Peroxisome proliferator-activated receptor delta limits the expansion of pathogenic Th cells during central nervous system autoimmunity.

Peroxisome proliferator-activated receptors (PPARs; PPAR-alpha, PPAR-delta, and PPAR-gamma) comprise a family of nuclear receptors that sense fatty acid levels and translate this information into altered gene transcription. Previously, it was reported that treatment of mice with a synthetic ligand activator of PPAR-delta, GW0742, ameliorates experimental autoimmune encephalomyelitis (EAE), indicating a possible role for this nuclear receptor in the control of central nervous system (CNS) autoimmune inflammation. We show that mice deficient in PPAR-delta (PPAR-delta(-/-)) develop a severe inflammatory response during EAE characterized by a striking accumulation of IFN-gamma(+)IL-17A(-) and IFN-gamma(+)IL-17A(+) CD4(+) cells in the spinal cord. The preferential expansion of these T helper subsets in the CNS of PPAR-delta(-/-) mice occurred as a result of a constellation of immune system aberrations that included higher CD4(+) cell proliferation, cytokine production, and T-bet expression and enhanced expression of IL-12 family cytokines by myeloid cells. We also show that the effect of PPAR-delta in inhibiting the production of IFN-gamma and IL-12 family cytokines is ligand dependent and is observed in both mouse and human immune cells. Collectively, these findings suggest that PPAR-delta serves as an important molecular brake for the control of autoimmune inflammation

HIV-1 Directly Kills CD4+ T Cells by a Fas-independent Mechanism

The mechanism by which HIV-1 induces CD4+ T cell death is not known. A fundamental issue is whether HIV-1 primarily induces direct killing of infected cells or indirectly causes death of uninfected bystander cells. This question was studied using a reporter virus system in which infected cells are marked with the cell surface protein placental alkaline phosphatase (PLAP). Infection by HIV-PLAP of peripheral blood mononuclear cells (PBMCs) and T cell lines leads to rapid depletion of CD4+ T cells and induction of apoptosis. The great majority of HIV-induced T cell death in vitro involves direct loss of infected cells rather than indirect effects on uninfected bystander cells. Because of its proposed role in HIV-induced cell death, we also examined the Fas (CD95/Apo1) pathway in killing of T cells by HIV-1. Infected PBMCs or CEM cells display no increase in surface Fas relative to uninfected cells. In addition, HIV-1 kills CEM and Jurkat T cells in the presence of a caspase inhibitor that completely blocks Fas-mediated apoptosis. HIV-1 also depletes CD4+ T cells in PBMCs from patients who have a genetically defective Fas pathway. These results suggest that HIV-1 induces direct apoptosis of infected cells and kills T cells by a Fas-independent mechanism

A systematic review of cost-effectiveness analyses of complex wound interventions reveals optimal treatments for specific wound types.

BackgroundComplex wounds present a substantial economic burden on healthcare systems, costing billions of dollars annually in North America alone. The prevalence of complex wounds is a significant patient and societal healthcare concern and cost-effective wound care management remains unclear. This article summarizes the cost-effectiveness of interventions for complex wound care through a systematic review of the evidence base.MethodsWe searched multiple databases (MEDLINE, EMBASE, Cochrane Library) for cost-effectiveness studies that examined adults treated for complex wounds. Two reviewers independently screened the literature, abstracted data from full-text articles, and assessed methodological quality using the Drummond 10-item methodological quality tool. Incremental cost-effectiveness ratios were reported, or, if not reported, calculated and converted to United States Dollars for the year 2013.ResultsOverall, 59 cost-effectiveness analyses were included; 71% (42 out of 59) of the included studies scored 8 or more points on the Drummond 10-item checklist tool. Based on these, 22 interventions were found to be more effective and less costly (i.e., dominant) compared to the study comparators: 9 for diabetic ulcers, 8 for venous ulcers, 3 for pressure ulcers, 1 for mixed venous and venous/arterial ulcers, and 1 for mixed complex wound types.ConclusionsOur results can be used by decision-makers in maximizing the deployment of clinically effective and resource efficient wound care interventions. Our analysis also highlights specific treatments that are not cost-effective, thereby indicating areas of resource savings. Please see related article: http://dx.doi.org/10.1186/s12916-015-0288-5

On the Formation Height of the SDO/HMI Fe 6173 Doppler Signal

The Helioseismic and Magnetic Imager (HMI) onboard the Solar Dynamics Observatory (SDO) is designed to study oscillations and the mag- netic field in the solar photosphere. It observes the full solar disk in the Fe I absorption line at 6173\AA . We use the output of a high-resolution 3D, time- dependent, radiation-hydrodynamic simulation based on the CO5BOLD code to calculate profiles F({\lambda},x,y,t) for the Fe I 6173{\AA} line. The emerging profiles F({\lambda},x,y,t) are multiplied by a representative set of HMI filter transmission profiles R_i({\lambda},1 \leq i \leq 6) and filtergrams I_i(x,y,t;1 \leq i \leq 6) are constructed for six wavelengths. Doppler velocities V_HMI(x,y,t) are determined from these filtergrams using a simplified version of the HMI pipeline. The Doppler velocities are correlated with the original velocities in the simulated atmosphere. The cross- correlation peaks near 100 km, suggesting that the HMI Doppler velocity signal is formed rather low in the solar atmosphere. The same analysis is performed for the SOHO/MDI Ni I line at 6768\AA . The MDI Doppler signal is formed slightly higher at around 125 km. Taking into account the limited spatial resolution of the instruments, the apparent formation height of both the HMI and MDI Doppler signal increases by 40 to 50 km. We also study how uncertainties in the HMI filter-transmission profiles affect the calculated velocities.Comment: 15 pages, 11 Figure

Health-related preferences of older patients with multimorbidity: the protocol for an evidence map

Introduction: Interaction of conditions and treatments, complicated care needs and substantial treatment burden make patient–physician encounters involving multimorbid older patients highly complex. To optimally integrate patients’ preferences, define and prioritise realistic treatment goals and individualise care, a patient-centred approach is recommended. However, the preferences of older patients, who are especially vulnerable and frequently multimorbid, have not been systematically investigated with regard to their health status. The purpose of this evidence map is to explore current research addressing health-related preferences of older patients with multimorbidity, and to identify the knowledge clusters and research gaps. Methods and analysis: To identify relevant research, we will conduct searches in the electronic databases MEDLINE, EMBASE, PsycINFO, PSYNDEX, CINAHL, Social Science Citation Index, Social Science Citation Index Expanded and the Cochrane library from their inception. We will check reference lists of relevant articles and carry out cited reference research (forward citation tracking). Two independent reviewers will screen titles and abstracts, check full texts for eligibility and extract the data. Any disagreement will be resolved and consensus reached with the help of a third reviewer. We will include both qualitative and quantitative studies, and address preferences from the patients’ perspectives in a multimorbid population of 60 years or older. There will be no restrictions on the publication language. Data extraction tables will present study and patient characteristics, aim of study, methods used to identify preferences and outcomes (ie, type of preferences). We will summarise the data using tables and figures (ie, bubble plot) to present the research landscape and to describe clusters and gaps. Ethics and dissemination: Due to the nature of the proposed evidence map, ethics approval will not be required. Results from our research will be disseminated by means of specifically prepared materials for patients, at relevant (inter)national conferences and via publication in peer-reviewed journals

The Co-occurrence of child and intimate partner maltreatment in the family: characteristics of the violent perpetrators

This study considers the characteristics associated with mothers and fathers who maltreat their child and each other in comparison to parents who only maltreat their child. One hundred and sixty-two parents who had allegations of child maltreatment made against them were considered. The sample consisted of 43 fathers (Paternal Family—PF) and 23 mothers (Maternal Family—MF) who perpetrated both partner and child maltreatment, together with 23 fathers (Paternal Child—PC) and 26 mothers (Maternal Child—MC) who perpetrated child maltreatment only. In addition, 2 fathers (Paternal Victim—PV) and 23 mothers (Maternal Victim—MV) were victims of intimate partner maltreatment and perpetrators of child maltreatment and 7 fathers (Paternal Non-abusive Carer—PNC) and 15 mothers (Maternal Non-abusive Carer—MNC) did not maltreat the child but lived with an individual who did. Within their family unit, 40.7% of parents perpetrated both intimate partner and child maltreatment. However, fathers were significantly more likely to maltreat both their partner and child than mothers and mothers were significantly more likely to be victims of intimate partner violence than fathers. PF fathers conducted the highest amount of physical and/or sexual child maltreatment while MC and MV mothers perpetrated the highest amount of child neglect. Few significant differences between mothers were found. PF fathers had significantly more factors associated with development of a criminogenic lifestyle than PC fathers. Marked sex differences were demonstrated with PF fathers demonstrating significantly more antisocial characteristics, less mental health problems and fewer feelings of isolation than MF mothers. MC mothers had significantly more childhood abuse, mental health problems, parenting risk factors and were significantly more likely to be biologically related to the child than PC fathers. This study suggests that violent families should be assessed and treated in a holistic manner, considering the effects of partner violence upon all family members, rather than exclusively intervening with the violent man

Decontextualizing contextual inversion

Contextual inversion, introduced as an analytical tool by David Lewin, is a concept of wide reach and value in music theory and analysis, at the root of neo-Riemannian theory as well as serial theory, and useful for a range of analytical applications. A shortcoming of contextual inversion as it is currently understood, however, is, as implied by the name, that the transformation has to be defined anew for each application. This is potentially a virtue, requiring the analyst to invest the transformational system with meaning in order to construct it in the first place. However, there are certainly instances where new transformational systems are continually redefined for essentially the same purposes. This paper explores some of the most common theoretical bases for contextual inversion groups and considers possible definitions of inversion operators that can apply across set class types, effectively decontextualizing contextual inversions.Accepted manuscrip

Contacting authors to retrieve individual patient data study protocol for a randomized controlled trial

BACKGROUND: Individual patient data (IPD) meta-analysis is considered the "gold standard" for exploring the effectiveness of interventions in different subgroups of patients. However, obtaining IPD is time-consuming and contact with the researchers responsible for the original trials is usually required. To date, there are no studies evaluating different strategies to optimize the process for retrieval of IPD from such researchers. Our aim is to examine the impact of providing incentives to the researchers responsible for the trials eligible for a meta-analysis to submit their IPD.METHODS/DESIGN: We updated our previously published systematic reviews for type 1 diabetes mellitus comparing long- and intermediate-acting insulin regimens (from January 2013 to June 2015) and for Alzheimer's dementia comparing cognitive enhancers (from January 2015 to May 2015). Eligible were randomized controlled trials (RCTs) fulfilling the eligibility criteria of the systematic reviews. We will randomly allocate authors of the reports of these RCTs into an intervention or control group. Those allocated to the intervention group will be contacted by email, mail, and phone, and will be asked to provide the IPD from their RCT and will be given a financial incentive. Those allocated to the control group will be contacted by email, mail, and phone, but will not receive a financial incentive. Our primary outcome will be the proportion of authors who provide the IPD. The secondary outcomes will be the time to return the dataset (defined as the period between the information request and the authors' response with the dataset), and completeness of data. We will compare the response rates in the two groups using the odds ratio and the corresponding 95 % confidence interval. We will also use binary logistic regression and cox regression analyses to examine whether different RCT characteristics, such as study size and sponsor information, influence the probability of providing IPD and the time needed to share the data.DISCUSSION: This study will determine whether a financial incentive affects response rates when seeking IPD from the original researchers. We will disseminate our findings in an open access scientific journal and present results at national and international conferences.TRIAL REGISTRATION: This trial is registered in Clinical Trials.gov, ID number NCT02569411 . Date of registration 5 October 2015.</p

Measurement of Sibling Violence: A Two-Factor Model of Severity

The measurement of violence is a major challenge in aggression research. Because of the heterogeneous nature of violent behavior, problems arise when applying blanket measures to inherently distinct subtypes of aggression. Incidents of intersibling violence (ISV) exacerbate these problems because siblinghood represents a unique offender–victim situation. This research explored whether an existing two-factor model for severe violence found in a sample of 250 adult offenders (age M = 26.8, SD = 5.9) could be generalized to deliberate severe ISV in a sample of 111 young offenders (age M = 14.83, SD = 1.45). Exploratory factor analysis revealed a two-factor model encompassing severe ISV perpetration with weapon use (Factor 1) and severe ISV perpetration without weapon use (Factor 2). The results provide strong empirical support for the two-factor model of violence severity previously established with adult offenders. This analysis demonstrates construct validity of the severity measures among the different types of offenders studied and provides support for generalization across populations