Claire Jones

Recognition of sialylated meningococcal lipopolysaccharide by siglecs expressed on myeloid cells leads to enhanced bacterial uptake

Sialic acid‐binding immunoglobulin‐like lectins (siglecs) are expressed predominantly in the haemopoietic and immune systems and exhibit specificities for both the linkage and the nature of sialic acids in N‐glycans, O‐glycans and glycolipids. Several siglecs, including sialoadhesin (Sn, siglec‐1) and siglec‐5, bind to NeuAcα2,3Gal, a terminal capping structure that can also be displayed on the lipopolysaccharide (LPS) of Neisseria meningitidis (Nm). In the present study, we examined the potential of siglecs expressed on cells of the immune system to function as receptors for sialylated Nm. We used sialylated and non‐sialylated LPS derivatives of two serogroups (A and B) of Nm in this study. Using recombinant chimeric soluble receptors, siglec‐transfected cell lines and macrophages from wild‐type and Sn‐deficient mice, we observed that sialylated but not non‐sialylated variants of either genetic background were specifically recognized by Sn and siglec‐5, whereas other siglecs examined were ineffective. In addition, macrophages expressing Sn, as well as transfectants expressing Sn or siglec‐5, bound and phagocytosed sialylated bacteria in a siglec‐ and sialic acid‐dependent manner. This study demonstrates that Nm LPS sialylation can lead to increased bacterial susceptibility to phagocytic uptake, a phenomenon in direct contrast to previously reported protective effects of LPS sialylation.

Siglec-9, a Novel Sialic Acid Binding Member of the Immunoglobulin Superfamily Expressed Broadly on Human Blood Leukocytes

Here we characterize the properties and expression pattern of Siglec-9 (sialic acid-bindingIg-like lectin-9), a new member of the Siglec subgroup of the immunoglobulin superfamily. A full-length cDNA encoding Siglec-9 was isolated from a dibutyryl cAMP-treated HL-60 cell cDNA library. Siglec-9 is predicted to contain three extracellular immunoglobulin-like domains that comprise an N-terminal V-set domain and two C2-set domains, a transmembrane region and a cytoplasmic tail containing two putative tyrosine-based signaling motifs. Overall, Siglec-9 is ∼80% identical in amino acid sequence to Siglec-7, suggesting that the genes encoding these two proteins arose relatively recently by gene duplication. Binding assays showed that, similar to Siglec-7, Siglec-9 recognized sialic acid in either the α2,3- or α2,6-glycosidic linkage to galactose. Using a specific mAb, Siglec-9 was found to be expressed at high or intermediate levels by monocytes, neutrophils, and a minor population of CD16+, CD56− cells. Weaker expression was observed on ∼50% of B cells and NK cells and minor subsets of CD8+ T cells and CD4+ T cells. These results show that despite their high degree of sequence similarity, Siglec-7 and Siglec-9 have distinct expression profiles.

Two decision aids for mode of delivery among women with previous caesarean section: randomised controlled trial

Objectives To determine the effects of two computer based decision aids on decisional conflict and mode of delivery among pregnant women with a previous caesarean section. Design Randomised trial, conducted from May 2004 to August 2006. Setting Four maternity units in south west England, and Scotland. Participants 742 pregnant women with one previous lower segment caesarean section and delivery expected at ≥37 weeks. Non-English speakers were excluded. Interventions Usual care: standard care given by obstetric and midwifery staff. Information programme: women navigated through descriptions and probabilities of clinical outcomes for mother and baby associated with planned vaginal birth, elective caesarean section, and emergency caesarean section. Decision analysis: mode of delivery was recommended based on utility assessments performed by the woman combined with probabilities of clinical outcomes within a concealed decision tree. Both interventions were delivered via a laptop computer after brief instructions from a researcher. Main outcome measures Total score on decisional conflict scale, and mode of delivery. Results Women in the information programme (adjusted difference −6.2, 95% confidence interval −8.7 to −3.7) and the decision analysis (−4.0, −6.5 to −1.5) groups had reduced decisional conflict compared with women in the usual care group. The rate of vaginal birth was higher for women in the decision analysis group compared with the usual care group (37% v 30%, adjusted odds ratio 1.42, 0.94 to 2.14), but the rates were similar in the information programme and usual care groups. Conclusions Decision aids can help women who have had a previous caesarean section to decide on mode of delivery in a subsequent pregnancy. The decision analysis approach might substantially affect national rates of caesarean section. Trial Registration Current Controlled Trials ISRCTN84367722.

Sialoadhesin-Deficient Mice Exhibit Subtle Changes in B- and T-Cell Populations and Reduced Immunoglobulin M Levels

ABSTRACT Sialoadhesin (Sn, also called Siglec-1 or CD169) is a transmembrane receptor and the prototypic member of the Siglec family of sialic acid binding immunoglobulin-like lectins. It is expressed on specialized subsets of resident macrophages in hematopoietic and lymphoid tissues and on inflammatory macrophages. In order to investigate its function, we generated Sn-deficient mice and confirmed that these mice are true nulls by fluorescence-activated cell sorter analysis and immunohistochemistry. Mice deficient in Sn were viable and fertile and showed no developmental abnormalities. Analysis of cell populations revealed no differences in bone marrow, peritoneal cavity, and thymus, but there was a small increase in CD8 T cells and a decrease in B220-positive cells in spleens and lymph nodes of Sn-deficient mice. Furthermore, in spleen there was a slight decrease in follicular B cells with an increase in numbers of marginal zone B cells. B- and T-cell maturation as well as responses to stimulation with thioglycolate were only slightly affected by Sn deficiency. Immunoglobulin titers in Sn-deficient mice were significantly decreased for immunoglobulin M (IgM) but similar for IgG subclasses. These results suggest a role for sialoadhesin in regulating cells of the immune system rather than in influencing steady-state hematopoiesis.

Experiences obtained from designing with children

This paper describes the experiences and insights obtained while using children-centred design during two software development projects. The authors describe critical difficulties experienced and how measures had to be taken to adapt the children-centred design methodologies to allow full involvement of children in the project design.

Can text messages reach the parts other process measures cannot reach: an evaluation of a behavior change intervention delivered by mobile phone?

Background Process evaluation is essential in developing, piloting and evaluating complex interventions. This often involves observation of intervention delivery and interviews with study participants. Mobile telephone interventions involve no face to face contact, making conventional process evaluation difficult. This study assesses the utility of novel techniques for process evaluation involving no face to face contact. Methods Text messages were delivered to 34 disadvantaged men as part of a feasibility study of a brief alcohol intervention. Process evaluation focused on delivery of the text messages and responses received from study participants. The computerized delivery system captured data on receipt of the messages. The text messages, delivered over 28 days, included nine which asked questions. Responses to these questions served as one technique for process evaluation by ascertaining the nature of engagement with the study and with steps on the causal chain to behavior change. Results A total of 646 SMS text messages were sent to participants. Of these, 613 messages (95%) were recorded as delivered to participants’ telephones. 88% of participants responded to messages that asked questions. There was little attenuation in responses to the questions across the intervention period. Content analysis of the responses revealed that participants engaged with text messages, thought deeply about their content and provided carefully considered personal responses to the questions. Conclusions Socially disadvantaged men, a hard to reach population, engaged in a meaningful way over a sustained period with an interactive intervention delivered by text message. The novel process measures used in the study are unobtrusive, low cost and collect real-time data on all participants. They assessed the fidelity of delivery of the intervention and monitored retention in the study. They measured levels of engagement and identified participants’ reactions to components of the intervention. These methods provide a valuable addition to conventional process evaluation techniques.

Decision‐making about mode of delivery after previous caesarean section: development and piloting of two computer‐based decision aids

Objective  To develop and pilot two computer‐based decision aids to assist women with decision‐making about mode of delivery after a previous caesarean section (CS), which could then be evaluated in a randomized‐controlled trial.

Developing and evaluating interventions to reduce inappropriate prescribing by general practitioners of antibiotics for upper respiratory tract infections: a randomised controlled trial to compare paper-based and web-based modelling experiments.

BackgroundMuch implementation research is focused on full-scale trials with little evidence of preceding modelling work. The Medical Research Council Framework for developing and evaluating complex interventions has argued for more and better theoretical and exploratory work prior to a trial as a means of improving intervention development. Intervention modelling experiments (IMEs) are a way of exploring and refining an intervention before moving to a full-scale trial. They do this by delivering key elements of the intervention in a simulation that approximates clinical practice by, for example, presenting general practitioners (GPs) with a clinical scenario about making a treatment decision.MethodsThe current proposal will run a full, web-based IME involving 250 GPs that will advance the methodology of IMEs by directly comparing results with an earlier paper-based IME. Moreover, the web-based IME will evaluate an intervention that can be put into a full-scale trial that aims to reduce antibiotic prescribing for upper respiratory tract infections in primary care. The study will also include a trial of email versus postal invitations to participate.DiscussionMore effective behaviour change interventions are needed and this study will develop one such intervention and a system to model and test future interventions. This system will be applicable to any situation in the National Health Service where behaviour needs to be modified, including interventions aimed directly at the public.Trial registrationClinicalTrials (NCT): NCT01206738

E-mail invitations to general practitioners were as effective as postal invitations and were more efficient

OBJECTIVE To evaluate which of two invitation methods, e-mail or post, was most effective at recruiting general practitioners (GPs) to an online trial. STUDY DESIGN AND SETTING Randomized controlled trial. Participants were GPs in Scotland, United Kingdom. RESULTS Two hundred and seventy GPs were recruited. Using e-mail did not improve recruitment (risk difference=0.7% [95% confidence interval -2.7% to 4.1%]). E-mail was, however, simpler to use and cheaper, costing £3.20 per recruit compared with £15.69 for postal invitations. Reminders increased recruitment by around 4% for each reminder sent for both invitation methods. CONCLUSIONS In the Scottish context, inviting GPs to take part in an online trial by e-mail does not adversely affect recruitment and is logistically easier and cheaper than using postal invitations.

Paper-based and web-based intervention modeling experiments identified the same predictors of general practitioners' antibiotic-prescribing behavior

OBJECTIVES To evaluate the robustness of the intervention modeling experiment (IME) methodology as a way of developing and testing behavioral change interventions before a full-scale trial by replicating an earlier paper-based IME. STUDY DESIGN AND SETTING Web-based questionnaire and clinical scenario study. General practitioners across Scotland were invited to complete the questionnaire and scenarios, which were then used to identify predictors of antibiotic-prescribing behavior. These predictors were compared with the predictors identified in an earlier paper-based IME and used to develop a new intervention. RESULTS Two hundred seventy general practitioners completed the questionnaires and scenarios. The constructs that predicted simulated behavior and intention were attitude, perceived behavioral control, risk perception/anticipated consequences, and self-efficacy, which match the targets identified in the earlier paper-based IME. The choice of persuasive communication as an intervention in the earlier IME was also confirmed. Additionally, a new intervention, an action plan, was developed. CONCLUSION A web-based IME replicated the findings of an earlier paper-based IME, which provides confidence in the IME methodology. The interventions will now be evaluated in the next stage of the IME, a web-based randomized controlled trial.