Brief opportunistic interventions by general practitioners to promote smoking cessation: A conversation analytic study.

Very brief opportunistic interventions for smoking cessation are effective, cost-saving for health systems, and universally recommended in guidelines. However, evidence suggests that clinicians are reluctant to intervene, citing interactional difficulties. Only one UK study has specifically examined smoking discussions, within naturally occurring primary care consultations. However smoking cessation treatment was not available at the time. We examined existing datasets amounting to 519 video-recordings of GP consultations in England for instances of talk about smoking. We used conversation analytic methods to assess patients' responses to doctors asking about smoking, giving advice on smoking, and offering cessation treatment. In 31 recordings it was apparent that the patient smoked, and, in 25/31 consultations, doctors initiated the topic of smoking. They did so by asking about smoking status, commonly during the history-taking phase of the consultation. In many instances, these questions led to active resistance from patients against being placed in a discreditable category, for example by minimising their smoking. This was more pronounced when GPs pursued efforts to quantify the amount smoked. Thereafter, where doctors returned to the topic of smoking, they did so typically by linking smoking to the patient's medical condition, which likewise led to resistance. Guidance recommends that GPs advise on how best to quit smoking where patients are interested in doing so, but this was only evident in a minority of consultations. Where GPs offered support for cessation, they did so using interactional practices that minimised the need for the patient to respond and thereby accept. Interactional difficulties were found to be common in consultations between GPs and people who smoke when GPs actions aligned with some VBA guidelines. Future research should examine when and how advice on how best to quit, and offers of support, should be delivered within primary care consultations.

Evaluation of the MP Rapid 2019-NCOV IgM/IgG combo POCT test vs. an established platform-based method.

BACKGROUND: Accurate and rapid testing for SARS-COV-2 antibodies could improve the diagnosis and management of COVID-19. In this study, we aim to evaluate the diagnostic accuracy of a commercially available point-of-care lateral flow kit independently and in comparison to an established platform-based system. METHOD: Samples from 144 PCR-confirmed COVID-19 cases and 130 pre-pandemic negative controls were tested in parallel by MP Rapid 2019-NCOV IgM/IgG Combo test and Roche Elecsys. Comparison of results based on serum and capillary blood testing was undertaken. RESULTS: Sensitivity at day 15 onwards was 100% for both methods. Between days 1 and 7 post admission, the IgM/IgG Combo test and Roche Elecsys shown sensitivity of 74% (95%CI: 62%-85%) vs. 67% (95% CI: 55%-79%, P = 0.3947). Combo test specificities were 100% for IgG, 98.5% for IgM vs. Roche Elecsys specificity of 100%. Concordance analysis showed 98.5% agreement to the Roche Elecsys method (Cohen's Kappa 0.96 95% CI [0.92-0.99]). Capillary blood results showed complete agreement with serum samples using the Combo test. CONCLUSION: In comparison to Roche Elecsys, our data show that the MP Rapid 2019-NCOV IgM/IgG Combo test provides a high-confidence assay system for the detection of previous exposure to SARS-COV-2 infection with advantage of affording near-patient testing.

Patient and Public Involvement (PPI) in evidence synthesis: how the PatMed study approached embedding audience responses into the expression of a meta-ethnography.

BACKGROUND: Patient and public involvement (PPI) has become enshrined as an important pillar of health services empirical research, including PPI roles during stages of research development and analysis and co-design approaches. Whilst user participation has been central to qualitative evidence synthesis (QES) for decades, as seen in the Cochrane consumer network and guidelines, meta-ethnography has been slow to incorporate user participation and published examples of this occurring within meta-ethnography are sparse. In this paper, drawing upon our own experience of conducting a meta-ethnography, we focus on what it means in practice to 'express a synthesis' (stage 7). We suggest the methodological importance of 'expression' in Noblit and Hare's seven stage process (Noblit, GW and Hare, RD. Meta-ethnography: synthesizing qualitative studies, 1988) has been overlooked, and in particular, opportunities for PPI user participation within it. METHODS: Meta-ethnography comprises a seven-stage process of evidence synthesis. Noblit and Hare describe the final 7th stage of the meta-ethnography process as 'expression of synthesis', emphasizing co-construction of findings with the audience. In a previous study we conducted a meta-ethnography exploring patient and student experience of medical education within primary care contexts. We subsequently presented and discussed initial meta-ethnography findings with PPI (students and patients) in focus groups and interviews. We transcribed patient and student PPI interpretations of synthesis findings. As a research team, we then translated these into our existing meta-ethnography findings. RESULTS: We describe, with examples, the process of involving PPI in stage 7 of meta-ethnography and discuss three methodological implications of incorporating PPI within an interpretative approach to QES: (1) we reflect on the construct hierarchy of user participants' interpretations and consider whether incorporating these additional 1st order, 2nd level constructs implies an additional logic of 3rd order 2nd level constructs of the QES team; (2) we discuss the link between PPI user participation and what Noblit and Hare may have meant by ideas of 'expression' and 'audience' as integral to stage 7; and (3) we link PPI user participation to Noblit and Hare's underlying theory of social explanation, i.e. how expression of the synthesis is underpinned by ideas of translation and that the synthesis must be 'translated in the audience's (user participants) particular language'. CONCLUSIONS: The paper aims to complement recent attempts in the literature to refine and improve guidance on conducting a meta-ethnography, highlighting opportunities for PPI user participation in the processes of interpretation, translation and expression. We discuss the implications of user participation in meta-ethnography on ideas of 'generalisability'.

'I'm not a real boozer': a qualitative study of primary care patients' views on drinking and its consequences.

BACKGROUND: The public health message around alcohol is complex, with benefits versus harms, the confusing concept of risk and drinking guidance changing over time. This provides a difficult context for alcohol screening in primary care, with established barriers from the practitioner perspective, but less is known about the patients' perspective. This study explores patients' views on drinking. METHODS: Eligible participants were recorded as drinking above low risk levels in primary care. Six practices in North London participated. Interviews were in-depth, semi-structured, transcribed verbatim and underwent detailed thematic analysis. FINDINGS: Interviews were conducted with 8 women and 12 men, aged 26-83 years, mostly educated to undergraduate level and of 'White' ethnicity. UK drinking guidance was viewed as irrelevant for reasons related to life stage, lifestyle and absence of harm. Dependence, loss of functionality and control were perceived as key features of problematic drinking. Healthy lifestyles, in terms of diet, exercise and not smoking, were thought to mitigate potential problems associated with alcohol intake. CONCLUSION: The findings suggest that public health messages and brief advice should focus on harm experienced at different life stages, among people with different lifestyles, to challenge the ubiquitous view that 'I'm not a real boozer'.

Early stages in the ontogeny of small B-cell lymphomas: genetics and microenvironment.

In this review, we focus on the mechanisms underlying lymphomagenesis in chronic lymphocytic leukaemia, follicular lymphoma, mantle cell lymphoma and splenic marginal zone lymphoma. The cells of origin of these small B-cell lymphomas are distinct, as are the characteristic chromosomal lesions and clinical courses. One shared feature is retention of expression of surface immunoglobulin. Analysis of this critical receptor reveals the point of differentiation reached by the cell of origin. Additionally, the sequence patterns of the immunoglobulin-variable domains can indicate a role for stimulants of the B-cell receptor before, during and after malignant transformation. The pathways driven via the B-cell receptor are now being targeted by specific kinase inhibitors with exciting clinical effects. To consider routes to pathogenesis, potentially offering earlier intervention, or to identify causative factors, genetic tools are being used to track pretransformation events and the early phases in lymphomagenesis. These methods are revealing that chromosomal changes are only one of the many steps involved, and that the influence of surrounding cells, probably multiple and variable according to tissue location, is required, both to establish tumours and to maintain growth and survival. Similarly, the influence of the tumour microenvironment may protect malignant cells from eradication by treatment, and the resulting minimal residual disease will eventually give rise to relapse. The common and different features of the four lymphomas will be summarized to show how normal B lymphocytes can be subverted to generate tumours, how these tumours evolve and how their weaknesses can be attacked by targeted therapies.

Randomised feasibility study of physiotherapy for patients with functional motor symptoms.

OBJECTIVE: To determine the feasibility of conducting a randomised controlled trial of a specialist physiotherapy intervention for functional motor symptoms (FMS). METHODS: A randomised feasibility study was conducted recruiting patients with a clinically established diagnosis of FMS from a tertiary neurology clinic in London, UK. Participants were randomised to the intervention or a treatment as usual control. Measures of feasibility and clinical outcome were collected and assessed at 6 months. RESULTS: 60 individuals were recruited over a 9-month period. Three withdrew, leaving 29 intervention and 28 controls participants in the final analysis. 32% of patients with FMS met the inclusion criteria, of which 90% enrolled. Acceptability of the intervention was high and there were no adverse events. At 6 months, 72% of the intervention group rated their symptoms as improved, compared to 18% in the control group. There was a moderate to large treatment effect across a range of outcomes, including three of eight Short Form 36 (SF36) domains (d=0.46-0.79). The SF36 Physical function was found to be a suitable primary outcome measure for a future trial; adjusted mean difference 19.8 (95% CI 10.2 to 29.5). The additional quality adjusted life years (QALY) with intervention was 0.08 (95% CI 0.03 to 0.13), the mean incremental cost per QALY gained was £12 087. CONCLUSIONS: This feasibility study demonstrated high rates of recruitment, retention and acceptability. Clinical effect size was moderate to large with high probability of being cost-effective. A randomised controlled trial is needed. TRIAL REGISTRATION NUMBER: NCT02275000; Results.

IL-10 production by CLL cells is enhanced in the anergic IGHV mutated subset and associates with reduced DNA methylation of the IL10 locus.

Chronic lymphocytic leukemias (CLLs) with unmutated (U-CLL) or mutated (M-CLL) IGHV have variable features of immunosuppression, possibly influenced by those CLL cells activated to produce interleukin 10 (IL-10). The two subsets differ in their levels of anergy, defined by low surface immunoglobulin M levels/signaling capacity, and in their DNA methylation profile, particularly variable in M-CLL. We have now found that levels of IL-10 produced by activated CLL cells were highly variable. Levels were higher in M-CLL than in U-CLL and correlated with anergy. DNA methylation analysis of IL10 locus revealed two previously uncharacterized 'variably methylated regions' (CLL-VMRs1/2) in the gene body, but similarly low methylation in the promoter of both U-CLL and M-CLL. CLL-VMR1/2 methylation was lower in M-CLL than in U-CLL and inversely correlated with IL-10 induction. A functional signal transducer and activator of transcription 3 (STAT3) binding site in CLL-VMR2 was confirmed by proximity ligation and luciferase assays, whereas inhibition of SYK-mediated STAT3 activation resulted in suppression of IL10. The data suggest epigenetic control of IL-10 production. Higher tumor load may compensate the reduced IL-10 production in U-CLL, accounting for clinical immunosuppression in both subsets. The observation that SYK inhibition also suppresses IL-10 provides a potential new rationale for therapeutic targeting and immunological rescue by SYK inhibitors in CLL.

Use of strategies to improve retention in primary care randomised trials: a qualitative study with in-depth interviews.

OBJECTIVE: To explore the strategies used to improve retention in primary care randomised trials. DESIGN: Qualitative in-depth interviews and thematic analysis. PARTICIPANTS: 29 UK primary care chief and principal investigators, trial managers and research nurses. METHODS: In-depth face-to-face interviews. RESULTS: Primary care researchers use incentive and communication strategies to improve retention in trials, but were unsure of their effect. Small monetary incentives were used to increase response to postal questionnaires. Non-monetary incentives were used although there was scepticism about the impact of these on retention. Nurses routinely used telephone communication to encourage participants to return for trial follow-up. Trial managers used first class post, shorter questionnaires and improved questionnaire designs with the aim of improving questionnaire response. Interviewees thought an open trial design could lead to biased results and were negative about using behavioural strategies to improve retention. There was consensus among the interviewees that effective communication and rapport with participants, participant altruism, respect for participant's time, flexibility of trial personnel and appointment schedules and trial information improve retention. Interviewees noted particular challenges with retention in mental health trials and those involving teenagers. CONCLUSIONS: The findings of this qualitative study have allowed us to reflect on research practice around retention and highlight a gap between such practice and current evidence. Interviewees describe acting from experience without evidence from the literature, which supports the use of small monetary incentives to improve the questionnaire response. No such evidence exists for non-monetary incentives or first class post, use of which may need reconsideration. An exploration of barriers and facilitators to retention in other research contexts may be justified.

Pharmacological inhibitors of NF-kappaB accelerate apoptosis in chronic lymphocytic leukaemia cells.

Nuclear factor-kappaB (NF-kappaB) is a transcription factor that plays a critical role in the inappropriate survival of various types of malignant cells. Chronic lymphocytic leukaemia (CLL) is the most common B-cell malignancy in the Western world. Although overexpression and regulation of NF-kappaB has been described in CLL, its function remains unclear. Exposure of CLL cells to BAY117082 or Kamebakaurin, potent pharmacological inhibitors of the NF-kappaB pathway, accelerated apoptosis in approximately 70% of cases. Sensitivity to NF-kappaB pathway inhibitors was not related to the prognostic markers VH status, CD38 or Zap70 expression, or to the levels of nuclear NF-kappaB. Normal peripheral B cells were resistant to the apoptosis-inducing effects of these compounds. Cell death induced by the inhibitors was associated with activation of caspase-9 and -3, and loss of mitochondrial membrane polarization, but did not involve changes in the expression of Bcl-2 or Mcl-1. Inhibitors caused an increase in c-jun NH2-terminal kinase activity in CLL, but this did not appear to be important for apoptosis. Microarray analysis identified some potential novel NF-kappaB target genes, including interleukin-16- and the Bcl-2- related survival protein Bcl-w. These results demonstrate that a substantial proportion of CLL are dependent on NF-kappaB for enhanced survival and suggest that inhibition of NF-kappaB may have therapeutic potential.

Effects of fall and spring seeding date and other agronomic factors on infestations of root maggots, Delia spp. (Diptera: Anthomyiidae), in canola.

Several agronomic benefits can result from fall seeding of canola (Brassica spp.), but extensive research data are lacking on the potential impact of this practice on infestations of root maggots (Delia spp.) (Diptera: Anthomyiidae), which are major pests of the crop in western Canada. Field experiments making up 13 location by year combinations were conducted in central Alberta, Canada, from 1998 to 2001 to determine the effect of fall versus spring seeding of canola on root maggot damage. Depending on the experiment, interactions with seeding rate, seed treatment, timing of weed removal, and canola species (cultivar) also were investigated. Root maggot damage declined with an increase in seeding rate for plots seeded in May but not in fall or April. Susceptibility to infestation was greater for plants of Brassica rapa L. than Brassica napus L., but seed treatment had no effect on damage by these pests. Combined analysis using data from all experiment by location by year combinations indicated that seeding date had no significant effect on root maggot damage. The extended emergence of Delia spp. adults, which spans the appearance of crop stages vulnerable to oviposition regardless of seeding date, prevented reduced root maggot attack. Covariance analysis demonstrated the importance of increasing seeding rate for reducing root maggot infestations, a practice that can be especially beneficial for May-seeded canola when growing conditions limit the ability of plants to compensate for root maggot damage. Results determined with the small plot studies described here should be validated in larger plots or on a commercial field scale, but both the combined and covariance analyses indicate that seeding canola in fall does not predispose plants to greater damage by larval root maggots than seeding in spring.

Measuring the appropriateness of prescribing in primary care: are current measures complete?

BACKGROUND AND OBJECTIVES: Appropriateness of prescribing is often assessed by standard instruments. We wished to establish whether judgements of appropriateness that included patients' perspectives and contextual factors could lead to different conclusions when compared with commonly used instruments. To explore the predictive accuracy of these instruments. METHODS: The design was interviews of patients, audio recordings of the consultation and interviews of the doctors, in varied primary care practices in England. Participants were patients who were likely to discuss a medication issue. The outcome measures were judgements of appropriateness made by the researchers and by two instruments: the Prescribing Appropriateness Index and the Medication Appropriateness Index. Implications for the predictive accuracy of the measures was also investigated. RESULTS: From 35 cases there was agreement between the judges and the instruments in 22 cases, 16 were appropriate and 6 inappropriate. Of 10 cases classified as inappropriate by the instruments the judges thought four were appropriate. Of 18 cases classified as appropriate by the instruments, two were considered inappropriate by the judges. In seven cases the prescribing decisions could not be classified by the instruments because the decision was to not prescribe. CONCLUSIONS: Current measures of appropriateness of prescribing depend predominantly on pharmacological criteria, and so do not represent cases that would be judged appropriate when including the patient's views and contextual factors. If most prescribing is appropriate then use of these measures may lead to more false negatives than real negatives. The instruments should be renamed as measures of 'pharmacological appropriateness' and are useful where the incidence of this type of inappropriate prescribing is relatively high.

Interactive health communication applications for chronic disease: patient and carer perspectives.

Interactive health communication applications (IHCAs) may be particularly useful to patients and carers managing chronic disease. We have run eight focus groups with patients and two with carers involving a total of 40 participants. The focus groups were designed to seek patients' and carers' requirements of IHCAs and to identify the criteria they would use to assess them. Analysis revealed that many participants saw the value and potential of IHCAs. Even those with modest previous computer experience could use them with little tuition. The findings from this study have policy implications for the development of applications to maximize the potential benefit of IHCAs to patients and carers.

Increased susceptibility of glutathione peroxidase-1 transgenic mice to kainic acid-related seizure activity and hippocampal neuronal cell death.

Glutathione peroxidase (GSHPx) has been demonstrated in several in vivo studies to reduce both the risk and severity of oxidatively-induced tissue damage. The seizure-inducing neurotoxin kainic acid (KA) has been suggested to elicit its toxic effects in part via generation of oxidative stress. In this study, we report that expression of elevated levels of murine GSHPx-1 in transgenic mice surprisingly results in increased rather than decreased KA susceptibility including increased seizure activity and neuronal hippocampal damage. Isolated transgenic primary hippocampal culture neurons also display increased susceptibility to KA treatment compared with those from wildtype animals. This could be due to alterations in the redox state of the glutathione system resulting in elevated glutathione disulfide (GSSG) levels which, in turn, may directly activate NMDA receptors or enhanced response of the NMDA receptor.

Developing a measure for the appropriateness of prescribing in general practice.

OBJECTIVE: To explore the feasibility of using a broader definition of the appropriateness of prescribing in general practice by developing ways of measuring this broader definition and by identifying possible relationships between different aspects of appropriateness and patient outcomes. DESIGN: A questionnaire study of patients and general practitioners before and after study consultations, supplemented by data collected from patients' medical records and telephone interviews with patients 1 week later. SETTING: General practices in the south of England. PARTICIPANTS: 24 general practitioners and 186 of their consulting patients. MAIN OUTCOME MEASURES: Unwanted, unnecessary, and pharmacologically inappropriate prescriptions; patients' adherence. RESULTS: Before the consultation 42% of patients said they wanted or expected a prescription for their main problem. Prescriptions were written in two thirds (65%) of study consultations, and 7% of these had not been wanted or expected beforehand. Doctors recorded that one in five prescriptions they wrote were not strictly indicated. Of the 92 independent assessments of these prescriptions, four were judged to be inappropriate and in 19 cases the assessors were uncertain. 41% of prescriptions written were wanted, necessary, and appropriate. Subsequently, 18% of patients for whom a prescription had been written were potentially non-adherent and 25% had worries or concerns about their medication. CONCLUSION: The attempt to measure appropriateness of prescribing along the three dimensions of patients', prescribers', and pharmacological perspectives is both feasible and likely to yield valuable insights into the nature of general practice prescribing and patients' use of medicines.