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There is growing clinical interest in addressing relationship dynamics between service-users and their voices. The Talking With Voices (TwV) trial aimed to establish feasibility and acceptability of a novel dialogical intervention to reduce distress associated with voices amongst adults diagnosed with schizophrenia spectrum disorders. The single-site, single-blind (rater) randomised controlled trial recruited 50 participants who were allocated 1:1 to treatment as usual (TAU), or TAU plus up to 26 sessions of TwV therapy. Participants were assessed at baseline and again at end of treatment (six-months). The primary outcomes were quantitative and qualitative assessments of feasibility and acceptability. Secondary outcomes involved clinical measures, including targeted instruments for voice-hearing, dissociation, and emotional distress. The trial achieved 100 % of the target sample, 24 of whom were allocated to therapy and 26 to TAU. The trial had high retention (40/50 [80 %] participants at six-months) and high intervention adherence (21/24 [87.5 %] receiving ≥8 sessions). Signals of efficacy were shown in targeted measures of voice-hearing, dissociation, and perceptions of recovery. Analysis on the Positive and Negative Syndrome Scale indicated that there were no differences in means of general psychosis symptom scores in TwV compared to the control group. There were four serious adverse events in the therapy group and eight in TAU, none of which were related to study proceedings. The trial demonstrates the acceptability of the intervention and the feasibility of delivering it under controlled, randomised conditions. An adequately powered definitive trial is necessary to provide robust evidence regarding efficacy evaluation and cost-effectiveness. Trial registration: ISRCTN 45308981.

Introduction Lenalidomide plus dexamethasone is effective and well tolerated in relapsed/refractory multiple myeloma (RRMM). In this observational, noninterventional European post-authorization safety study, the safety profile of lenalidomide plus dexamethasone was investigated and compared with that of other agents in the treatment of RRMM in a real-world setting. Patients and Methods Patients had received ≥ 1 prior antimyeloma therapy; prior lenalidomide was excluded. Treatment was per investigator’s routine practice. Adverse events were analyzed by incidence rates per 100 person-years to account for differences in observation length and treatment duration. Results In total, 2150 patients initiated lenalidomide, and 1479 initiated any other antimyeloma therapy, predominately bortezomib (80.3%), which was primarily administered intravenously (74.3%). The incidence rate of neuropathy was lower with lenalidomide (10.5) than with bortezomib (78.9) or thalidomide (38.7). Lenalidomide also had a lower incidence rate of infections (68.7) versus bortezomib (95.9) and thalidomide (76.0). Conversely, the incidence rate of neutropenia was higher with lenalidomide (38.0) than with bortezomib (18.2) or thalidomide (25.7). The incidence rates of thrombocytopenia were 24.4, 40.4, and 14.4 with lenalidomide, bortezomib, and thalidomide, respectively. Conclusion No new safety signals for lenalidomide were identified in this study, which is the largest prospective real-world European study of lenalidomide in patients with RRMM to date. These results confirm that the safety profile of lenalidomide plus dexamethasone in RRMM in a real-world setting is comparable to that reported in clinical trials.

Chlamydia (C.) abortus is an emerging zoonotic pathogen. Since data on its antimicrobial susceptibility are lacking, we aimed to determine minimal inhibitory (MIC) and minimal bactericidal concentrations (MBC) for azithromycin and doxycycline in HeLa-cells and primary human macrophages (M1). We also examined the MDM2-p53-inhibitor nutlin-3, an anti-infective imidazoline analog. Azithromycin and doxycycline demonstrated MICs and MBCs equal or below their peak serum concentrations (PSC) after standard dosing in both cell types. While doxycycline exhibited an MIC 64-fold and an MBC 4-fold below its PSC in HeLa-cells, the MIC of azithromycin was 4-fold below, the MBC equal to the PSC. However, azithromycin revealed lower MBCs in M1. The pharmacological advantage of azithromycin accumulation in phagocytes and their role as chlamydial reservoirs remain uncertain. However, our data suggest possible therapeutic advantages of doxycycline in epithelial cells and we provide first evidence for an anti-C. abortus effect of nutlin-3 in M1.

Objective: Co-occuring physical symptoms, unexplained by organic pathology (known as Functional Syndromes, FS), are common and disabling presentations. However, FS is absent or inconsistently taught within undergraduate medical training. This study investigates the reasons for this and identifies potential solutions to improved implementation. Methods: Twenty-eight medical educators from thirteen different UK medical schools participated in semi-structured interviews. Thematic analysis proceeded iteratively, and in parallel with data production. Results: Barriers to implementing FS training are beliefs about the complexity of FS, tutors’ negative attitudes towards FS, and FS being perceived as a low priority for the curriculum. In parallel participants recognised FS as ubiquitous within medical practice and erroneously assumed it must be taught by someone. They recommended that students should learn about FS through managed exposure, but only if tutors’ negative attitudes and behaviour are also addressed. Conclusion: Negative attitudes towards FS by educators prevents designing and delivering effective education on this common medical presentation. Whilst there is recognition of the need to implement FS training, recommendations are multifaceted. Practice Implications: Increased liaison between students, patients and educators is necessary to develop more informed and effective teaching methods for trainee doctors about FS and in order to minimise the impact of the hidden curriculum.

Objective: To investigate the relationship between trainee doctors’ attachment style and their performance in qualifying clinical and communication skills assessments.Methods: Participants were 190 undergraduate medical students whose performance was assessed by examiners across two areas (communication and clinical skills) during their qualifying Objective Structured Clinical Examination (OSCE). Simulated patients also rated communication skills. Participants’ attachment style was rated across two dimensions, avoidance and anxiety, with the Relationship Questionnaire (RQ). Results: Lower levels of attachment avoidance and anxiety were significant predictors of higher performance in both communication and clinical skills. Conclusion: Trainee doctors’ attachment styles are associated with patient communication and clinical performance. Further research is needed to investigate the impact of attachment on consultations between doctors and patients within clinical settings. Practice implication: Attachment theory can inform our understanding why, for some student doctors, interacting with patients may be particularly challenging and require additional support by medical educators.

Exposure to environmental contaminants, particularly pesticides, may be an important etiological factor in Parkinson's disease (PD); and evidence suggests a role for microglia-dependent inflammatory and oxidative processes in nigrostriatal pathology induced by such toxins. Yet, the events mediating microglial activation and their effects are not fully known. To this end, we hypothesized that the proinflammatory cytokine, interferon-gamma (IFN-γ), may be a prime factor in the pathogenesis of PD, given its critical role in regulating microglial responses to pathogens. Indeed, the present investigation demonstrated that genetic deletion of IFN-γ protected substantia nigra pars compacta (SNc) dopamine (DA) neurons from the toxic effects of the pesticide, paraquat, and normalized changes in inflammatory and oxidative factors within this brain region. Specifically, IFN-γ knockout prevented the paraquat-induced morphological signs of microglial activation and expression of key nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, while also preventing time-dependent changes in proinflammatory enzymes (inducible nitric oxide synthase [iNOS], cyclooxygenase-2 [COX-2]), cytokines (interleukin-1β [IL-1β], tumor necrosis factor-α [TNF-α]), and signaling factors (c-Jun N-terminal kinase [JNK], p38 MAP kinase [p38], Signal transducer and activator of transcription-1 [STAT1], nuclear factor kappa B [NF-κB]). Moreover, paraquat transiently suppressed substantia nigra pars compacta expression of trophic and proneuroplastic factors (cyclic-AMP response element binding protein [CREB], brain-derived neurotrophic factor [BDNF]), and IFN-γ deficiency again reversed these effects. These data suggest that IFN-γ is important for paraquat-induced neurodegeneration and the accompanying oxidative, inflammatory, and trophic changes that characterize the response to the toxin. Targeting IFN-γ could thus have therapeutic implications for PD and other neurodegenerative conditions that involve multiple inflammatory pathways.

Equitable access to primary care for people with common mental health problems in the UK remains problematic. The experiences of people from hard-to-reach groups offer important insights into barriers to accessing care. In this study, we report on secondary analysis of qualitative data generated within seven previously-reported studies. Thirty-three of ninety-two available transcripts were re-analysed using a new heuristic of access, generated to frame narrative-based comparative case analysis. The remaining transcripts were used to triangulate the findings via a process of collaborative analysis between a secondary researcher, naïve to research findings of the original studies, and primary researchers involved in data generation and analysis within the original studies. This method provided a rich body of 'fine grain' insights into the ways in which problem formulation, help-seeking, use of services and perceptions of service quality are interlinked in a recursive and socially embedded matrix of inequitable access to primary mental health care. The findings indicate both extensive commonalities between experiences of people from different 'hard-to-reach groups', and considerable diversity within each group. An idiographic generalisation and aggregation of this variety of experiences points to one main common facilitator (communicated availability of acceptable mental health services) and two main common barriers (lack of effective information and multiple forms of stigma) to equitable access to primary mental health care. We conclude that there is a need to provide local care that is pluralistic, adaptive, holistic, resonant and socially conscious in order to ensure that equitable access to mental health services can become a reality.

Background Few systematic studies have examined the reasons why patients with bipolar disorder and substance use disorders misuse alcohol and drugs of abuse. Such reasons may depend heavily on context so qualitative research methods that made no prior theoretical assumptions were employed. We explored the reasons patients give for misusing drugs and alcohol and how these relate to their illness course. Method Qualitative semi-structured interviews and thematic analysis with a purposive sample of 15 patients with bipolar disorder and a current or past history of drug or alcohol use disorders. Results Patients based their patterns of and reasons for substance use on previous personal experiences rather than other sources of information. Reasons for substance use were idiosyncratic, and were both mood related and unrelated. Contextual factors such as mood, drug and social often modified the patient's personal experience of substance use. Five thematic categories emerged: experimenting in the early illness; living with serious mental illness; enjoying the effects of substances; feeling normal; and managing stress. Limitations The prevalence of these underlying themes was not established and the results may not apply to populations with different cultural norms. Conclusions Patterns of substance use and reasons for use are idiosyncratic to the individual and evolve through personal experience. Motivating the patient to change their substance use requires an understanding of their previous personal experience of substance use both in relation to the different phases of their bipolar disorder and their wider personal needs.

Hyaluronate lyase, which catalyses the degradation of hyaluronic acid (HA), has been described from several pathogenic streptococcal species. We describe, for the first time, identification and purification of hyaluronate lyase from the zoonotic pig pathogen Streptococcus suis. We have cloned the hyaluronate lyase gene from S. suis and used it to generate an allelic replacement knock-out mutant of S. suis serotype 7 that can no longer biosynthesise the enzyme. Interestingly, a limited strain survey indicates that hyaluronate lyase activity is not present in all disease isolates of S. suis. Polyclonal anti-hyaluronate lyase anti-serum raised against our recombinant hyaluronate lyase has been used in Western blots, showing that hyaluronate lyase activity is always associated with the presence of protein of the expected size, whereas lack of hyaluronate lyase activity is due to truncation or absence of the enzyme. We show that hyaluronate lyase activity is required for S. suis to use HA polymer as a carbon source and that supplying exogenous recombinant hyaluronate lyase to all S. suis strains tested allowed fermentation of the resultant HA breakdown products.

Summary One response to the increasing demand for physiotherapy services from primary care is to develop group exercise programmes led by physiotherapists operating in an educational/advisory role. However, since physical symptoms in patients referred from primary care are often mediated by complex and unrecognised psychosocial factors, it is not clear what format of group physiotherapy will engage such patients in a programme of exercise training. This paper reports problems experienced with patient engagement in physiotherapist-led groups undertaking either an aerobic exercise or a stretching and relaxation programme. The programmes formed, respectively, the intervention and control arms of a study investigating the role of exercise in primary care patients with persistent unexplained physical symptoms. We outline ways in which these problems were addressed and review our experience in the light of previous research on patient engagement with exercise.

This paper reports the case of a patient with a peripheral spelling impairment who is much more severely impaired at writing in lower-case letters than in upper-case letters. This pattern can be observed when writing both words and single letters of the alphabet. Despite this, his problems in writing lower-case letters are no longer present when he is writing cursively. This case therefore indicates that the ability to print letters in lower-case can be selectively impaired in the absence of similar problems in printing,,upper-case letters or in writing lower-case letters cursively. In terms of the model of writing put forward by Ellis (1982, 1988), this suggests that allographic level representations for print handwriting styles can be functionally dissociated from allographic representations for cursive styles.