflammation and reduce disease severity.

Abstract The Bulletin of the International Seismological Centre (ISC) remains in demand for a wide range of geophysical studies. Users of the ISC Bulletin benefit from its long-term coverage, the most comprehensive set of measurements from the majority of permanent seismic stations and networks, and homogeneity of included parameters of earthquakes and other seismic events worldwide. Despite a reasonably conservative approach in preserving the operational procedures, changes are inevitable in order to achieve the best possible accuracy of published earthquake parameters. The last fundamental change in procedures has fully affected the data for years 2011 and beyond (Bondár and Storchak in Geophys J Int 186: 1220-1244, 2011). This is why it was decided to rebuild the earlier part (1964–2010) of the ISC Bulletin to achieve compatibility in earthquake hypocentres and magnitudes through its entire period. The first article on this project (Storchak et al. in Geosci Lett 4: 32, 2017) covered the period from 1964 to 1979, as it was publicly released. This article covers the remaining period from 1980 to 2010 with all seismic events re-processed and re-located in line with the modern ISC procedures, with ~ 489,000 new events, ~ 2600 new stations, ~15.5 million new seismic arrivals, and more robust and reliable mb and MS magnitude evaluations. We give statistics of departures in epicentre location and depth between the original and rebuilt ISC hypocentres. We also provide a summary for the entire rebuilt period (1964–2010). We give a brief account of events deleted from and added to the Bulletin, based on additional reports from permanent and temporary seismic deployments. We explain that newly re-computed (rebuilt) mb is on average larger that the original mb by 0.05 unit of magnitude. The rebuilt MS is only 0.01 unit larger that its predecessor. We announce that the entire reviewed part of the ISC Bulletin (1964–2017) is now based on the same velocity model, ak135, and the same earthquake location and magnitude computation procedures. Finally, we provide advice on how to obtain the original ISC Bulletin data, where necessary.

A hallmark of Listeria (L.) monocytogenes pathogenesis is bacterial escape from maturing entry vacuoles, which is required for rapid bacterial replication in the host cell cytoplasm and cell-to-cell spread. The bacterial transcriptional activator PrfA controls expression of key virulence factors that enable exploitation of this intracellular niche. The transcriptional activity of PrfA within infected host cells is controlled by allosteric coactivation. Inhibitory occupation of the coactivator site has been shown to impair PrfA functions, but consequences of PrfA inhibition for L. monocytogenes infection and pathogenesis are unknown. Here we report the crystal structure of PrfA with a small molecule inhibitor occupying the coactivator site at 2.0 Å resolution. Using molecular imaging and infection studies in macrophages, we demonstrate that PrfA inhibition prevents the vacuolar escape of L. monocytogenes and enables extensive bacterial replication inside spacious vacuoles. In contrast to previously described spacious Listeria-containing vacuoles, which have been implicated in supporting chronic infection, PrfA inhibition facilitated progressive clearance of intracellular L. monocytogenes from spacious vacuoles through lysosomal degradation. Thus, inhibitory occupation of the PrfA coactivator site facilitates formation of a transient intravacuolar L. monocytogenes replication niche that licenses macrophages to effectively eliminate intracellular bacteria. Our findings encourage further exploration of PrfA as a potential target for antimicrobials and highlight that intra-vacuolar residence of L. monocytogenes in macrophages is not inevitably tied to bacterial persistence. Author summary Listeria monocytogenes is a bacterial pathogen that causes severe, often fatal disease in vulnerable individuals. Listeria monocytogenes infects host cells, where it needs to escape from its entry vacuole to replicate inside the host cell cytoplasm and spread to neighboring cells. Inability of Listeria to escape from vacuoles has been associated with long-term bacterial survival inside infected immune cells and chronic infection. We discovered that inhibition of the master regulator of the bacterial factors that orchestrate the intracellular lifestyle of Listeria monocytogenes traps the bacteria inside their entry vacuoles and facilitates extensive bacterial replication in spacious vacuoles. Yet, the majority of infected host immune cells survive the infection and ultimately clear the bacteria. Thus, our data demonstrate that intra-vacuolar existence of Listeria monocytogenes in immune cells is not inevitably tied to bacterial persistence and chronic infection. We provide high resolution structural insights into how an effective inhibitory molecule interacts with the master regulator of Listeria virulence, which may be exploited for rational drug design.

Abstract Background To examine whether Borderline Intellectual Functioning (BIF) and Adverse Childhood Experiences independently predict adult psychiatric morbidity. Methods We performed a secondary analysis of longitudinal data derived from the 1970 British Birth Cohort Study to examine whether BIF and Adverse Childhood Experiences independently predict adult mental distress as measured by the Malaise Inventory. Factor analysis was used to derive a proxy measure of IQ from cognitive testing at age 10 or 5. Variables that could be indicators of exposure to Adverse Childhood Experiences were identified and grouped into health related and socio-economic related adversity. Results Children with BIF were significantly more likely than their peers to have been exposed to Adverse Childhood Experiences (BIF mean 5.90, non-BIF mean 3.19; Mann-Whitney z = 31.74, p

Glucocorticoid-induced leucine zipper (GILZ) mimics many of the anti-inflammatory effects of glucocorticoids, suggesting it as a point of therapeutic intervention that could bypass GC adverse effects. We previously reported that GILZ down-regulation is a feature of human SLE, and loss of GILZ permits the development of autoantibodies and lupus-like autoimmunity in mice. To further query the contribution of GILZ to protection against autoimmune inflammation, we studied the development of the lupus phenotype in Lyn-deficient (Lyn-/-) mice in which GILZ expression was genetically ablated. In Lyn-/- mice, splenomegaly, glomerulonephritis, anti-dsDNA antibody titres and cytokine expression were exacerbated by GILZ deficiency, while other autoantibody titres and glomerular immune complex deposition were unaffected. Likewise, in patients with SLE, GILZ was inversely correlated with IL23A, and in SLE patients not taking glucocorticoids, GILZ was also inversely correlated with BAFF and IL18. This suggests that at the onset of autoimmunity, GILZ protects against tissue injury by modulating pro-inflammatory pathways, downstream of antibodies, to regulate the cycle of inflammation in SLE.

BackgroundSocial factors associated with poor childbirth outcomes and experiences of maternity care include minority ethnicity, poverty, young motherhood, homelessness, difficulty speaking or understanding English, migrant or refugee status, domestic violence, mental illness and substance abuse. It is not known what specific aspects of maternity care work to improve the maternal and neonatal outcomes for these under-served, complex populations.MethodsThis study aimed to compare maternal and neonatal clinical birth outcomes for women with social risk factors accessing different models of maternity care. Quantitative data on pregnancy and birth outcome measures for 1000 women accessing standard care, group practice and specialist models of care at two large, inner-city maternity services were prospectively collected and analysed using multinominal regression. The level of continuity of care and place of antenatal care were used as independent variables to explore these potentially influential aspects of care. Outcomes adjusted for women's social and medical risk factors and the service attended.ResultsWomen who received standard maternity care were significantly less likely to use water for pain relief in labour (RR 0.11, CI 0.02-0.62) and have skin to skin contact with their baby shortly after birth (RR 0.34, CI 0.14-0.80) compared to the specialist model of care. Antenatal care based in the hospital setting was associated with a significant increase in preterm birth (RR 2.38, CI 1.32-4.27) and low birth weight (RR 2.31, CI 1.24-4.32), and a decrease in induction of labour (RR 0.65, CI 0.45-0.95) compared to community-based antenatal care, this was despite women's medical risk factors. A subgroup analysis found that preterm birth was increased further for women with the highest level of social risk accessing hospital-based antenatal care (RR 3.11, CI1.49-6.50), demonstrating the protective nature of community-based antenatal care.ConclusionsThis research highlights how community-based antenatal care, with a focus on continuity of carer reduced health inequalities and improved maternal and neonatal clinical outcomes for women with social risk factors. The findings support the current policy drive to increase continuity of midwife-led care, whilst adding that community-based care may further improve outcomes for women at increased risk of health inequalities. The relationship between community-based models of care and neonatal outcomes require further testing in future research. The identification of specific mechanisms such as help-seeking and reduced anxiety, to explain these findings are explored in a wider evaluation.

Objective Fas/Fas ligand (FasL) and B cell-activating factor (BAFF) signalling have pivotal roles in SLE pathogenesis. We investigated the clinical associations of serum concentrations of soluble Fas (sFas) and soluble FasL (sFasL) in SLE and their relationship with BAFF.Methods Serum sFas and sFasL were quantified by multiplex assay, and BAFF by ELISA, in 118 patients with SLE and 17 healthy controls (HC). SLE disease activity and organ damage were assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics Damage Index.Results sFas, sFasL and BAFF were detectable in all samples. Serum sFas and sFasL were significantly higher in SLE compared with HC. In univariable regression analyses, patients with active renal disease and those with flare had significantly higher levels of sFas compared with those without. High serum BAFF in patients with SLE was associated with increased sFas but not sFasL. The association between sFas and renal disease remained significant after adjusting for BAFF, but the association with flare attenuated. High sFas levels were associated with increased time-adjusted mean SLEDAI-2K, even after adjusting for BAFF, and with higher odds of flare over time. In contrast, high sFasL was associated with reduced organ damage over time. Serum sFasL/sFas ratio was negatively associated with active overall disease, flare and organ damage.Conclusions Serum sFas is associated with active renal SLE, and active disease and flare over time, while sFasL/sFas ratio is negatively associated with disease activity and organ damage accrual. Treatments correcting abnormal levels of sFas/FasL may be worthy of evaluation in SLE.

I argue that one of John Locke's intentions in writing Two Treatises of Government was to turn the tables on Sir Robert Filmer and his followers when it came to the question of practical consequences of writing and publishing political philosophy. According to Locke, it was Filmer's thesis of natural subjection that had seditious ramifications. The doctrine of natural liberty and equality, by contrast, was no threat to the peace and order of a well-governed state. I show first that Locke is correct in his claim that in Patriarcha Filmer is, by his own admission and according to the logic of his own argument, a theorist of de factopolitical power. This meant, according to Locke, that Filmer has no account of the moral basis of allegiance. To that extent, Filmer has no case to make against the usurper. On other hand, I then argue, there is evidence in the Second Treatise that Locke was attuned to the worries that Filmer raises about the consequences of the thesis of natural liberty. Locke sought, in a number of ways, to contain the potentially destabilizing implications of his own conclusions. In conclusion I make a tentative suggestion as to how this concern with the practical consequences of flawed political theory might explain Locke's decision to publish both of the two Treatises in 1689.

Abstract Background Type 2 diabetes is characterised by abnormal glucose metabolism, and treatment is aimed at normalising glycaemia. Outcomes measured in clinical trials should be meaningful to patients, health care professionals and researchers, yet there is heterogeneity in the outcomes used across trials of glucose-lowering interventions. This inconsistency affects the ability to compare findings and may mean that the results have little importance to health care professionals and the patients for whom they care. The SCORE-IT study aims to develop a core outcome set (COS) for use in all trials of glucose-lowering interventions for people with type 2 diabetes. Methods/design This study will involve three key stages in the development of a COS: (1) A list of outcomes will be identified from multiple sources, specifically registered clinical trials, online patient resources, the qualitative literature and landmark studies identified by a Study Steering Committee. (2) The list of outcomes will be scored by multiple stakeholder groups in a two-round online international Delphi survey. (3) The results of the online Delphi will be summarised and discussed at a face-to-face consensus meeting with representation from all stakeholder groups. Discussion The SCORE-IT study aims to develop an internationally relevant set of core outcomes for use in future trials of glucose-lowering interventions for type 2 diabetes. The use of a COS will improve the consistency of outcomes, allowing results of studies to be compared and combined and for new effective treatments to made available more quickly. Trial registration The COS study, of which this is a part, is registered in the Core Outcome Measures in Effectiveness Trials (COMET) database, http://www.comet-initiative.org/studies/details/956. Registered January 2017.

MIF is a cytokine best known for its modulatory effect on expression of proinflammatory cytokines. Here the authors show that MIF facilitates the NLRP3–vimentin interaction, resulting in Nlrp3 inflammasome activation.

Abstract The data from the Bulletin of the International Seismological Centre (ISC) have always been and still remain in demand for a wide range of studies in Geosciences. The unique features of the Bulletin include long-term coverage (1904-present), the most comprehensive set of included seismic data from the majority of permanent seismic networks at any given time in the history of instrumental recording (currently ~ 150) and homogeneity of the data and their representation. In order to preserve this homogeneity, the ISC has followed its own standard seismic event processing procedures that have not substantially changed until the early 2000s. Several considerable and necessary advancements in the ISC data collection and seismic event location procedures have created a need to rebuild the data for preceding years in line with the new procedures. Thus was set up a project to rebuild the ISC Bulletin for the period from the beginning of the ISC data till the end of data year 2010. The project is known as the Rebuild of the ISC Bulletin. From data month of January 2011, the ISC data have already been processed with the fully tested and established new procedures and do not require an alteration. It was inconceivable even to think about such a project for many tens of years, but great advances in computer power and increased support by the ISC Member-Institutions and Sponsors have given us a chance to perform this project. Having obtained a lot of experience on the way, we believe that within a few years the entire period of the ISC data will be reprocessed and extended for the entire period of instrumental seismological recordings from 1904 till present. The purpose of this article is to describe the work on reprocessing the ISC Bulletin data under the Rebuild project. We also announce the release of the rebuilt ISC Bulletin for the period 1964–1979 with all seismic events reprocessed and relocated in line with the modern ISC procedures, ~ 68,000 new events, 255 new stations, ~ 815,000 new seismic phases, more robust and reliable mb and M S magnitude evaluations and the addition of ~ 2700 new M S magnitudes.

Autophagy is a homeostatic and inducible process affecting multiple aspects of the immune system. This intrinsic cellular process is involved in MHC-antigen (Ag) presentation, inflammatory signaling, cytokine regulation, and cellular metabolism. In the context of T cell responses, autophagy has an influential hand in dictating responses to self and non-self by controlling extrinsic factors (e.g., MHC-Ag, cytokine production) in antigen-presenting cells (APC) and intrinsic factors (e.g., cell signaling, survival, cytokine production, and metabolism) in T cells. These attributes make autophagy an attractive therapeutic target to modulate T cell responses. In this review, we examine the impact autophagy has on T cell responses by modulating multiple aspects of APC function; the importance of autophagy in the activation, differentiation and homeostasis of T cells; and discuss how the modulation of autophagy could influence T cell responses.

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease characterized by biological and clinical heterogeneity. The interleukin (IL)-1 superfamily is a group of innate cytokines that contribute to pathogenesis in many autoimmune diseases. IL-1β and IL-18 are two members that have been shown to play a role in murine lupus-like models, but their role in human SLE remains poorly understood. Here, IL-1β and IL-18 were quantified by enzyme-linked immunosorbent assay in the serum of healthy controls (HCs) and SLE patients from a prospectively followed cohort. Disease activity and organ damage were assessed using SLE disease activity index 2000 (SLEDAI-2K) and SLE damage index scores (SDI), respectively. 184 SLE patients (mean age 44.9 years, 91% female, 56% double-stranded deoxyribonucleic acid positive) were compared to 52 HC. SLE patients had median [IQR] SLEDAI-2K of 4 [2,6], and SDI of 1 [0–2]. Serum IL-18 levels were statistically significantly higher in SLE patients compared to HCs. Univariable linear regression analyses showed that patients with active renal disease or irreversible organ damage had statistically significantly elevated serum IL-18 levels. The association between serum IL-18 and active renal disease was confirmed in multivariable analysis after adjusting for ethnicity and organ damage. High baseline serum IL-18 levels were associated with organ damage at the subsequent visit. Serum IL-1β levels were not significantly elevated in SLE patients when compared to HCs and had no association with overall or organ-specific disease activity or organ damage in cross-sectional and longitudinal analyses. Our data suggest that serum IL-18 and IL-1β have different clinical implications in SLE, with IL-18 being potentially associated with active renal disease.

This article covers Spanish and Catalan clitic pronouns according to the fundamental theoretical principles of Distributed Morphology. The author postulates that the syntax-phonology mapping of clitics consists of two sub­mappings, the first from syntax to morphology and the second from morphology to phonology. In this second mapping, the clitics may suffer the effect of various morphological rules, specifically, the structural operations of Impoverishment, Adjunction, Fusion and Fission. The author proves that the complex and quirky behaviour of clitics and clitic clusters in Spanish and Barceloní can be easily explained by taking into account that these four operations act on the clitics' syntactical terminals in a morphological component which is intermediate between phonology and syntax.

В 1917 г. большевики обещали освобождение трудящихся масс от эксплуатации. Но в течение 20 лет они установили режим гораздо более эксплуататорский и репрессивный по своей сути, чем побежденный ими царизм. Автор утверждает, что спустя более четверти века после открытия архивов мы все еще остаемся в неведении по поводу того, почему так случилось. Историки склонны рассматривать этот исход как запрограммированный либо преднамеренно спланированный, поскольку большевики были авторитарны по своей природе, или же Сталин «оседлал» революцию и установил личную диктатуру, удовлетворяя жажду власти. До сих пор нет ясности в понимании того, в какой степени положительная программа освобождения народа продолжала мотивировать большевистское руководство в межвоенный период. Большевики недооценили препятствия на пути создания общественного порядка, основанного на согласованном политическом участии. Существенный прогресс был достигнут на пути ликвидации неграмотности, но значительно труднее было создать функционирующий государственный аппарат, бороться и выиграть Гражданскую войну, а также восстановить разрушенную экономику. Падение либеральных («буржуазных») демократий в Европе укрепляло ощущение превосходства «переходной» пролетарской диктатуры. Борьба за власть после смерти Ленина направила местные партийные организации на борьбу с внутрипартийной демократией. Возрождать ее в условиях коллективизации и ускоренной индустриализации казалось неуместным. Гораздо более важным представлялось выживание революции и стремление догнать передовые капиталистические страны. Автор отмечает, что если относиться к проявлениям политического насилия и диктатуре как к конечной цели советской власти, невозможно должным образом понять судьбу революции.

Previous research suggests that computer security counter­measures are effective in preventing computer abuse in organizations. However, the computer abuse problem still persists despite such measures. This study examines the sociological perspective of Internet abuse that explains a causal link between abusive behavior and an actor’s psychological state, drawn on theory of pluralistic ignorance (TPI). Pluralistic ignorance is a form of erroneous social interference that is both an immediate cause and a consequence of literal inconsistency between private attitudes and public behavior. Under pluralistic ignorance, mistakenly perceived social norms overwhelm personal attitudes and subsequently lead to overt behavior contrary to an actor’s attitude. This new approach contributes to the theoretical body of knowledge on Internet abuse by providing a new angle to view the problem. In addition, it suggests to practitioners that social aspects should be considered, along with technical countermeasures, to reduce the pervasive Internet abuse problem.