Why do healthcare professionals fail to escalate as per the early warning system (EWS) protocol? A qualitative evidence synthesis of the barriers and facilitators of escalation.

BACKGROUND: Early warning systems (EWSs) are used to assist clinical judgment in the detection of acute deterioration to avoid or reduce adverse events including unanticipated cardiopulmonary arrest, admission to the intensive care unit and death. Sometimes healthcare professionals (HCPs) do not trigger the alarm and escalate for help according to the EWS protocol and it is unclear why this is the case. The aim of this qualitative evidence synthesis was to answer the question 'why do HCPs fail to escalate care according to EWS protocols?' The findings will inform the update of the National Clinical Effectiveness Committee (NCEC) National Clinical Guideline No. 1 Irish National Early Warning System (INEWS). METHODS: A systematic search of the published and grey literature was conducted (until February 2018). Data extraction and quality appraisal were conducted by two reviewers independently using standardised data extraction forms and quality appraisal tools. A thematic synthesis was conducted by two reviewers of the qualitative studies included and categorised into the barriers and facilitators of escalation. GRADE CERQual was used to assess the certainty of the evidence. RESULTS: Eighteen studies incorporating a variety of HCPs across seven countries were included. The barriers and facilitators to the escalation of care according to EWS protocols were developed into five overarching themes: Governance, Rapid Response Team (RRT) Response, Professional Boundaries, Clinical Experience, and EWS parameters. Barriers to escalation included: Lack of Standardisation, Resources, Lack of accountability, RRT behaviours, Fear, Hierarchy, Increased Conflict, Over confidence, Lack of confidence, and Patient variability. Facilitators included: Accountability, Standardisation, Resources, RRT behaviours, Expertise, Additional support, License to escalate, Bridge across boundaries, Clinical confidence, empowerment, Clinical judgment, and a tool for detecting deterioration. These are all individual yet inter-related barriers and facilitators to escalation. CONCLUSIONS: The findings of this qualitative evidence synthesis provide insight into the real world experience of HCPs when using EWSs. This in turn has the potential to inform policy-makers and HCPs as well as hospital management about emergency response system-related issues in practice and the changes needed to address barriers and facilitators and improve patient safety and quality of care.

Infection by Nanophyetus salmincola and Toxic Contaminant Exposure in Out-migrating Steelhead from Puget Sound, Washington: Implications for Early Marine Survival.

Out-migrating steelhead Oncorhynchus mykiss from four Puget Sound rivers and associated marine basins of Puget Sound in Washington State were examined for the parasite, Nanophyetus salmincola in 2014 to determine whether recent trends in reduced marine survival are associated with the presence of this pathogen. A subset of steelhead from three of these river-marine basin combinations was analyzed for the presence of persistent organic pollutants (POPs) to assess whether exposure to these contaminants is a contributing factor to their reduced marine survival. The prevalence and parasite load of N. salmincola were significantly higher in fish from central and southern Puget Sound than in fish from river systems in northern Puget Sound. The proportion of steelhead samples with concentrations of POPs higher than adverse effects thresholds (AETs) or concentrations known to cause adverse effects was also greater in fish from the central and southern regions of Puget Sound than in those from the northern region. Polybrominated diphenyl ether concentrations associated with increased disease susceptibility were observed in 10% and 40% of the steelhead sampled from central and southern Puget Sound regions, respectively, but in none of the fish sampled from the northern region. The AET for polychlorinated biphenyls was exceeded in steelhead collected from marine habitats: 25% of the samples from the marine basins in the central and southern regions of Puget Sound and 17% of samples from northern Puget Sound region. Both N. salmincola and POP levels suggest there are adverse health effects on out-migrating steelhead from one southern and one central Puget Sound river that have lower early marine survival than those from a river system in northern Puget Sound.

Emergency endovascular management of acute thoracic aortic pathology A safe and feasible option.

Endovascular repair has revolutionised the emergency treatment of thoracic aortic disease. We report our 10 year experience using this treatment in emergency cases. A prospectively maintained vascular database was analysed. Patients' medical records and CT images stored on the hospital PACS system were also reviewed. Statistical analysis was done using IBM SPSS V21. There were a total of 59 thoracic aortic stenting procedures of which 33 (60% males with a mean age of 58 yrs) were performed for emergency thoracic pathologies: traumatic transection (n = 10), ruptured aneurysm (n = 6), non-traumatic dissection (n = 8) and penetrating aortic ulcer (n = 9). All patients had self-expanding endografts implanted. Two patients required debranching procedures before the endovascular treatment. Thirty-day mortality was 12.1% (4/33). 70% of patients received a single device. There were 7 procedure related complications, 6 requiring re-intervention: thoracotomy and drainage in 2 patients, proximal graft extension in 2, open drainage of groin haematoma in 1 and open repair of a common femoral artery pseudo-aneurysm in one patient. In total 23 patients were transferred from 11 centres nationwide. There were no mortalities or other complications related to patient transfer from peripheral centres. Although acute thoracic aortic pathology is life threatening, appropriate blood pressure management and treatment of associated injuries can result in favourable outcomes. Endovascular repair is a safe and effective treatment option which enables patients to be treated with reduced morbidity and mortality. Transfer of patients with acute pathology to a tertiary centre can safely be performed.

Mast cells: new therapeutic target in helminth immune modulation.

Helminth infection and their secreted antigens have a protective role in many immune-mediated inflammatory disorders such as inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. However, studies have focused primarily on identifying immune protective mechanisms of helminth infection and their secreted molecules on dendritic cells and macrophages. Given that mast cells have been shown to be implicated in the pathogenesis and progression of many inflammatory disorders, their role should also be examined and considered as cellular target for helminth-based therapies. As there is a dearth of studies examining the interaction of helminth-derived antigens and mast cells, this review will focus on the role of mast cells during helminth infection and examine our current understanding of the involvement of mast cells in TH 1/TH 17-mediated immune disorders. In this context, potential mechanisms by which helminths could target the TH 1/TH 17 promoting properties of mast cells can be identified to unveil novel therapeutic mast cell driven targets in combating these inflammatory disorders.

A prospective view of animal and human Fasciolosis.

Fasciolosis, a food-borne trematodiasis, results following infection with the parasites, Fasciola hepatica and Fasciola gigantica. These trematodes greatly affect the global agricultural community, infecting millions of ruminants worldwide and causing annual economic losses in excess of US $3 billion. Fasciolosis, an important zoonosis, is classified by WHO as a neglected tropical disease with an estimated 17 million people infected and a further 180 million people at risk of infection. The significant impact on agriculture and human health together with the increasing demand for animal-derived food products to support global population growth demonstrate that fasciolosis is a major One Health problem. This review details the problematic issues surrounding fasciolosis control, including drug resistance, lack of diagnosis and the threat that hybridization of the Fasciola species poses to future animal and human health. We discuss how these parasites may mediate their long-term survival through regulation and modulation of the host immune system, by altering the host immune homeostasis and/or by influencing the intestinal microbiome particularly in respect to concurrent infections with other pathogens. Large genome, transcriptome and proteomic data sets are now available to support an integrated One Health approach to develop novel diagnostic and control strategies for both animal and human disease.

Increased thrombin generation potential in symptomatic versus asymptomatic moderate or severe carotid stenosis and relationship with cerebral microemboli.

INTRODUCTION: The importance of thrombin generation in the pathogenesis of TIA or stroke and its relationship with cerebral microembolic signals (MES) in asymptomatic and symptomatic carotid stenosis has not been comprehensively assessed. METHODS: Plasma thrombin generation parameters from patients with moderate or severe (≥ 50%) asymptomatic carotid stenosis were compared with those from patients with symptomatic carotid stenosis in the early (≤ 4 weeks) and late phases (≥ 3 months) after TIA or stroke in this prospective, pilot observational study. Thrombin generation profile was longitudinally assessed in symptomatic patients with data at each time point. Bilateral transcranial Doppler ultrasound monitoring of the middle cerebral arteries was performed whenever possible to classify patients as MES-positive or MES-negative. RESULTS: Data from 31 asymptomatic, 46 'early symptomatic' and 35 'late symptomatic' patients were analysed. Peak thrombin (344.2 nM vs 305.3 nM; p = 0.01) and endogenous thrombin potential (1772.4 vs 1589.7; p = 0.047) were higher in early symptomatic than asymptomatic patients. Peak thrombin production decreased in symptomatic patients followed up from the early to late phase after TIA or stroke (339.7 nM vs 308.6 nM; p = 0.02). Transcranial Doppler ultrasound data were available in 25 asymptomatic, 31 early symptomatic and 27 late symptomatic patients. Early symptomatic MES-positive patients had a shorter 'time-to-peak thrombin' than asymptomatic MES-positive patients (p=0.04), suggesting a more procoagulant state in this early symptomatic subgroup. DISCUSSION: Thrombin generation potential is greater in patients with recently symptomatic than asymptomatic carotid stenosis, and decreases over time following TIA or stroke associated with carotid stenosis. These data improve our understanding of the haemostatic/thrombotic biomarker profile in moderate-severe carotid stenosis.

Time to subsequent live birth according to mode of delivery in the first birth.

OBJECTIVE: To estimate the rate and time to next live birth by mode of delivery. DESIGN: Hospital-based cohort. SETTING: Aarhus University Hospital (AUH), Denmark. POPULATION: All pregnant women attending AUH were invited to enroll in the Aarhus Birth Cohort (ABC) study between 1989 and 2010 (n = 91,625). METHODS: Women were followed from their first live birth until the subsequent live birth or until censoring due to study end using Cox regression models. MAIN OUTCOME MEASURES: Rate and time to subsequent live birth according to mode of delivery. RESULTS: 46,162 index live births were identified, of which 22,462 (49%) had a subsequent live birth. Women with any type of caesarean had a 6% reduction in the rate of subsequent live birth (HR 0.94, 95% CI 0.89, 0.98), which remained unchanged in the analysis by type (emergency, HR 0.95, 95% CI 0.89, 1.02; elective, HR 0.91, 95% CI 0.85, 0.98) compared with women who had a spontaneous vaginal delivery (SVD). Operative vaginal delivery was associated with an 8% reduction in subsequent live birth rates (HR 0.92, 95% CI 0.86, 0.98) and vaginal delivery complicated by shoulder dystocia with a 19% reduction compared with SVD. Median time to next birth in days was shortest in women with a first caesarean (994 days, 95% CI 973, 1026) and longest in women with a vaginal delivery complicated by shoulder dystocia (1065 days, 95% CI 994, 1191). In women with planned pregnancies, the shortest median time to second birth was in women with breech vaginal deliveries (859 days, 95% CI 737, 1089) and the longest in women with vaginal deliveries complicated by shoulder dystocia (1193 days, 95% CI 1028, 1430). CONCLUSION: The impact of mode of delivery on subsequent rate and time to next birth was minimal in this study. The greatest reduction was among women with assisted vaginal delivery complicated by shoulder dystocia. This study is strengthened by data on pregnancy planning as well as information on complications of pregnancy, delivery and neonatal morbidities, all of which may influence a woman's decision on subsequent birth.

Targeting adipose tissue via systemic gene therapy.

Adipose tissue has a critical role in energy and metabolic homeostasis, but it is challenging to adapt techniques to modulate adipose function in vivo. Here we develop an in vivo, systemic method of gene transfer specifically targeting adipose tissue using adeno-associated virus (AAV) vectors. We constructed AAV vectors containing cytomegalovirus promoter-regulated reporter genes, intravenously injected adult mice with vectors using multiple AAV serotypes, and determined that AAV2/8 best targeted adipose tissue. Altering vectors to contain adiponectin promoter/enhancer elements and liver-specific microRNA-122 target sites restricted reporter gene expression to adipose tissue. As proof of efficacy, the leptin gene was incorporated into the adipose-targeted expression vector, package into AAV2/8 and administered intravenously to 9- to 10-week-old ob/ob mice. Phenotypic changes were measured over an 8-week period. Leptin mRNA and protein were expressed in adipose and leptin protein was secreted into plasma. Mice responded with reversal of weight gain, decreased hyperinsulinemia and improved glucose tolerance. AAV2/8-mediated systemic delivery of an adipose-targeted expression vector can replace a gene lacking in adipose tissue and correct a mouse model of human disease, demonstrating experimental application and therapeutic potential in disorders of adipose.

Mood and anxiety disorders across the adult lifespan: a European perspective.

BACKGROUND: The World Mental Health Survey Initiative (WMHSI) has advanced our understanding of mental disorders by providing data suitable for analysis across many countries. However, these data have not yet been fully explored from a cross-national lifespan perspective. In particular, there is a shortage of research on the relationship between mood and anxiety disorders and age across countries. In this study we used multigroup methods to model the distribution of 12-month DSM-IV/CIDI mood and anxiety disorders across the adult lifespan in relation to determinants of mental health in 10 European Union (EU) countries. METHOD: Logistic regression was used to model the odds of any mood or any anxiety disorder as a function of age, gender, marital status, urbanicity and employment using a multigroup approach (n = 35500). This allowed for the testing of specific lifespan hypotheses across participating countries. RESULTS: No simple geographical pattern exists with which to describe the relationship between 12-month prevalence of mood and anxiety disorders and age. Of the adults sampled, very few aged ≥ 80 years met DSM-IV diagnostic criteria for these disorders. The associations between these disorders and key sociodemographic variables were relatively homogeneous across countries after adjusting for age. CONCLUSIONS: Further research is required to confirm that there are indeed stages in the lifespan where the reported prevalence of mental disorders is low, such as among younger adults in the East and older adults in the West. This project illustrates the difficulties in conducting research among different age groups simultaneously.

Fasciola hepatica tegumental antigens indirectly induce an M2 macrophage-like phenotype in vivo.

The M2 subset of macrophages has a critical role to play in host tissue repair, tissue fibrosis and modulation of adaptive immunity during helminth infection. Infection with the helminth, Fasciola hepatica, is associated with M2 macrophages in its mammalian host, and this response is mimicked by its excretory-secretory products (FhES). The tegumental coat of F. hepatica (FhTeg) is another major source of immune-modulatory molecules; we have previously shown that FhTeg can modulate the activity of both dendritic cells and mast cells inhibiting their ability to prime a Th1 immune response. Here, we report that FhTeg does not induce Th2 immune responses but can induce M2-like phenotype in vivo that modulates cytokine production from CD4(+) cells in response to anti-CD3 stimulation. FhTeg induces a RELMα expressing macrophage population in vitro, while in vivo, the expression of Arg1 and Ym-1/2 but not RELMα in FhTeg-stimulated macrophages was STAT6 dependent. To support this finding, FhTeg induces RELMα expression in vivo prior to the induction of IL-13. FhTeg can induce IL-13-producing peritoneal macrophages following intraperitoneal injection This study highlights the important role of FhTeg as an immune-modulatory source during F. hepatica infection and sheds further light on helminth-macrophage interactions.

Increased endothelial activation in recently symptomatic versus asymptomatic carotid artery stenosis and in cerebral microembolic-signal-negative patient subgroups.

BACKGROUND AND PURPOSE: von Willebrand factor propeptide (VWF:Ag II) is potentially a more sensitive marker of acute endothelial activation than von Willebrand factor antigen (VWF:Ag). These biomarkers have not been simultaneously assessed in asymptomatic versus symptomatic carotid stenosis patients. The relationship between endothelial activation and cerebral microembolic signals (MESs) detected on transcranial Doppler ultrasound is unknown. METHODS: In this multicentre observational analytical study, plasma VWF:Ag and VWF:Ag II levels in patients with ≥50% asymptomatic carotid stenosis were compared with those from patients with ≥50% symptomatic carotid stenosis in the 'early' (≤4 weeks) and 'late' (≥3 months) phases after transient ischaemic attack or ischaemic stroke. Endothelial activation was also longitudinally assessed in symptomatic patients during follow-up. Transcranial Doppler ultrasound monitoring classified patients as MES-positive or MES-negative. RESULTS: Data from 31 asymptomatic patients were compared with those from 46 early symptomatic and 35 late phase symptomatic carotid stenosis patients, 23 of whom had undergone carotid intervention. VWF:Ag II levels were higher in early (12.8 µg/ml; P < 0.001), late (10.6 µg/ml; P = 0.01) and late post-intervention (10.6 µg/ml; P = 0.038) symptomatic patients than asymptomatic patients (8.9 µg/ml). VWF:Ag levels decreased in symptomatic patients followed up from the early to late phase after symptom onset (P = 0.048). Early symptomatic MES-negative patients had higher VWF: Ag II levels (13.3 vs. 9.0 µg/ml; P < 0.001) than asymptomatic MES-negative patients. CONCLUSIONS: Endothelial activation is enhanced in symptomatic versus asymptomatic carotid stenosis patients, in early symptomatic versus asymptomatic MES-negative patients, and decreases over time in symptomatic patients. VWF:Ag II levels are a more sensitive marker of endothelial activation than VWF:Ag levels in carotid stenosis. The potential value of endothelial biomarkers and concurrent cerebral MES detection at predicting stroke risk in carotid stenosis warrants further study.

Fasciola hepatica tegumental coat antigen suppresses MAPK signalling in dendritic cells and up-regulates the expression of SOCS3.

Fasciola hepatica tegumental coat antigen (FhTeg) suppresses dendritic cell maturation and function by inhibiting IL-6, tumour necrosis factor (TNF)-α, IL-10 and IL-12 production and CD80, CD86 and CD40 cell surface marker expression in TLR4-stimulated dendritic cells. Fasciola hepatica also impairs dendritic cell function by inhibiting its phagocytic capacity and its ability to prime T cells. We have shown previously that activation of mast cells with bacterial ligands is also inhibited by FhTeg. Fasciola hepatica suppresses LPS-induced NF-κB and MAPK pathway (ERK) activation in these cells. Previously, we demonstrated that FhTeg induces expression of suppressor of cytokine signalling (SOCS)3, a negative regulator of the TLR pathway in mast cells. In this study, we show the same inhibitory effect of FhTeg on the activation of the other members of the MAPKs pathway (ERK, p38, JNK) in dendritic cells and demonstrate an enhanced expression of SOCS3, but not SOCS1, SOCS5 or PIAS3 in this process. These studies enhance our understanding of the immunomodulatory effect of helminth molecules on the TLR pathway.

Caesarean section and subsequent ectopic pregnancy: a systematic review and meta-analysis.

BACKGROUND: Caesarean section rates are increasing worldwide, and the long-term effects are unknown. OBJECTIVE: To evaluate the risk of subsequent ectopic pregnancy in women with a previous caesarean section, compared with vaginal delivery. SEARCH STRATEGY: Systematic review of the literature using CINAHL, the Cochrane Library, Embase, Medline, PubMed, SCOPUS and Web of Knowledge, published from 1945 until 17 July 2011. SELECTION CRITERIA: Cohort and case-control designs reporting on the mode of delivery and subsequent ectopic pregnancy. Two reviewers independently assessed the titles, abstracts, and full articles to identify eligible studies, using a standardised data collection form, and also assessed the study quality. Reference lists of the studies included were also cross-checked. DATA COLLECTION AND ANALYSIS: Odds ratios (ORs) were combined using a random-effect model to estimate the overall association between caesarean section delivery and the risk of subsequent ectopic pregnancy. MAIN RESULTS: Thirteen studies were included, which recruited a total of 61,978 women. Five studies reported adjustment for confounding factors, and the pooled OR of subsequent ectopic pregnancy following a caesarean section was 1.05 (95% CI 0.51-2.15). The removal of one study that reported outlier results yielded a pooled OR of 0.82 (95% CI 0.42-1.61). The pooled crude OR for all 13 studies was 1.36 (95% CI 0.99-1.88). AUTHOR'S CONCLUSIONS: This review found no evidence of an association between prior caesarean section delivery and the occurrence of a subsequent ectopic pregnancy, but the studies included were of poor or variable quality, and only a small number adjusted for potential confounding factors. Further research of a higher methodological quality is required to assess any potential association between mode of delivery and subsequent ectopic pregnancy.

The menopausal transition does not appear to accelerate age-related increases in arterial stiffness.

OBJECTIVE: Arterial stiffness is an independent marker of cardiovascular risk that increases with age, hypertension, diabetes and hyperlipidemia, both for men and women (although more pronounced in women). This study was designed to establish whether menopause augments the age-dependent change. METHODS: The study evaluated pulse wave analysis and pulse wave velocity using applanation tonometry in 468 women (aged 40-80 years) sampled from the general population. In multiple linear regression models, age was the predominant correlate of increasing aortic augmentation pressure (p < 0.0001), augmentation index (p < 0.0001), augmentation index adjusted to a heart rate of 75 beats/min (p < 0.0001) and carotid-femoral pulse wave velocity (p < 0.0001). RESULTS: Analysis of covariance showed no significant difference in adjusted mean of augmentation pressure, augmentation index or pulse wave velocity between menopause groups (pre-, peri-, postmenopause). Adjusted means of augmentation pressure and pulse wave velocity were comparable between women on hormone therapy (n = 130) and non-users (n = 338). CONCLUSIONS: The results of the present study challenge the assertion by some researchers that menopause accelerates age-dependent changes in arterial stiffness.

Familial and Bullying Victimisation: The Impact of Early Adversity Within the Home and Peer Settings on Late Adolescence and Adult Psychopathology.

Background: Awareness of adverse childhood experiences and their impact on adult psychopathology primarily focuses on adversities within the home. There is limited insight into the impact of adversities across peer environments. Objective: This study investigates 19 items related to adverse experiences across the home, school and peer environments and their relationship to 12-month and lifetime psychopathology. Data: Secondary analysis of the Ulster University Student Well-being Study. The dataset included completed responses across all selected variables for 729 participants. Method and Results: Latent profile analysis identified a low adversity profile, bullying adversity profile and higher prevalence adversity profile. Regression analysis of the three profiles and demographics variables indicated their impact on adult psychopathology lifetime and 12-month prevalence rates. Conclusion: Schools and HE institutions should acknowledge the impact of childhood adversities. In doing so, it is important to consider the deeper impact of bullying due to its links with psychopathology across the lifespan. Educational institutions should take appropriate steps to mitigate continued exposure as students' progress through the education system.

Lifetime prevalence of mental health disorders and delay in treatment following initial onset: evidence from the Northern Ireland Study of Health and Stress.

BACKGROUND: The current study provides the first epidemiological estimates of lifetime mental disorders across NI based on DSM-IV criteria. Risk factors, delays in treatment and the experience of conflict are also examined. METHOD: Nationally representative face-to-face household survey of 4340 individuals aged > or =18 years in NI using the composite international diagnostic interview. Analyses were implemented using SAS and STATA software. RESULTS: Lifetime prevalence of any disorder was 39.1% while projected lifetime risk was 48.6%. Individuals who experienced conflict were more likely to have had an anxiety, mood or impulse-control disorder. Treatment delays were substantial for anxiety and substance disorders. CONCLUSIONS: Results from this study show that mental disorders are highly prevalent in Northern Ireland. The elevated rates of post-traumatic stress disorder in relation to other countries and the association of living 'in a region of terror' disorders suggests that civil conflict has had an additional impact on mental health. Given substantial delays in treatment, further research is required to investigate the factors associated with failure and delay in treatment seeking.

RNA-seq analysis of murine peyer's patches at 6 and 18 h post infection with Fasciola hepatica metacecariae.

Fasciola hepatica is a zoonotic parasite that not only economically burdens the agribusiness sector, but also infects up to 1 million people worldwide, with no commercial vaccine yet available. An ideal vaccine would induce protection in the gut, curtailing the extensive tissue damage associated with parasite's migration from the gut to the bile ducts. The design of such a vaccine requires greater knowledge of gut mucosal responses during the early stage of infection. We examined total mRNA expression of the peyer's patches at 6 and 18 h post F. hepatica infection using RNA sequencing. Differential expression analysis revealed 1341 genes upregulated and 61 genes downregulated at 6 h post infection, while 1562 genes were upregulated and 10 genes downregulated after 18 h. Gene-set enrichment analysis demonstrated that immune specific biological processes were amongst the most downregulated. The Toll-like receptor pathway in particular was significantly affected, the suppression of which is a well-documented immune evasive strategy employed by F. hepatica. In general, the genes identified were associated with suppression of inflammatory responses, helminth induced immune responses and tissue repair/homeostasis. This study provides a rich catalogue of the genes expressed in the early stages of F. hepatica infection, adding to the understanding of early host-parasite interactions and assisting in the design of future studies that look to advance the development of a novel F. hepatica vaccine.

Sarcocystis fusiformis whole cyst antigen activates pro-inflammatory dendritic cells.

Sarcocystis fusiformis is a coccidian tissue parasite that causes infection in buffalo in countries such an Egypt, China, Iraq and Iran, resulting in significant economic losses to the agricultural industry annually. There is a lack of studies examining host-parasite interactions at the level of the immune response and the present study investigates the interaction between S. fusiformis whole cyst antigens (SFWCA) and dendritic cells (DCs), cells critical to the activation of adaptive immunity. In this study bone marrow derived DCs (BMDCs) were phenotyped following treatment with SFWCA by measuring cell viability, cytokine secretion, and cell surface marker expression. While SFWCA exhibited cytotoxic effects on BMDCs at higher concentrations, lower concentrations of SFWCA activated pro-inflammatory DCs that significantly secreted interleukin (IL)-12p40, tumor necrosis factor alpha, IL-6 and IL-10. These cells also displayed enhanced expression of TLR4, CD80, CD86 and MHC II on their surface, which is indicative of full DCs maturation. Moreover, SFWCA significantly attenuated the capacity of BMDCs to suppress Th2 associated cytokines, notably IL-5 and IL-13, while simultaneously exhibiting no effects on the secretion of interferon (IFN)-γ, IL-2, IL-17, and IL-10. In conclusion, this is the first study to provide fundamental insight into the activation of DCs by SFWCA, providing us with some awareness into the interaction of the Sarcosystis parasite with its host. The pro-inflammatory inducing ability of this antigen is in keeping with studies performed in other protozoan parasites and therefore understanding these interactions is important in the development of future therapeutic strategies.

Relationship between 'on-treatment platelet reactivity', shear stress, and micro-embolic signals in asymptomatic and symptomatic carotid stenosis.

BACKGROUND: Assessment of 'high on-treatment platelet reactivity (HTPR)' could enhance understanding of the pathophysiology of first or recurrent vascular events in carotid stenosis patients on antiplatelet therapy. METHODS: This prospective, multi-centre study assessed antiplatelet-HTPR status and its relationship with micro-emboli signals (MES) in asymptomatic vs. symptomatic ≥ 50-99% carotid stenosis. Platelet function/reactivity was assessed under 'moderately high shear stress' with the PFA-100® and 'low shear stress' with VerifyNow® and Multiplate® analysers. Bilateral 1-h transcranial Doppler ultrasound of the middle cerebral arteries classified patients as MES + ve or MES - ve. RESULTS: Data from 34 asymptomatic patients were compared with 43 symptomatic patients in the 'early phase' (≤ 4 weeks) and 37 patients in the 'late phase' (≥ 3 months) after TIA/ischaemic stroke. Median daily aspirin doses were higher in early symptomatic (225 mg; P < 0.001), but not late symptomatic (75 mg; P = 0.62) vs. asymptomatic patients (75 mg). There was a lower prevalence of aspirin-HTPR in early (28.6%; P = 0.028), but not late symptomatic (38.9%; P = 0.22) compared with asymptomatic patients (56.7%) on the PFA-100®, but not on the VerifyNow® or Multiplate® (P ≤ 0.53). Early symptomatic patients had a higher prevalence of aspirin-HTPR on the PFA-100® (28.6%) vs. VerifyNow® (9.5%; P = 0.049), but not Multiplate® assays (11.9%, P = 0.10). There was no difference in aspirin-HTPR prevalence between any symptomatic vs. asymptomatic MES + ve or MES - ve subgroup. DISCUSSION: Recently symptomatic moderate-severe carotid stenosis patients had a lower prevalence of aspirin-HTPR than their asymptomatic counterparts on the PFA-100®, likely related to higher aspirin doses. The prevalence of antiplatelet-HTPR was positively influenced by higher shear stress levels, but not MES status.