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BackgroundProgressive supranuclear palsy is a neurodegenerative disorder associated with tau protein aggregation. Tilavonemab (ABBV-8E12) is a monoclonal antibody that binds to the N-terminus of human tau. We assessed the safety and efficacy of tilavonemab for the treatment of progressive supranuclear palsy.MethodsWe did a phase 2, multicentre, randomised, placebo-controlled, double-blind study at 66 hospitals and clinics in Australia, Canada, France, Germany, Italy, Japan, Spain, and the USA. Participants (aged ≥40 years) diagnosed with possible or probable progressive supranuclear palsy who were symptomatic for less than 5 years, had a reliable study partner, and were able to walk five steps with minimal assistance, were randomly assigned (1:1:1) by interactive response technology to tilavonemab 2000 mg, tilavonemab 4000 mg, or matching placebo administered intravenously on days 1, 15, and 29, then every 28 days through to the end of the 52-week treatment period. Randomisation was done by the randomisation specialist of the study sponsor, who did not otherwise participate in the study. The sponsor, investigators, and participants were unaware of treatment allocations. The primary endpoint was the change from baseline to week 52 in the Progressive Supranuclear Palsy Rating Scale (PSPRS) total score in the intention-to-treat population. Adverse events were monitored in participants who received at least one dose of study drug. Prespecified interim futility criteria were based on a model-based effect size of 0 or lower when 60 participants had completed the 52-week treatment period and 0·12 or lower when 120 participants had completed the 52-week treatment period. This study is registered at ClinicalTrials.gov, number NCT02985879.FindingsBetween Dec 12, 2016, and Dec 31, 2018, 466 participants were screened, 378 were randomised. The study was terminated on July 3, 2019, after prespecified futility criteria were met at the second interim analysis. A total of 377 participants received at least one dose of study drug and were included in the efficacy and safety analyses (2000 mg, n=126; 4000 mg, n=125; placebo, n=126). Least squares mean change from baseline to week 52 in PSPRS was similar in all groups (between-group difference vs placebo: 2000 mg, 0·0 [95% CI -2·6 to 2·6], effect size 0·000, p>0·99; 4000 mg, 1·0 [-1·6 to 3·6], -0·105, p=0·46). Most participants reported at least one adverse event (2000 mg, 111 [88%]; 4000 mg, 111 [89%]; placebo, 108 [86%]). Fall was the most common adverse event (2000 mg, 42 [33%]; 4000 mg, 54 [43%]; placebo, 49 [39%]). Proportions of patients with serious adverse events were similar among groups (2000 mg, 29 [23%]; 4000 mg, 34 [27%]; placebo, 33 [26%]). Fall was the most common treatment-emergent serious adverse event (2000 mg, five [4%]; 4000 mg, six [5%]; placebo, six [5%]). 26 deaths occurred during the study (2000 mg, nine [7%]; 4000 mg, nine [7%]; placebo, eight [6%]) but none was drug related.InterpretationA similar safety profile was seen in all treatment groups. No beneficial treatment effects were recorded. Although this study did not provide evidence of efficacy in progressive supranuclear palsy, the findings provide potentially useful information for future investigations of passive immunisation using tau antibodies for progressive supranuclear palsy.FundingAbbVie Inc.

Sensory issues are highly prevalent in autism and previous findings support a relationship between questionnaires of sensitivity and autistic symptoms and traits, whereas studies that examine this relationship through behavioural assessments of sensitivity are less consistent. The current study explores these differences and suggests that behavioural thresholds for sensitivity and subjective sensitivity are distinct constructs. One hundred and eighteen adults completed a visual and auditory detection task and questionnaires on sensory processing and autistic traits. Visual thresholds and subjective visual sensitivity were not correlated, but both were related to autistic traits. Auditory thresholds and subjective auditory sensitivity were also unrelated. Overall, sensitivity is highly associated with autistic traits, however, behavioural and questionnaire assessments lack convergent validity and therefore, likely assess distinct constructs.

Tracking one’s performance over time is essential to efficientself-guided learning but it is not clear whether young childrencan accurately monitor their past performance. Here, welooked at whether 4-6-year-olds can use the trajectory of theirpast performance to allocate future resources. Across fourexperiments (N = 274), we found that children were sensitiveto their rate of change in past performance: Children assignedto a condition in which they got better over time were morelikely to take on challenges and teach others than children inconditions where they got worse or stayed the same.Furthermore, children privileged their rate and direction ofchange more than their total or final score. These resultssuggest that young children monitor their rate of improvementand can use this information to guide their future efforts.

Restricted interests and repetitive behaviors (RRBs) are core symptoms of autism spectrum disorder (ASD), and commonly occur in attention-deficit/hyperactivity disorder (ADHD). Little is known about how RRBs manifest in ADHD. We quantified and compared factor structures of RRBs in children with ASD (n = 634) or ADHD (n = 448), and related factors to sex and IQ. A four-factor solution emerged, including Stereotypy, Self-Injury, Compulsions, and Ritualistic/Sameness. Factor structures were equivalent across diagnoses, though symptoms were more severe in ASD. IQ negatively correlated with Stereotypy, Self-Injury, and Compulsions in ASD, and negatively correlated with Compulsions and Ritualistic/Sameness behaviors in ADHD. In ASD only, females exhibited higher Self-Injury. Thus, patterns of RRBs are preserved across ASD and ADHD, but severity and relationship with IQ differed.

Recent studies have suggested that individuals who exhibit heightened sensitivity also exhibit higher rates and severity of restricted interests and repetitive behaviours. This line of research has been conducted almost exclusively through caregiver reports of sensitivity. Here, a more rigorous psychophysics paradigm was applied to assess sensory sensitivity and relate hypersensitivity to restricted interests and repetitive behaviours. In addition, commonly used questionnaire measures of sensory sensitivity were collected to determine if self-reported measures accurately reflect behavioural measures of sensory sensitivity. In all, 90 typically developing participants completed a visual detection task, a questionnaire measure of sensory processing and a measure of restricted interests and repetitive behaviours. Visual sensitivity, measured both behaviourally and with questionnaires, is positively related to restricted interests and repetitive behaviours. Surprisingly, visual sensitivity as measured behaviourally and through self-report are unrelated. Furthermore, a regression analysis suggests that while restricted interests and repetitive behaviours can be predicted based on both behavioural and self-reported sensitivity, these two predictors account for different portions of the variance in restricted interests and repetitive behaviours. Thus, while these results provide evidence supporting the contribution of sensory sensitivity to restricted interests and repetitive behaviours, these results also indicate that behavioural and questionnaire measures of sensory sensitivity are measuring two distinct constructs. We hypothesize that behavioural measures are measuring sensory "sensitivity", while questionnaires measures are in fact measuring sensory "reactivity."

It has been assumed that dental conditions cause disorders of the equine temporomandibular joint (TMJ), due to biomechanical overload or aberrant loading. However, the incidence of published TMJ disorders in horses is low and this leads to the question whether the equine TMJ is adapted well to its biomechanical requirements or is able to remodel its articular surfaces in response to modified loading conditions. The aim of this study was to determine the histological characteristics of healthy equine TMJs. The tissue components of the articular surfaces of 10 TMJs obtained from horses without any clinical history of dental or TMJ disorders were analysed. Apart from the mandibular fossa of the temporal bone, the osseous aspects of the TMJ exhibited a uniform zoning pattern. The articular surfaces were composed of three tissue layers: (1) a superficial cell-rich dense connective tissue layer; (2) a middle fibrocartilage layer; and (3) a deep hyaline-like cartilage layer. The articular disc was composed of an inner core of fibrocartilage and hyaline-like cartilage meshwork covered with both cell-rich dense connective tissue and fibrocartilage at its dorsal and ventral aspects. In contrast, the mandibular fossa was only covered by a dense connective tissue, frequently supplemented by a synovial membrane, suggesting low biomechanical stress. Glycosaminoglycans, which are indicative of compressive loads, were predominantly present within the rostral part of the articular tubercle and the retroarticular process, the dorsal part of articular disc and the entire mandibular head, but were absent within the mandibular fossa. The results of this study suggest the presence of different biomechanical demands in the dorsal and ventral compartment of the equine TMJ.

In this study, we investigate whether emotional expressionsprovide cues to knowledge sufficient for predicting others’behavior based on their true and false beliefs. We adapted theclassic Sally-Anne task (Baron-Cohen, Leslie, & Frith, 1985)such that children (N = 62, mean: 5.58 years, range: 4.05-6.98years) were not told whether Sally saw Anne move the objector not. However, when Sally came back looking angry, evenfour-year-olds inferred that she had seen Anne move her toy;when she came back looking happy, children inferred that shehad not seen the transfer. Based on these inferences, five andsix-year-olds, although not four-year-olds, were able topredict where Sally would look for her toy.

Emotional expressions are typically transient; while we mayreact emotionally to a new event, we are unlikely to respondwith the same emotion once the event becomes familiar. Herewe look at whether toddlers understand the relationshipbetween people’s epistemic states and their emotionalresponses. Younger (12-17-month) and older (18-24-month)toddlers were familiarized with a movie in which an observerwas knowledgeable or ignorant about a recurring event. On thetest trial, the observer saw the event and either remained neutralor changed to a valenced emotional reaction (positive ornegative). We predicted that the change from a neutral to avalenced expression would be more surprising if the event wasfamiliar to the observer than if the event was novel. We foundan interaction between epistemic state and emotion for olderbut not younger toddlers. These results suggest that before agetwo, children begin to understand the transient nature ofemotional reactions and their dependence on people’sepistemic states.

In cooperative activities, all parties have a shared goalbut may not have the same set of skills. The currentstudy considers whether preschoolers are sensitive toprobable differences in individuals’ competence whenallocating roles. We found that 3.5- to 5.5-year-olds userelative competence, as indexed by the age of theirintended partner, to determine who should do the harderand easier of two tasks in a cooperative interaction. Asecond experiment demonstrated that children allocateroles differently in a competitive context. Youngchildren infer differences in others’ ability and candivide labor efficiently to achieve their goals.

We investigate children’s ability to use social display rules toinfer agents’ otherwise under-determined desires. InExperiment 1, seven-to-ten-year-olds saw a protagonistexpress one emotional reaction to an event in front of hersocial partner (the Social Context), and a different expressionbehind her social partner’s back (the Nonsocial Context).Children were able to use the expression in the Social Contextto infer the social partner’s desire and the expression in theNonsocial Context to infer the protagonist’s desire. Thisability increased between ages seven and ten (Experiment 1).When task demands were reduced (Experiment 2), seven-to-eight-year-olds, but not five-to-six-year-olds, succeeded.These results suggest that although it is not easy for observersto infer emotions masked by social display rules, changingemotional expressions between social and non-social contextsallow even children to recover not only the desire of theperson displaying the emotions, but also that of the audience.

The objective of this study was to examine the relationship between sensory hypersensitivity and restricted interests and repetitive behaviours associated with autism spectrum disorder and their typically-developing peers. Furthermore, the aims included the examination of the relationship across sensory modalities and various types of restricted interests and repetitive behaviours. Data were collected from the parents of 114 children: 49 of whom were diagnosed with autism spectrum disorder and 65 typically-developing children. Parents completed the Sensory Profile 2 -- Child Version and the Repetitive Behaviours Questionnaire, Second Edition. The results suggested that sensory hypersensitivity is strongly related to the core autism spectrum disorder symptom of repetitive behaviours. This relationship was not specific to autism spectrum disorder; repetitive behaviours significantly increased with sensory hypersensitivity in typically-developing individuals as well. This effect was consistent across all modalities in both autism spectrum disorder and typically developing groups; group differences were observed in the oral and tactile modalities. Furthermore, sensory hypersensitivity was significantly predictive of repetitive behaviours in all participants, autism spectrum disorder and typically-developing, and importantly, autism spectrum disorder diagnosis did not add any predictive influence above and beyond sensory hypersensitivity. Finally, sensory hypersensitivity was significantly predictive of all subdomains of repetitive behaviours, including repetitive motor movements, rigidity and adherence to routine, preoccupation with restricted patterns of interest and unusual sensory interests, and diagnosis added no predictive ability beyond sensory hypersensitivity.

In the last decade, the equine masticatory apparatus has received much attention. Numerous studies have emphasized the importance of the temporomandibular joint (TMJ) in the functional process of mastication. However, ultrastructural and histological data providing a basis for biomechanical and histopathological considerations are not available. The aim of the present study was to analyze the architecture of the collagen fiber apparatus in the articular surfaces of the equine TMJ to reveal typical morphological features indicating biomechanical adaptions. Therefore, the collagen fiber alignment was visualized using the split-line technique in 16 adult warmblood horses without any history of TMJ disorders. Within the central two-thirds of the articular surfaces of the articular tubercle, the articular disc and the mandibular head, split-lines ran in a correspondent rostrocaudal direction. In the lateral and medial aspects of these articular surfaces, the split-line pattern varied, displaying curved arrangements in the articular disc and punctual split-lines in the bony components. Mediolateral orientated split-lines were found in the rostral and caudal border of the articular disc and in the mandibular fossa. The complex movements during the equine chewing cycle are likely assigned to different areas of the TMJ. The split-line pattern of the equine TMJ is indicative of a relative movement of the joint components in a preferential rostrocaudal direction which is consigned to the central aspects of the TMJ. The lateral and medial aspects of the articular surfaces provide split-line patterns that indicate movements particularly around a dorsoventral axis.

Knowledgeable agents always choose what they like best,thus revealing their preferences. But naïve agents only choosewhat they believe they like best, and may end up dislikingtheir choice. As such, sensitivity to an agent’s priorexperience is critical for interpreting their behavior. Here weshow that four- and five-year-olds expect knowledgeableagents, as compared to naïve agents, to have stable choicesthat lead to higher rewards (Experiments 1 and 2).Additionally, we show that four- and five-year-olds can inferwhich of two agents is naïve given information about therewards they obtained and the stability of their choices(Experiments 3 and 4). These results show that youngchildren understand that beliefs and desires are interconnectedand that, in addition to having uncertainty about the world,agents can also be uncertain about their own desires

Previous research suggests that the ability to make finegraineddistinctions among emotions emerges gradually overdevelopment. However, such studies have looked primarily atchildren’s first-person responses to emotional expressions orat whether children can match emotion labels to emotionalexpressions. Relatively little work has looked at children’sability to link emotional responses to their probable causes.Here we ask two, three, and four year-old children and adultsto identify the causes of vocal expressions. Because we wereinterested in the ability to make nuanced distinctions, welooked within a single valence and asked whether childrencould distinguish expressions elicited by exciting, delicious,adorable, funny, and sympathetic events. Our results suggestboth an early emerging ability to distinguish within-valenceemotions and rapid development; by four, children’sperformance mirrored that of the adults. This suggests thatvery early in development, children have a rich representationof emotions that allows them to link distinct positivelyvalenced emotional expressions to their probable causes

The understanding that agents have goals, and the ability to infer them, is fundamental in social cognition. However, much of our social understanding goes beyond goal attribution. Drawing on both behavioral studies throughout development, and on the limitations of past models, we propose that humans have a naïve utility calculus to reason about the costs and rewards underlying agents’ goals. We show that the naïve utility calculus model, embedded in a Bayesian framework, can jointly infer the costs and rewards of agents navigating in complex scenarios. Using this model we test humans’ ability to make quantitative cost-reward inferences in scenarios with various sources of costs and rewards. Our results suggest the naïve utility calculus model fits human inferences better than simple goal inference models.

Perseverance, above and beyond IQ, predicts academic outcomes in school age children. Yet, little is known about how very young children learn the contexts in which persistence is valuable (or not). Here, we explore how young children and infants learn about the rational deployment of effort through observing adults’ persistent behavior. Results from Experiments 1 and 2 indicate that preschoolers persist more after watching an adult persist, but only if the adult is successful at reaching their goal. Experiment 3 extends these findings, showing that even infants use adult models to modulate their persistence, and can generalize this inference to novel situations. Thus, both preschoolers and infants are sensitive to adult persistence and use it to calibrate their own tenacity.