Mice Infected with Low-virulence Strains of Toxoplasma gondii Lose their Innate Aversion to Cat Urine, Even after Extensive Parasite Clearance

Toxoplasma gondii chronic infection in rodent secondary hosts has been reported to lead to a loss of innate, hard-wired fear toward cats, its primary host. However the generality of this response across T. gondii strains and the underlying mechanism for this pathogen mediated behavioral change remain unknown. To begin exploring these questions, we evaluated the effects of infection with two previously uninvestigated isolates from the three major North American clonal lineages of T. gondii, Type III and an attenuated strain of Type I. Using an hour-long open field activity assay optimized for this purpose, we measured mouse aversion toward predator and non-predator urines. We show that loss of innate aversion of cat urine is a general trait caused by infection with any of the three major clonal lineages of parasite. Surprisingly, we found that infection with the attenuated Type I parasite results in sustained loss of aversion at times post infection when neither parasite nor ongoing brain inflammation were detectable. This suggests that T. gondii-mediated interruption of mouse innate aversion toward cat urine may occur during early acute infection in a permanent manner, not requiring persistence of parasitecysts or continuing brain inflammation.Comment: 14 pages, 3 figure

Adding web-based support to exercise referral schemes improves symptoms of depression in people with elevated depressive symptoms:A secondary analysis of the e-coachER randomised controlled trial

Background: Exercise referral schemes (ERS) reduce depression but the additional effect on mental health from web-based behavioural support is unknown. The e-coachER trial reported no effect of augmenting usual ERS with theory-driven web-based behavioural support on moderate to vigorous physical activity (MVPA) at 12 months for patients with chronic physical and mental health conditions. The present study reports the effects of the e-coachER intervention on depression, anxiety and MVPA only among participants with elevated depressive symptoms and investigates whether these were mediated by changes in MVPA and hypothesised cognitive and behavioural processes. Methods: Of the original 450 adults recruited into the e-coachER trial, 205 had at least mild depression, based on the Hospital Anxiety and Depression Scale (HADS), and were included in the present analysis. Data collected included the HADS, accelerometer measured and self-reported MVPA and survey process measures on physical activity action planning, self-monitoring and goal reviewing, and perceived importance, confidence, competence, autonomy and support. Linear mixed models were used to compare groups for change in depression and anxiety at 4 and 12 months using intention-to-treat complete case analysis, controlling for baseline. We also examined whether changes in physical activity and process variables at 4 months mediated changes in depression and anxiety at 12 months. Results: Of the 205 participants, 138 (67%) provided follow-up data at four months and 126 (61%) at 12 months. For those that provided follow-up data, those randomised to e-coachER reported improved levels of depression (−1.36, 95% CI: −2.55 to −0.18) but not anxiety, or MVPA, compared with controls at four months. No differences were observed at 12 months for depression, anxiety or MVPA. Intervention effects on accelerometer-measured or self-reported MVPA did not mediate improvements in depression or anxiety. However, intervention effects on confidence, competence and self-monitoring at four months significantly mediated the reduction in depression scores at four months. Intervention effects on competence and self-monitoring at four months also significantly mediated improvements in anxiety scores at four months. Interpretation: Adding web-based support to usual ERS leads to reductions in depression but not anxiety at four months. Changes in depression and anxiety were influenced by changing people's motivational regulations toward physical activity. The benefit of adding web-based support to usual ERS on mental health appears to be from increasing a sense of confidence, competence and self-monitoring rather than from increasing physical activity in people with elevated depression. ERS should focus more on strengthening motivational regulations than just doing more exercise. Trial registration: ISRCTN15644451.</p

Adding web-based support to exercise referral schemes improves symptoms of depression in people with elevated depressive symptoms:A secondary analysis of the e-coachER randomised controlled trial

Background: Exercise referral schemes (ERS) reduce depression but the additional effect on mental health from web-based behavioural support is unknown. The e-coachER trial reported no effect of augmenting usual ERS with theory-driven web-based behavioural support on moderate to vigorous physical activity (MVPA) at 12 months for patients with chronic physical and mental health conditions. The present study reports the effects of the e-coachER intervention on depression, anxiety and MVPA only among participants with elevated depressive symptoms and investigates whether these were mediated by changes in MVPA and hypothesised cognitive and behavioural processes. Methods: Of the original 450 adults recruited into the e-coachER trial, 205 had at least mild depression, based on the Hospital Anxiety and Depression Scale (HADS), and were included in the present analysis. Data collected included the HADS, accelerometer measured and self-reported MVPA and survey process measures on physical activity action planning, self-monitoring and goal reviewing, and perceived importance, confidence, competence, autonomy and support. Linear mixed models were used to compare groups for change in depression and anxiety at 4 and 12 months using intention-to-treat complete case analysis, controlling for baseline. We also examined whether changes in physical activity and process variables at 4 months mediated changes in depression and anxiety at 12 months. Results: Of the 205 participants, 138 (67%) provided follow-up data at four months and 126 (61%) at 12 months. For those that provided follow-up data, those randomised to e-coachER reported improved levels of depression (−1.36, 95% CI: −2.55 to −0.18) but not anxiety, or MVPA, compared with controls at four months. No differences were observed at 12 months for depression, anxiety or MVPA. Intervention effects on accelerometer-measured or self-reported MVPA did not mediate improvements in depression or anxiety. However, intervention effects on confidence, competence and self-monitoring at four months significantly mediated the reduction in depression scores at four months. Intervention effects on competence and self-monitoring at four months also significantly mediated improvements in anxiety scores at four months. Interpretation: Adding web-based support to usual ERS leads to reductions in depression but not anxiety at four months. Changes in depression and anxiety were influenced by changing people's motivational regulations toward physical activity. The benefit of adding web-based support to usual ERS on mental health appears to be from increasing a sense of confidence, competence and self-monitoring rather than from increasing physical activity in people with elevated depression. ERS should focus more on strengthening motivational regulations than just doing more exercise. Trial registration: ISRCTN15644451.</p

Proteomic profiling of high risk medulloblastoma reveals functional biology

Genomic characterization of medulloblastoma has improved molecular risk classification but struggles to define functional biological processes, particularly for the most aggressive subgroups. We present here a novel proteomic approach to this problem using a reference library of stable isotope labeled medulloblastoma-specific proteins as a spike-in standard for accurate quantification of the tumor proteome. Utilizing high-resolution mass spectrometry, we quantified the tumor proteome of group 3 medulloblastoma cells and demonstrate that high-risk MYC amplified tumors can be segregated based on protein expression patterns. We cross-validated the differentially expressed protein candidates using an independent transcriptomic data set and further confirmed them in a separate cohort of medulloblastoma tissue samples to identify the most robust proteogenomic differences. Interestingly, highly expressed proteins associated with MYC-amplified tumors were significantly related to glycolytic metabolic pathways via alternative splicing of pyruvate kinase (PKM) by heterogeneous ribonucleoproteins (HNRNPs). Furthermore, when maintained under hypoxic conditions, these MYC-amplified tumors demonstrated increased viability compared to non-amplified tumors within the same subgroup. Taken together, these findings highlight the power of proteomics as an integrative platform to help prioritize genetic and molecular drivers of cancer biology and behavior

A process evaluation, with mediation analysis, of a web-based intervention to augment primary care exercise referral schemes: the e-coachER randomised controlled trial

Background: The e-coachER trial aimed to determine whether adding web-based behavioural support to exercise referral schemes (ERS) increased long-term device-measured physical activity (PA) for patients with chronic conditions, compared to ERS alone, within a randomised controlled trial. This study explores the mechanisms of action of the e-coachER intervention using measures of the behaviour change processes integral to the intervention’s logic model. Methods: Four hundred fifty adults with obesity, diabetes, hypertension, osteoarthritis or history of depression referred to an ERS were recruited in Plymouth, Birmingham and Glasgow. The e-coachER intervention comprising 7-Steps to Health was aligned with Self-Determination Theory and mapped against evidence-based behaviour change techniques (BCTs). Participants completed questionnaires at 0, 4, and 12 months to assess PA and self-reported offline engagement with core BCTs in day-to-day life (including action planning and self-monitoring) and beliefs relating to PA (including perceived importance, confidence, competence, autonomy and support). We compared groups at 4 and 12 months, controlling for baseline measures and other covariates. Mediation analysis using the product of coefficients method was used to determine if changes in process variables mediated intervention effects on moderate to vigorous physical activity (MVPA) recorded by accelerometer and self-report at 4- and 12-months. Results: The internal reliability (Cronbach’s alpha) for all multi-item scales was &gt; 0.77. At 4-months, those randomised to e-coachER reported higher levels of PA beliefs relating to importance (1.01, 95% confidence interval (CI): 0.42 to 1.61, p = 0.001), confidence (1.28, 95% CI: 0.57 to 1.98, p &lt; 0.001), competence (1.61, 95% CI: .68 to 2.54, p = 0.001), availability of support (0.77, 95% CI: 0.07 to 1.48, p = 0.031), use of action planning (1.54, 95% CI: 0.23 to 2.85, p = 0.021) and use of self-monitoring (0.76, 95% CI: 0.19 to 1.32, p = 0.009) compared to ERS alone. There were no intervention effects on autonomous beliefs or perceived frequency of support, compared to ERS alone. At the 12-month follow-up, participants belief in the importance of PA was the only process measure to remain significantly higher in the e-coachER group when compared to ERS alone (0.75, 95% CI: 0.05 to 1.45). Intervention effects on perceived importance (2.52, 95% CI: 0.45 to 5.39), action planning (1.56, 95% CI: 0.10 to 3.54) and self-monitoring (1.92, 95% CI: 0.21 to 4.33) at 4-months significantly mediated change in accelerometer measured MVPA at 12-months (recorded in ≥ 10-min bouts). Conclusions: e-coachER led to some short-term changes in most process outcomes. Some of these processes also appeared to mediate e-coachER effects on changes in accelerometer measured MVPA. Further work should be carried out to understand how best to design and implement theoretically underpinned web-based physical activity promotion interventions within ERS. Trial registration: ISRCTN, ISRCTN15644451. Registered 12 February 2015

Longitudinal realist evaluation of the dementia PersonAlised care team (D-PACT) intervention: protocol

BACKGROUND: Different dementia support roles exist but evidence is lacking on which aspects are best, for whom and in what circumstance, and on their associated costs and benefits. Phase 1 of the Dementia PersonAlised Care Team programme (D-PACT), developed a post-diagnostic primary care-based intervention for people with dementia and their carers and assessed the feasibility of a trial. AIM: Phase 2 of the programme aims to 1) refine our programme theory on how, when and for whom the intervention works and 2) evaluate its value and impact. DESIGN & SETTING: A realist longitudinal mixed-methods evaluation will be conducted in urban, rural, and coastal areas across Southwest and Northwest England where low-income groups or ethnic minorities (eg, South Asian) are represented. Design was informed by patient, public and professional stakeholder input and Phase one findings. METHOD: High volume qualitative and quantitative data will be collected longitudinally from people with dementia, carers and practitioners. Analyses will comprise: 1) realist longitudinal case studies; 2) conversation analysis of recorded interactions; 3) statistical analyses of outcome and experience questionnaires; 4 a) health economic analysis examining costs of delivery; 4b) realist economic analysis of high-cost events and 'near misses'. All findings will be synthesised using a joint display table, evidence appraisal tool, triangulation and stakeholder co-analysis. CONCLUSION: Our realist evaluation will describe how, why and for whom the intervention leads (or not) to change over time; it also demonstrates how a non-randomised design can be more appropriate for complex interventions with similar questions or populations

Patient-orientated longitudinal study of multiple sclerosis in south west England (The South West Impact of Multiple Sclerosis Project, SWIMS) 1: protocol and baseline characteristics of cohort

<p>Abstract</p> <p>Background</p> <p>There is a need for greater understanding of the impact of multiple sclerosis (MS) from the perspective of individuals with the condition. The South West Impact of MS Project (SWIMS) has been designed to improve understanding of disease impact using a patient-centred approach. The purpose is to (1) develop improved measurement instruments for clinical trials, (2) evaluate longitudinal performance of a variety of patient-reported outcome measures, (3) develop prognostic predictors for use in individualising drug treatment for patients, particularly early on in the disease course.</p> <p>Methods</p> <p>This is a patient-centred, prospective, longitudinal study of multiple sclerosis and clinically isolated syndrome (CIS) in south west England. The study area comprises two counties with a population of approximately 1.7 million and an estimated 1,800 cases of MS. Self-completion questionnaires are administered to participants every six months (for people with MS) or 12 months (CIS). Here we present descriptive statistics of the baseline data provided by 967 participants with MS.</p> <p>Results</p> <p>Seventy-five percent of those approached consented to participate. The male:female ratio was 1.00:3.01 (n = 967). Average (standard deviation) age at time of entry to SWIMS was 51.6 (11.5) years (n = 961) and median (interquartile range) time since first symptom was 13.3 (6.8 to 24.5) years (n = 934). Fatigue was the most commonly reported symptom, with 80% of participants experiencing fatigue at baseline. Although medication use for symptom control was common, there was little evidence of effectiveness, particularly for fatigue. Nineteen percent of participants were unable to classify their subtype of MS. When patient-reported subtype was compared to neurologist assessment for a sample of participants (n = 396), agreement in disease sub-type was achieved in 63% of cases. There were 836 relapses, reported by 931 participants, in the twelve months prior to baseline. Twenty-three percent of the relapsing-remitting group and 12% of the total sample were receiving disease-modifying therapy at baseline.</p> <p>Conclusions</p> <p>Demographics of this sample were similar to published data for the UK. Overall, the results broadly reflect clinical experience in confirming high symptom prevalence, with relatively little complete symptom relief. Participants often had difficulty in defining MS relapses and their own MS type.</p

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

A human Dectin-2 deficiency associated with invasive aspergillosis

Immunocompromised patients are highly susceptible to invasive aspergillosis. Herein, we identified a homozygous deletion mutation (507 del C) resulting in a frameshift (N170I) and early stop codon in the fungal binding Dectin-2 receptor, in an immunocompromised patient. The mutated form of Dectin-2 was weakly expressed, did not form clusters at/near the cell surface and was functionally defective. PBMCs from this patient were unable to mount a cytokine (TNF, IL-6) response to A. fumigatus and this first identified Dectin-2-deficient patient succumbed to invasive aspergillosis

Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations.

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening