Transcriptome and proteome profiling reveals stress-induced expression signatures of imiquimod-treated Tasmanian devil facial tumor disease (DFTD) cells

As a topical cancer immunotherapy, the toll-like receptor 7 ligand imiquimodactivates tumor regression via stimulation of immune cell infiltration and cytotoxicresponses. Imiquimod also exerts direct pro-apoptotic effects on tumor cells invitro, but a role for these effects in imiquimod-induced tumor regression remainsundefined. We previously demonstrated that cell lines derived from devil facial tumordisease (DFTD), a transmissible cancer threatening the survival of the Tasmaniandevil (Sarcophilus harrisii), are sensitive to imiquimod-induced apoptosis. In thisstudy, the pro-apoptotic effects of imiquimod in DFTD have been investigated usingRNA-sequencing and label-free quantitative proteomics. This analysis revealedthat changes to gene and protein expression in imiquimod treated DFTD cells areconsistent with the onset of oxidative and endoplasmic reticulum stress responses,and subsequent activation of the unfolded protein response, autophagy, cell cyclearrest and apoptosis. Imiquimod also regulates the expression of oncogenic pathways,providing a direct mechanism by which this drug may increase tumor susceptibilityto immune cytotoxicity in vivo. Our study has provided the first global analysis ofimiquimod-induced effects in any tumor cell line. These findings have highlightedthe potential of cell stress pathways as therapeutic targets in DFTD, and will allowfor improved mechanistic use of imiquimod as a therapy in both the Tasmanian deviland human cancers

Experiences of Mental Distress during COVID-19: Thematic Analysis of Discussion Forum Posts for Anxiety, Depression, and Obsessive-Compulsive Disorder

The psychological impact of the COVID-19 pandemic on coronavirus patients, health care workers, and the general population is clear. Relatively few studies have, however, considered the impact of the pandemic on those with pre-existing mental health conditions. Therefore, the present study investigates the personal experiences of those with anxiety, depression, and obsessive-compulsive disorder during COVID-19. We conducted a qualitative study utilising Reddit discussion forum posts. We conducted three separate thematic analyses from 130 posts in subreddit forums aimed for people identifying with anxiety, depression, and obsessive-compulsive disorder. We identified a number of similar discussion forum themes (e.g., COVID-19 intensifying symptoms and a lack of social support), as well as themes that were unique to each forum type (e.g., hyperawareness and positive experiences during the pandemic). Findings should guide future practice and the support provided to those living with mental distress

Activation of Ventral Tegmental Area 5-HT2C Receptors Reduces Incentive Motivation

FUNDING AND DISCLOSURE The research was funded by Wellcome Trust (WT098012) to LKH; and National Institute of Health (DK056731) and the Marilyn H. Vincent Foundation to MGM. The University of Michigan Transgenic Core facility is partially supported by the NIH-funded University of Michigan Center for Gastrointestinal Research (DK034933). The remaining authors declare no conflict of interest. ACKNOWLEDGMENTS We thank Dr Celine Cansell, Ms Raffaella Chianese and the staff of the Medical Research Facility for technical assistance. We thank Dr Vladimir Orduña for the scientific advice and technical assistance.Peer reviewedPublisher PD

Support and Assessment for Fall Emergency Referrals (SAFER 1) trial protocol. Computerised on-scene decision support for emergency ambulance staff to assess and plan care for older people who have fallen: evaluation of costs and benefits using a pragmatic cluster randomised trial

Background: Many emergency ambulance calls are for older people who have fallen. As half of them are left at home, a community-based response may often be more appropriate than hospital attendance. The SAFER 1 trial will assess the costs and benefits of a new healthcare technology - hand-held computers with computerised clinical decision support (CCDS) software - to help paramedics decide who needs hospital attendance, and who can be safely left at home with referral to community falls services. Methods/Design: Pragmatic cluster randomised trial with a qualitative component. We shall allocate 72 paramedics ('clusters') at random between receiving the intervention and a control group delivering care as usual, of whom we expect 60 to complete the trial. Patients are eligible if they are aged 65 or older, live in the study area but not in residential care, and are attended by a study paramedic following an emergency call for a fall. Seven to 10 days after the index fall we shall offer patients the opportunity to opt out of further follow up. Continuing participants will receive questionnaires after one and 6 months, and we shall monitor their routine clinical data for 6 months. We shall interview 20 of these patients in depth. We shall conduct focus groups or semi-structured interviews with paramedics and other stakeholders. The primary outcome is the interval to the first subsequent reported fall (or death). We shall analyse this and other measures of outcome, process and cost by 'intention to treat'. We shall analyse qualitative data thematically. Discussion: Since the SAFER 1 trial received funding in August 2006, implementation has come to terms with ambulance service reorganisation and a new national electronic patient record in England. In response to these hurdles the research team has adapted the research design, including aspects of the intervention, to meet the needs of the ambulance services. In conclusion this complex emergency care trial will provide rigorous evidence on the clinical and cost effectiveness of CCDS for paramedics in the care of older people who have fallen

Organizational factors and depression management in community-based primary care settings

Abstract Background Evidence-based quality improvement models for depression have not been fully implemented in routine primary care settings. To date, few studies have examined the organizational factors associated with depression management in real-world primary care practice. To successfully implement quality improvement models for depression, there must be a better understanding of the relevant organizational structure and processes of the primary care setting. The objective of this study is to describe these organizational features of routine primary care practice, and the organization of depression care, using survey questions derived from an evidence-based framework. Methods We used this framework to implement a survey of 27 practices comprised of 49 unique offices within a large primary care practice network in western Pennsylvania. Survey questions addressed practice structure (e.g., human resources, leadership, information technology (IT) infrastructure, and external incentives) and process features (e.g., staff performance, degree of integrated depression care, and IT performance). Results The results of our survey demonstrated substantial variation across the practice network of organizational factors pertinent to implementation of evidence-based depression management. Notably, quality improvement capability and IT infrastructure were widespread, but specific application to depression care differed between practices, as did coordination and communication tasks surrounding depression treatment. Conclusions The primary care practices in the network that we surveyed are at differing stages in their organization and implementation of evidence-based depression management. Practical surveys such as this may serve to better direct implementation of these quality improvement strategies for depression by improving understanding of the organizational barriers and facilitators that exist within both practices and practice networks. In addition, survey information can inform efforts of individual primary care practices in customizing intervention strategies to improve depression management.http://deepblue.lib.umich.edu/bitstream/2027.42/78269/1/1748-5908-4-84.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78269/2/1748-5908-4-84-S1.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78269/3/1748-5908-4-84.pdfPeer Reviewe

Barriers to Bystander Intervention in Sexual Harassment: The Dark Triad and Rape Myth acceptance in Indonesia, Singapore, and United Kingdom

Bystanders have an important role in preventing sexual violence, but they are often reluctant to intervene due to a range of barriers. In this study, we investigated relationships between the Dark Triad of personality (i.e. psychopathy, Machiavellianism and narcissism), rape myth acceptance and five bystander barriers. We addressed the paucity of research by collecting data from three countries (Indonesia, Singapore, and United Kingdom). In total, 716 University staff and students participated in an online survey. We found very few country-level differences in the correlations between the variables. In regression analyses, Machiavellianism and rape myth acceptance both had significant, positive relationships with failure to identify risk, failure to take responsibility, skills deficits and audience inhibition. Narcissism and psychopathy were significantly, negatively associated with audience inhibition and skills deficits. Findings indicate similarity in predictors of perceived barriers to bystander intervention across the three countries

In vivo bioluminescence imaging of locally disseminated colon carcinoma in rats

Animal tumour models using orthotopic tumours for the evaluation of cancer therapies are of greater clinical relevance than subcutaneous models, but they also pose greater difficulties for measuring tumour size and quantifying response to treatment. In this study, we used noninvasive bioluminescence imaging to monitor the intraperitoneal growth of luciferase-transfected CC531 colorectal cells in adult WAG/RIJ rats. The bioluminescence signal correlated well with post-mortem assessment of tumour load by visual inspection of the peritoneal cavity at specific follow-up times. Using bioluminescence imaging, we were able to monitor peritoneal tumour growth sequentially in time and to calculate a tumour growth rate for each animal; this is not possible with invasive methods of evaluating tumour load. Bioluminescence imaging of rats treated with a single dose of cisplatin (4 mg x kg(-1), i.p.) demonstrated a significant delay in peritoneal tumour growth relative to saline controls (mean 45.0+/-s.d. 13.0 vs 28.2+/-10.3 days; P=0.04). Similar protocols evaluated by visual scoring of tumour load at 40 days after inoculation supported these findings, although no quantitative assessment of treatment-induced growth delay could be made by this method. This study shows that in vivo imaging of luciferase-transfected tumour cells is a useful tool to investigate the dynamics of disseminated tumour growth and efficacy of anticancer treatment in orthotopic models of peritoneal cancer in rats. It offers an attractive alternative to invasive methods, and requires fewer animals for measuring tumour response to therapy

Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn's disease

For most immune-mediated diseases, the main determinant of patient well-being is not the diagnosis itself but instead the course that the disease takes over time (prognosis). Prognosis may vary substantially between patients for reasons that are poorly understood. Familial studies support a genetic contribution to prognosis, but little evidence has been found for a proposed association between prognosis and the burden of susceptibility variants. To better characterize how genetic variation influences disease prognosis, we performed a within-cases genome-wide association study in two cohorts of patients with Crohn's disease. We identified four genome-wide significant loci, none of which showed any association with disease susceptibility. Conversely, the aggregated effect of all 170 disease susceptibility loci was not associated with disease prognosis. Together, these data suggest that the genetic contribution to prognosis in Crohn's disease is largely independent of the contribution to disease susceptibility and point to a biology of prognosis that could provide new therapeutic opportunities.This work was supported by the NIHR Cambridge Biomedical Research Centre (in particular John Todd and the NIHR BRC Genomics Theme), Crohn's and Colitis UK (Medical Research Award M/14/2), the Evelyn Trust (17/07), and the Medical Research Council (Programme Grant MR/L019027/1). J.C.L. is supported by a Wellcome Trust Intermediate Clinical Fellowship (105920/Z/14/Z) and D.B. by a Marie Curie PhD Fellowship (TranSVIR FP7-PEOPLE-ITN-2008 #238756). C.A.A. is supported by the Wellcome Trust (098051). K.G.C.S. is an NIHR Senior Investigator. This study makes use of data generated by the UK10K Consortium, derived from samples from ALSPAC and DTR cohorts. A full list of the investigators who contributed to the generation of the data is available from www.UK10K.org. Funding for UK10K was provided by the Wellcome Trust (WT091310)