Induction of humoral immune response to multiple recombinant Rhipicephalus appendiculatus antigens and their effect on tick feeding success and pathogen transmission

BACKGROUND: Rhipicephalus appendiculatus is the primary vector of Theileria parva, the etiological agent of East Coast fever (ECF), a devastating disease of cattle in sub-Saharan Africa. We hypothesized that a vaccine targeting tick proteins that are involved in attachment and feeding might affect feeding success and possibly reduce tick-borne transmission of T. parva. Here we report the evaluation of a multivalent vaccine cocktail of tick antigens for their ability to reduce R. appendiculatus feeding success and possibly reduce tick-transmission of T. parva in a natural host-tick-parasite challenge model. METHODS: Cattle were inoculated with a multivalent antigen cocktail containing recombinant tick protective antigen subolesin as well as two additional R. appendiculatus saliva antigens: the cement protein TRP64, and three different histamine binding proteins. The cocktail also contained the T. parva sporozoite antigen p67C. The effect of vaccination on the feeding success of nymphal and adult R. appendiculatus ticks was evaluated together with the effect on transmission of T. parva using a tick challenge model. RESULTS: To our knowledge, this is the first evaluation of the anti-tick effects of these antigens in the natural host-tick-parasite combination. In spite of evidence of strong immune responses to all of the antigens in the cocktail, vaccination with this combination of tick and parasite antigens did not appear to effect tick feeding success or reduce transmission of T. parva. CONCLUSION: The results of this study highlight the importance of early evaluation of anti-tick vaccine candidates in biologically relevant challenge systems using the natural tick-host-parasite combination

The impact of traumatic stress on Pavlovian biases

BACKGROUND: Disturbances in Pavlovian valuation systems are reported to follow traumatic stress exposure. However, motivated decisions are also guided by instrumental mechanisms, but to date the effect of traumatic stress on these instrumental systems remain poorly investigated. Here, we examine whether a single episode of severe traumatic stress influences flexible instrumental decisions through an impact on a Pavlovian system. METHODS: Twenty-six survivors of the 2011 Norwegian terror attack and 30 matched control subjects performed an instrumental learning task in which Pavlovian and instrumental associations promoted congruent or conflicting responses. We used reinforcement learning models to infer how traumatic stress affected learning and decision-making. Based on the importance of dorsal anterior cingulate cortex (dACC) for cognitive control, we also investigated if individual concentrations of Glx (=glutamate + glutamine) in dACC predicted the Pavlovian bias of choice. RESULTS: Survivors of traumatic stress expressed a greater Pavlovian interference with instrumental action selection and had significantly lower levels of Glx in the dACC. Across subjects, the degree of Pavlovian interference was negatively associated with dACC Glx concentrations. CONCLUSIONS: Experiencing traumatic stress appears to render instrumental decisions less flexible by increasing the susceptibility to Pavlovian influences. An observed association between prefrontal glutamatergic levels and this Pavlovian bias provides novel insight into the neurochemical basis of decision-making, and suggests a mechanism by which traumatic stress can impair flexible instrumental behaviours

Under pressure: Response urgency modulates striatal and insula activity during decision-making under risk

When deciding whether to bet in situations that involve potential monetary loss or gain (mixed gambles), a subjective sense of pressure can influence the evaluation of the expected utility associated with each choice option. Here, we explored how gambling decisions, their psychophysiological and neural counterparts are modulated by an induced sense of urgency to respond. Urgency influenced decision times and evoked heart rate responses, interacting with the expected value of each gamble. Using functional MRI, we observed that this interaction was associated with changes in the activity of the striatum, a critical region for both reward and choice selection, and within the insula, a region implicated as the substrate of affective feelings arising from interoceptive signals which influence motivational behavior. Our findings bridge current psychophysiological and neurobiological models of value representation and action-programming, identifying the striatum and insular cortex as the key substrates of decision-making under risk and urgency

Effect of parasympathetic stimulation on brain activity during appraisal of fearful expressions

Autonomic nervous system activity is an important component of human emotion. Mental processes influence bodily physiology, which in turn feeds back to influence thoughts and feelings. Afferent cardiovascular signals from arterial baroreceptors in the carotid sinuses are processed within the brain and contribute to this two-way communication with the body. These carotid baroreceptors can be stimulated non-invasively by externally applying focal negative pressure bilaterally to the neck. In an experiment combining functional neuroimaging (fMRI) with carotid stimulation in healthy participants, we tested the hypothesis that manipulating afferent cardiovascular signals alters the central processing of emotional information (fearful and neutral facial expressions). Carotid stimulation, compared with sham stimulation, broadly attenuated activity across cortical and brainstem regions. Modulation of emotional processing was apparent as a significant expression-by-stimulation interaction within left amygdala, where responses during appraisal of fearful faces were selectively reduced by carotid stimulation. Moreover, activity reductions within insula, amygdala, and hippocampus correlated with the degree of stimulation-evoked change in the explicit emotional ratings of fearful faces. Across participants, individual differences in autonomic state (heart rate variability, a proxy measure of autonomic balance toward parasympathetic activity) predicted the extent to which carotid stimulation influenced neural (amygdala) responses during appraisal and subjective rating of fearful faces. Together our results provide mechanistic insight into the visceral component of emotion by identifying the neural substrates mediating cardiovascular influences on the processing of fear signals, potentially implicating central baroreflex mechanisms for anxiolytic treatment targets

A retrospective study of cochlear implant outcomes in children with residual hearing

BACKGROUND: There has been increasing demand for the cochlear implantation of children who demonstrate some auditory capacity with conventional hearing aids. The purpose of this study was to examine speech recognition outcomes in a group of children who were regarded as borderline candidates for cochlear implantation as their residual hearing and/or auditory functioning levels exceeded typical audiologic candidacy criteria. METHODS: A retrospective chart review was undertaken at one Canadian cochlear implant centre to identify children implanted at age 4 or older with a pure-tone-average of 90 dB or better and speech recognition of 30% or greater. Pre-implant and post-implant open-set word and sentence test scores were analyzed. RESULTS: Eleven children of 195 paediatric cochlear implant recipients met the inclusion criteria for this study. Speech recognition results for the10 English-speaking children indicated significant gains in both open-set word and sentence understanding within the first 6 to 12 months of implant use. Seven of 9 children achieved 80% open-set sentence recognition within 12 months post-surgery. CONCLUSION: Children with several years of experience using conventional amplification demonstrated rapid progress in auditory skills following cochlear implantation. These findings suggest that cochlear implantation may be an appropriate intervention for selected children with severe hearing losses and/or auditory capacity outside current candidacy criteria

Globally convergent evolution strategies for constrained optimization

International audienceIn this paper we propose, analyze, and test algorithms for constrained optimization when no use of derivatives of the objective function is made. The proposed methodology is built upon the globally convergent evolution strategies previously introduced by the authors for unconstrained optimization. Two approaches are encompassed to handle the constraints. In a first approach, feasibility is first enforced by a barrier function and the objective function is then evaluated directly at the feasible generated points. A second approach projects first all the generated points onto the feasible domain before evaluating the objective function.The resulting algorithms enjoy favorable global convergence properties (convergence to stationarity from arbitrary starting points), regardless of the linearity of the constraints.The algorithmic implementation (i) includes a step where previously evaluated points are used to accelerate the search (by minimizing quadratic models) and (ii) addresses the particular cases of bounds on the variables and linear constraints. Our solver is compared to others, and the numerical results confirm its competitiveness in terms of efficiency and robustness

Trading people versus trading time: What is the difference?

BACKGROUND: Person trade-off (PTO) elicitations yield different values than standard utility measures, such as time trade-off (TTO) elicitations. Some people believe this difference arises because the PTO captures the importance of distributive principles other than maximizing treatment benefits. We conducted a qualitative study to determine whether people mention considerations related to distributive principles other than QALY-maximization more often in PTO elicitations than in TTO elicitations and whether this could account for the empirical differences. METHODS: 64 members of the general public were randomized to one of three different face-to-face interviews, thinking aloud as they responded to TTO and PTO elicitations. Participants responded to a TTO followed by a PTO elicitation within contexts that compared either: 1) two life-saving treatments; 2) two cure treatments; or 3) a life-saving treatment versus a cure treatment. RESULTS: When people were asked to choose between life-saving treatments, non-maximizing principles were more common with the PTO than the TTO task. Only 5% of participants considered non-maximizing principles as they responded to the TTO elicitation compared to 68% of participants who did so when responding to the PTO elicitation. Non-maximizing principles that emerged included importance of equality of life and a desire to avoid discrimination. However, these principles were less common in the other two contexts. Regardless of context, though, participants were significantly more likely to respond from a societal perspective with the PTO compared to the TTO elicitation. CONCLUSION: When lives are at stake, within the context of a PTO elicitation, people are more likely to consider non-maximizing principles, including the importance of equal access to a life-saving treatment, avoiding prejudice or discrimination, and in rare cases giving treatment priority based purely on the position of being worse-off

The impact of a decision aid about heart disease prevention on patients' discussions with their doctor and their plans for prevention: a pilot randomized trial

BACKGROUND: Low utilization of effective coronary heart disease (CHD) prevention strategies may be due to many factors, but chief among them is the lack of patient involvement in prevention decisions. We undertook this study to test the effectiveness of an individually-tailored, computerized decision aid about CHD on patients' discussions with their doctor and their plans for CHD prevention. METHODS: We conducted a pilot randomized trial in a convenience sample of adults with no previous history of cardiovascular disease to test the effectiveness of an individually-tailored, computerized decision aid about CHD prevention against a risk factor list that patients could present to their doctor. RESULTS: We enrolled 75 adults. Mean age was 53. 59% were female, 73% white, and 23% African-American. 66% had some college education. 43% had a 10-year CHD risk of 0–5%, 25% a risk of 6–10%, 24% a risk of 11–20%, and 5% a risk of > 20%. 78% had at least one option to reduce their CHD risk, but only 45% accurately identified the strategies best supported by evidence. 41 patients received the decision aid, 34 received usual care. In unadjusted analysis, the decision aid increased the proportion of patients who discussed CHD risk reduction with their doctor from 24% to 40% (absolute difference 16%; 95% CI -4% to +37%) and increased the proportion who had a specific plan to reduce their risk from 24% to 37% (absolute difference 13%; 95% CI -7% to +34%). In pre-post testing, the decision aid also appeared to increase the proportion of patients with plans to intervene on their CHD risk (absolute increase ranging from 21% to 47% for planned medication use and 5% to 16% for planned behavioral interventions). CONCLUSION: Our study confirms patients' limited knowledge about their CHD risk and effective risk reduction options and provides preliminary evidence that an individually-tailored decision aid about CHD prevention might be expected to increase patients' discussions about CHD prevention with their doctor and their plans for CHD risk reduction. These findings should be replicated in studies with a larger sample size and patients at overall higher risk of CHD. Trial Registration: ClinicalTrials.gov NCT0031597