Context dependence of the event-related brain potential associated with reward and punishment

The error-related negativity (ERN) is an event-related brain potential elicited by error commission and by presentation of feedback stimuli indicating incorrect performance. In this study, the authors report two experiments in which participants tried to learn to select between response options by trial and error, using feedback stimuli indicating monetary gains and losses. The results demonstrate that the amplitude of the ERN is determined by the value of the eliciting outcome relative to the range of outcomes possible, rather than by the objective value of the outcome. This result is discussed in terms of a recent theory that holds that the ERN reflects a reward prediction error signal associated with a neural system for reinforcement learning

Face Coverings Differentially Alter Valence Judgments of Emotional Expressions

Face masks that prevent disease transmission obscure facial expressions, impairing nonverbal communication. We assessed the impact of lower (masks) and upper (sunglasses) face coverings on emotional valence judgments of clearly valenced (fearful, happy) and ambiguously valenced (surprised) expressions, the latter of which have both positive and negative meanings. Masks, but not sunglasses, impaired judgments of clearly valenced expressions compared to faces without coverings. Drift diffusion models revealed that lower, but not upper, face coverings slowed evidence accumulation and affected differences in non-judgment processes (i.e., stimulus encoding, response execution time) for all expressions. Our results confirm mask-interference effects in nonverbal communication. The findings have implications for nonverbal and intergroup communication, and we propose guidance for implementing strategies to overcome mask-related interference

Fixation of osteochondral fragments in the human knee using Meniscus Arrows®

The aim of this study is to compare the hold in bone of Meniscus Arrows® and Smart Nails®, followed by the report of the results of the clinical application of Meniscus Arrows® as fixation devices. First, pull-out tests were performed to analyse the holdfast of both nails in bone. Statistical analysis showed no significant difference; therefore, the thinner Meniscus Arrow® was chosen as fixation device in the patient series of two patients with a symptomatic Osteochondritis dissecans fragment and three patients with an osteochondral fracture of a femur condyle. The cartilage margins were glued with Tissuecoll®. All fragments consolidated. Second look arthroscopy in three patients showed fixed fragments with stable, congruent cartilage edges. At an average follow-up period of 5 years no pain, effusion, locking, restricted range of motion or signs of osteoarthritis were reported. Based on the results of the pull-out tests and available clinical studies, Meniscus Arrows® and Smart Nails® are both likely to perform adequately as fixation devices in the treatment of Osteochondritis dissecans and osteochondral fractures in the knee. They both provide the advantage of one stage surgery. However, based on their smaller diameter, the Meniscus Arrows® should be preferred for this indication

A pragmatic cluster randomized trial evaluating the impact of a community pharmacy intervention on statin adherence: rationale and design of the Community Pharmacy Assisting in Total Cardiovascular Health (CPATCH) study

<p>Abstract</p> <p>Background</p> <p>Traditional randomized controlled trials are considered the gold standard for evaluating the efficacy of a treatment. However, in adherence research, limitations to this study design exist, especially when evaluating real-world applicability of an intervention. Although adherence interventions by community pharmacists have been tested, problems with internal and external validity have limited the usefulness of these studies, and further well-designed and well-conducted research is needed. We aimed to determine the real-world effectiveness of a community pharmacy adherence intervention using a robust study design. This novel design integrates cluster randomization and an outcome evaluation of medication adherence using a population-based administrative data source in the province of Saskatchewan, Canada.</p> <p>Methods/Design</p> <p>Community pharmacies from across the province of Saskatchewan, Canada were randomized to deliver an adherence intervention to their patients or usual care. Intervention pharmacies were trained to employ a practical adherence strategy targeted at new users of statin medications. While randomization and implementation of the intervention occurred at the community pharmacy level, the outcome analysis will occur at the level of the individual subjects. The primary outcome is the mean statin adherence among all eligible new users of statin medications. Secondary outcomes include the proportion of new statin users who exhibit adherence ≥80%, and persistence with statin use.</p> <p>Discussion</p> <p>This novel study design was developed to combine the rigor of a randomized trial with a pragmatic approach to implementing and capturing the results in a real-world fashion. We believe this approach can serve as an example for future study designs evaluating practice-based adherence interventions.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov no. NCT00971412.</p

Enhancer viruses and a transgenic platform for combinatorial cell subclass-specific labeling

The rapid pace of cell type identification by new single-cell analysis methods has not been met with efficient experimental access to the newly discovered types. To enable flexible and efficient access to specific neural populations in the mouse cortex, we collected chromatin accessibility data from individual cells and clustered the single-cell data to identify enhancers specific for cell classes and subclasses. When cloned into adeno-associated viruses (AAVs) and delivered to the brain by retro-orbital injections, these enhancers drive transgene expression in specific cell subclasses in the cortex. We characterize several enhancer viruses in detail to show that they result in labeling of different projection neuron subclasses in mouse cortex, and that one of them can be used to label the homologous projection neuron subclass in human cortical slices. To enable the combinatorial labeling of more than one cell type by enhancer viruses, we developed a three-color Cre-, Flp- and Nigri- recombinase dependent reporter mouse line, Ai213. The delivery of three enhancer viruses driving these recombinases via a single retroorbital injection into a single Ai213 transgenic mouse results in labeling of three different neuronal classes/subclasses in the same brain tissue. This approach combines unprecedented flexibility with specificity for investigation of cell types in the mouse brain and beyond

Metabolism and Toxicity of Thioacetamide and Thioacetamide SOxide in Rat Hepatocytes

“This document is the Accepted Manuscript version of a Published Work that appeared in final form in Chemical Research in Toxicology, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/tx3002719The hepatotoxicity of thioacetamide (TA) has been known since 1948. In rats, single doses cause centrilobular necrosis accompanied by increases in plasma transaminases and bilirubin. To elicit these effects TA requires oxidative bioactivation leading first to its S-oxide (TASO) and then to its chemically reactive S,S-dioxide (TASO2) which ultimately modifies amine-lipids and proteins. To generate a suite of liver proteins adducted by TA metabolites for proteomic analysis, and to reduce the need for both animals and labeled compounds, we treated isolated hepatocytes directly with TA. Surprisingly, TA was not toxic at concentrations up to 50 mM for 40 hr. On the other hand, TASO was highly toxic to isolated hepatocytes as indicated by LDH release, cellular morphology and vital staining with Hoechst 33342/propidium iodide. TASO toxicity was partially blocked by the CYP2E1 inhibitors diallyl sulfide and 4-methylpyrazole, and was strongly inhibited by TA. Significantly, we found that hepatocytes produce TA from TASO relatively efficiently by back-reduction. The covalent binding of [14C]-TASO is inhibited by unlabeled TA which acts as a “cold-trap” for [14C]-TA and prevents its re-oxidation to [14C]-TASO. This in turn increases the net consumption of [14C]-TASO despite the fact that its oxidation to TASO2 is inhibited. The potent inhibition of TASO oxidation by TA, coupled with the back-reduction of TASO and its futile redox cycling with TA may help explain phenomena previously interpreted as “saturation toxicokinetics” in the in vivo metabolism and toxicity of TA and TASO. The improved understanding of the metabolism and covalent binding of TA and TASO facilitates the use of hepatocytes to prepare protein adducts for target protein identification

A Critical Role for CD8 T Cells in a Nonhuman Primate Model of Tuberculosis

The role of CD8 T cells in anti-tuberculosis immunity in humans remains unknown, and studies of CD8 T cell–mediated protection against tuberculosis in mice have yielded controversial results. Unlike mice, humans and nonhuman primates share a number of important features of the immune system that relate directly to the specificity and functions of CD8 T cells, such as the expression of group 1 CD1 proteins that are capable of presenting Mycobacterium tuberculosis lipids antigens and the cytotoxic/bactericidal protein granulysin. Employing a more relevant nonhuman primate model of human tuberculosis, we examined the contribution of BCG- or M. tuberculosis-elicited CD8 T cells to vaccine-induced immunity against tuberculosis. CD8 depletion compromised BCG vaccine-induced immune control of M. tuberculosis replication in the vaccinated rhesus macaques. Depletion of CD8 T cells in BCG-vaccinated rhesus macaques led to a significant decrease in the vaccine-induced immunity against tuberculosis. Consistently, depletion of CD8 T cells in rhesus macaques that had been previously infected with M. tuberculosis and cured by antibiotic therapy also resulted in a loss of anti-tuberculosis immunity upon M. tuberculosis re-infection. The current study demonstrates a major role for CD8 T cells in anti-tuberculosis immunity, and supports the view that CD8 T cells should be included in strategies for development of new tuberculosis vaccines and immunotherapeutics

A Multi-Lab Test of the Facial Feedback Hypothesis by the Many Smiles Collaboration

Following theories of emotional embodiment, the facial feedback hypothesis suggests that individuals’ subjective experiences of emotion are influenced by their facial expressions. However, evidence for this hypothesis has been mixed. We thus formed a global adversarial collaboration and carried out a preregistered, multicentre study designed to specify and test the conditions that should most reliably produce facial feedback effects. Data from n = 3,878 participants spanning 19 countries indicated that a facial mimicry and voluntary facial action task could both amplify and initiate feelings of happiness. However, evidence of facial feedback effects was less conclusive when facial feedback was manipulated unobtrusively via a pen-in-mouth task