A retrospective observational study to evaluate the clinical outcomes and routine management of patients with chronic lymphocytic leukaemia treated with idelalisib and rituximab in the UK and Ireland (RETRO-idel).

Idelalisib (IDL) is an oral first-in-class phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor approved for chronic lymphocytic leukaemia (CLL) alongside rituximab (R) since 2014. However, little data exist on routine practice. The RETRO-idel was a protocol-led, retrospective study of 110 patients [n = 27 front-line (1L)] who received IDL-R. The primary end-point was clinical overall response rate (ORR). The median (range) follow-up of the whole cohort was 30·2 (0·1-51·9) months. The median (range) age was 72 (48-89) years. Tumour protein p53-disruption was common [100% 1L, 32·5% relapsed/refractory (R/R)]. The best ORR (intention-to-treat) was 88·2% (1L 96·3%, R/R 85·5%). Overall, the median event-free survival (mEFS) was 20·3 months and time-to-next treatment was 29·2 months. The mEFS for 1L patients was 18·7 months and R/R patients was 21·7 months. The 3-year overall survival was 56·1% (95% confidence interval 45·7-65·3). IDL was discontinued in 87·3% (n = 96). More patients discontinued due to adverse events in the front-line setting (1L 63·0% vs. R/R 44·6%) and due to progressive disease in R/R patients (20·5% vs. 3·7% in 1L). Lower respiratory tract infection/pneumonia were reported in 34·5% (Grade ≥3, 19·1%), diarrhoea in 30·9% (Grade ≥3, 6·4%), and colitis in 9·1% (Grade ≥3, 5·5%). Overall, these data describe clear efficacy for IDL-R in routine practice. No new safety signals were identified, although careful management of known toxicities is required.

Predictive action perception from explicit intention information in autism.

Social difficulties in autism spectrum disorder (ASD) may originate from a reduced top-down modulation of sensory information that prevents the spontaneous attribution of intentions to observed behaviour. However, although people with autism are able to explicitly reason about others' mental states, the effect of abstract intention information on perceptual processes has remained untested. ASD participants (n = 23) and a neurotypical (NT) control group (n = 23) observed a hand either reaching for an object or withdrawing from it. Prior to action onset, the participant either instructed the actor to "Take it" or "Leave it", or heard the actor state "I'll take it" or "I'll leave it", which provided an explicit intention that was equally likely to be congruent or incongruent with the subsequent action. The hand disappeared before completion of the action, and participants reported the last seen position of the tip of the index finger by touching the screen. NT participants exhibited a predictive bias in response to action direction (reaches perceived nearer the object, withdrawals perceived farther away), and in response to prior knowledge of the actor's intentions (nearer the object after "Take it", farther away after "Leave it"). However, ASD participants exhibited a predictive perceptual bias only in response to the explicit intentions, but not in response to the motion of the action itself. Perception in ASD is not immune from top-down modulation. However, the information must be explicitly presented independently from the stimulus itself, and not inferred from cues inherent in the stimulus.

Linking metacognition and mindreading: Evidence from autism and dual-task investigations.

Questions of how we know our own and other minds, and whether metacognition and mindreading rely on the same processes, are longstanding in psychology and philosophy. In Experiment 1, children/adolescents with autism (who tend to show attenuated mindreading) showed significantly lower accuracy on an explicit metacognition task than neurotypical children/adolescents, but not on an allegedly metacognitive implicit one. In Experiment 2, neurotypical adults completed these tasks in a single-task condition or a dual-task condition that required concurrent completion of a secondary task that tapped mindreading. Metacognitive accuracy was significantly diminished by the dual-mindreading-task on the explicit task but not the implicit task. In Experiment 3, we included additional dual-tasks to rule out the possibility that any secondary task (regardless of whether it required mindreading) would diminish metacognitive accuracy. Finally, in both Experiments 1 and 2, metacognitive accuracy on the explicit task, but not the implicit task, was associated significantly with performance on a measure of mindreading ability. These results suggest that explicit metacognitive tasks (used frequently to measure metacognition in humans) share metarepresentational processing resources with mindreading, whereas implicit tasks (which are claimed by some comparative psychologists to measure metacognition in nonhuman animals) do not. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The self-reference effect on memory is not diminished in autism: Three studies of incidental and explicit self-referential recognition memory in autistic and neurotypical adults and adolescents.

Three experiments investigated the extent to which (a) individuals with autism show a self-reference effect (i.e., better memory for self-relevant information), and (b) the size of the self-reference effect is associated with autism traits. Participants studied trait adjectives in relation to their own name (self-referent) or a celebrity's name (other-referent) under explicit and incidental/implicit encoding conditions. Explicit encoding involved judging whether the adjectives applied to self or other (denoted by proper names). Implicit encoding involved judging whether the adjectives were presented to the right or left of one's own or a celebrity's name. Recognition memory for the adjectives was tested using a yes/no procedure. Experiment 1 (individual differences; N = 257 neurotypical adults) employed the Autism-spectrum Quotient as a measure of autistic traits. Experiments 2 (n = 60) and 3 (n = 52) involved case-control designs with closely matched groups of autistic and neurotypical adults and children/adolescents, respectively. Autistic traits were measured using the Autism-spectrum Quotient and Social Responsiveness Scale, respectively. In all experiments, a significant self-reference effect was observed in both explicit and implicit encoding conditions. Most importantly, however, there was (a) no significant relation between size of the self-reference effect and number of autistic traits (Experiments 1, 2, and 3), and (b) no significant difference in the size of the self-reference effect between autistic and neurotypical participants (Experiments 2 and 3). In these respects, Bayesian analyses consistently suggested that the data supported the null hypothesis. These results challenge the notion that subjective or objective self-awareness are impaired in autism. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Putting Your Money Where Your Mouth is: Examining Metacognition in ASD Using Post-decision Wagering.

It has been argued that metacognition and mindreading rely on the same cognitive processes (Carruthers in The opacity of mind: an integrative theory of self-knowledge, Oxford University Press, Oxford, 2011). It is widely accepted that mindreading is diminished among individuals diagnosed with autism (Brunsdon and Happé in Autism 18(1):17-30, 2014), however, little is known about metacognition. This study examined metacognition in relation to mindreading and autism using post-decision wagering. Results from a student sample showed negative associations between autism traits and metacognitive accuracy, and metacognitive reaction times and mindreading. These findings were replicated in a general population sample, providing evidence of a reliable association between metacognition, mindreading and autism traits. However, adults diagnosed with autism showed equivalent levels of metacognitive accuracy to age- and IQ-matched comparison participants, albeit only with an overall increase in meta-level processing time.

A unique presentation of destructive shoulder arthropathy in the chronic phase of chronic myeloid leukaemia.

We present a previously unreported case of rapidly progressing, destructive shoulder arthropathy as an initial presentation of chronic phase chronic myeloid leukaemia. This patient initially presented to clinic for consideration of an arthroplasty for symptom relief; however, her loss to follow-up yielded a rapid progression of her symptoms. Bone marrow aspirate and targeted biopsy of the humeral head excluded blast cell crisis, in contrast to previously reported cases. She was treated conservatively with medical management of her underlying disease. Although leukaemic arthritis is a recognized phenomenon, chronic myeloid leukaemia is not known to cause bone destruction of this kind, particularly in the absence of blast crisis. Medical treatment with a tyrosine kinase inhibitor provided a dramatic improvement in our patient's pain, without the risk of attempted arthroplasty in unknown bone quality. We describe a unique presentation of severe bone destruction as a manifestation of chronic myeloid leukaemia in the absence of blast crisis. This should be considered as a rare differential diagnosis in joint arthropathy and may be appropriately managed initially with medical therapy, whereas future arthroplasty comprises uncharted territory in unknown bone quality.

Interoception is Impaired in Children, But Not Adults, with Autism Spectrum Disorder.

Interoception (the ability to sense what's going on inside one's body) is considered integral to many higher-order cognitive processes. Some have speculated that impaired interoception may underpin some features of ASD. Yet, in Experiment 1, we found no evidence of a between-group difference in either cardiac or respiratory interoceptive accuracy among 21 adults with ASD and 21 matched controls. Bayesian analyses suggested the data strongly supported the null hypothesis. In Experiment 2, we measured cardiac interoceptive accuracy in 21 children with ASD and 21 matched controls. Here interoceptve accuracy was significantly diminished in the ASD group and was associated with a moderate-to-large effect size. Results suggest early interoception difficulties are resolved or compensated for by adulthood in people with ASD.

Relationships between implicit and explicit uncertainty monitoring and mindreading: Evidence from autism spectrum disorder.

We examined performance on implicit (non-verbal) and explicit (verbal) uncertainty-monitoring tasks among neurotypical participants and participants with autism, while also testing mindreading abilities in both groups. We found that: (i) performance of autistic participants was unimpaired on the implicit uncertainty-monitoring task, while being significantly impaired on the explicit task; (ii) performance on the explicit task was correlated with performance on mindreading tasks in both groups, whereas performance on the implicit uncertainty-monitoring task was not; and (iii) performance on implicit and explicit uncertainty-monitoring tasks was not correlated. The results support the view that (a) explicit uncertainty-monitoring draws on the same cognitive faculty as mindreading whereas (b) implicit uncertainty-monitoring only test first-order decision making. These findings support the theory that metacognition and mindreading are underpinned by the same meta-representational faculty/resources, and that the implicit uncertainty-monitoring tasks that are frequently used with non-human animals fail to demonstrate the presence of metacognitive abilities.

Interoceptive impairments do not lie at the heart of autism or alexithymia.

Quattrocki and Friston (2014) argued that abnormalities in interoception-the process of representing one's internal physiological states-could lie at the heart of autism, because of the critical role interoception plays in the ontogeny of social-affective processes. This proposal drew criticism from proponents of the alexithymia hypothesis, who argue that social-affective and underlying interoceptive impairments are not a feature of autism per se, but of alexithymia (a condition characterized by difficulties describing and identifying one's own emotions), which commonly co-occurs with autism. Despite the importance of this debate for our understanding of autism spectrum disorder (ASD), and of the role of interoceptive impairments in psychopathology, more generally, direct empirical evidence is scarce and inconsistent. Experiment 1 examined in a sample of 137 neurotypical (NT) individuals the association among autistic traits, alexithymia, and interoceptive accuracy (IA) on a standard heartbeat-tracking measure of IA. In Experiment 2, IA was assessed in 46 adults with ASD (27 of whom had clinically significant alexithymia) and 48 NT adults. Experiment 1 confirmed strong associations between autistic traits and alexithymia, but yielded no evidence to suggest that either was associated with interoceptive difficulties. Similarly, Experiment 2 provided no evidence for interoceptive impairments in autistic adults, irrespective of any co-occurring alexithymia. Bayesian analyses consistently supported the null hypothesis. The observations pose a significant challenge to notions that interoceptive impairments constitute a core feature of either ASD or alexithymia, at least as far as the direct perception of interoceptive signals is concerned. (PsycINFO Database Record

Can you spot a liar? Deception, mindreading, and the case of autism spectrum disorder.

Detection of deception is of fundamental importance for everyday social life and might require "mindreading" (the ability to represent others' mental states). People with diminished mindreading, such as those with autism spectrum disorder (ASD), might be at risk of manipulation because of lie detection difficulties. In Experiment 1, performance among 216 neurotypical adults on a realistic lie detection paradigm was significantly negatively associated with number of ASD traits, but not with mindreading ability. Bayesian analyses complemented null hypothesis significance testing and suggested the data supported the alternative hypothesis in this key respect. Cross validation of results was achieved by randomly splitting the full sample into two subsamples of 108 and rerunning analyses. The association between lie detection and ASD traits held in both subsamples, showing the reliability of findings. In Experiment 2, lie detection was significantly impaired in 27 adults with a diagnosis of ASD relative to 27 matched comparison participants. Results suggest that people with ASD (or ASD traits) may be particularly vulnerable to manipulation and may benefit from lie detection training. Autism Res 2018, 11: 1129-1137. © 2018 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. LAY SUMMARY: Detection of deception is of fundamental importance for everyday social life. People with diminished understanding of other minds, such as those with autism spectrum disorder (ASD), might be at risk of manipulation because of lie detection difficulties. We found that lie detection ability was related to how many ASD traits neurotypical people manifested and also was significantly diminished among adults with a full diagnosis of ASD.

You said you would! The predictability of other's behavior from their intentions determines predictive biases in action perception.

The perception of an action is shifted farther along the observed trajectory if the observer has prior knowledge of the actor's intention. This intention-action prediction effect is explained by predictive perception models, wherein sensory input is interpreted in light of expectancies. This study altered the precision of the prediction by varying the predictability of the action from the intention, to increase/decrease the predictive perceptual bias. Participants heard an actor state an intention ("I'll take it"/"I'll leave it") before the actor reached or withdrew from an object, thus confirming or contradicting the intention. The intention was predictive of the action (75% congruency) for one group and counterpredictive (25%) for another. The action disappeared midmovement and participants estimated the disappearance position. The intention-action prediction effect was greater if the intention was predictive than if counterpredictive. However, participants needed to explicitly know the predictability rates (Experiments 1 and 3). No group differences emerged when both groups believed the intention was nonpredictive (Experiment 2a), nor when a nonpredictive intention was believed to be (counter)predictive (Experiment 2b). The perception of others behavior is determined by its predictability from their intentions, and the precision of our social predictions is adapted to individual differences in behavior. (PsycINFO Database Record

The Self-Reference Effect on Perception: Undiminished in Adults with Autism and No Relation to Autism Traits.

Memory for (and perception of) information about the self is superior to memory for (and perception of) other kinds of information. This self-reference effect (SRE) in memory appears diminished in ASD and related to the number of ASD traits manifested by neurotypical individuals (fewer traits = larger SRE). Here, we report the first experiments exploring the relation between ASD and the SRE in perception. Using a "Shapes" Task (Sui et al., Journal of Experimental Psychology: Human Perception and Performance, 38, 1105, 2012), participants learned to associate three different shapes (triangle, circle, square) with three different labels representing self, a familiar other, or an unfamiliar other (e.g., "you", "mother", "stranger"). Participants then completed trials during which they were presented with one shape and one label for 100 ms, and made judgments about whether the shape and label was a match. In Experiment 1, neurotypical participants (n = 124) showed the expected SRE, detecting self-related matches more reliably and quickly than matches involving familiar or unfamiliar other. Most important, number of ASD traits was unrelated to the size of the SRE for either accuracy or RT. Bayesian association analyses strongly supported the null hypothesis. In Experiment 2, there were no differences between 22 adults with ASD and 21 matched comparison adults in performance on the Shapes Task. Despite showing large and significant theory of mind impairments, participants with ASD showed the typical SRE and there were no associations with ASD traits in either group. In every case, Bayesian analyses favored the null hypothesis. These findings challenge theories about self-representation in ASD, as discussed in the article. Autism Res 2018, 11: 331-341. © 2017 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. LAY SUMMARY: Neurotypical people tend to find it easier to perceive and remember information that relates to themselves than information that relates to others. Research suggests that people with ASD show a diminished (or absent) self-bias in memory and that severity of ASD predicts the extent of this diminution (more severe ASD = smaller self-bias in memory). However, the current research suggests strongly that people with ASD do show a self-bias in their perception. This research informs our understanding of psychological functioning in ASD and challenges theories regarding self-awareness in this disorder.

Understanding the Goals of Everyday Instrumental Actions Is Primarily Linked to Object, Not Motor-Kinematic, Information: Evidence from fMRI.

Prior research conceptualised action understanding primarily as a kinematic matching of observed actions to own motor representations but has ignored the role of object information. The current study utilized fMRI to identify (a) regions uniquely involved in encoding the goal of others' actions, and (b) to test whether these goal understanding processes draw more strongly on regions involved in encoding object semantics or movement kinematics. Participants watched sequences of instrumental actions while attending to either the actions' goal (goal task), the movements performed (movement task) or the objects used (object task). The results confirmed, first, a unique role of the inferior frontal gyrus, middle temporal gyrus and medial frontal gyrus in action goal understanding. Second, they show for the first time that activation in the goal task overlaps directly with object- but not movement-related activation. Moreover, subsequent parametric analyses revealed that movement-related regions become activated only when goals are unclear, or observers have little action experience. In contrast to motor theories of action understanding, these data suggest that objects-rather than movement kinematics-carry the key information about others' actions. Kinematic information is additionally recruited when goals are ambiguous or unfamiliar.

I see what you say: Prior knowledge of other's goals automatically biases the perception of their actions.

We investigated whether top-down expectations about an actor's intentions affect action perception in a representational momentum (RM) paradigm. Participants heard an actor declare an intention to either take or leave an object and then saw him either reach for or withdraw from it, such that action and intention were either congruent or incongruent. Observers generally misperceived the hand's disappearance point further along the trajectory than it actually was, in line with the idea that action perception incorporates predictions of the action's future course. Importantly, this RM effect was larger for actions congruent with the actor's goals than for incongruent actions. These results demonstrate that action prediction integrates both current motion and top-down knowledge about the actor's intention. They support recent theories that emphasise the role of prior expectancies and prediction errors in social (and non-social) cognitive processing.

One step ahead: The perceived kinematics of others' actions are biased toward expected goals.

Action observation is often conceptualized in a bottom-up manner, where sensory information activates conceptual (or motor) representations. In contrast, here we show that expectations about an actor's goal have a top-down predictive effect on action perception, biasing it toward these goals. In 3 experiments, participants observed hands reach for or withdraw from objects and judged whether a probe stimulus corresponded to the hand's final position. Before action onset, participants generated action expectations on the basis of either object types (safe or painful, Experiments 1 and 2) or abstract color cues (Experiment 3). Participants more readily mistook probes displaced in a predicted position (relative to unpredicted positions) for the hand's final position, and this predictive bias was larger when the movement and expectation were aligned. These effects were evident for low-level movement and high-level goal expectancies. Expectations bias action observation toward the predicted goals. These results challenge current bottom-up views and support recent predictive models of action observation.

The affordance-matching hypothesis: how objects guide action understanding and prediction.

Action understanding lies at the heart of social interaction. Prior research has often conceptualized this capacity in terms of a motoric matching of observed actions to an action in one's motor repertoire, but has ignored the role of object information. In this manuscript, we set out an alternative conception of intention understanding, which places the role of objects as central to our observation and comprehension of the actions of others. We outline the current understanding of the interconnectedness of action and object knowledge, demonstrating how both rely heavily on the other. We then propose a novel framework, the affordance-matching hypothesis, which incorporates these findings into a simple model of action understanding, in which object knowledge-what an object is for and how it is used-can inform and constrain both action interpretation and prediction. We will review recent empirical evidence that supports such an object-based view of action understanding and we relate the affordance matching hypothesis to recent proposals that have re-conceptualized the role of mirror neurons in action understanding.

A randomized trial of genotype-guided dosing of warfarin.

BACKGROUND: The level of anticoagulation in response to a fixed-dose regimen of warfarin is difficult to predict during the initiation of therapy. We prospectively compared the effect of genotype-guided dosing with that of standard dosing on anticoagulation control in patients starting warfarin therapy. METHODS: We conducted a multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism. Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (-1639G→A) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days. Patients in the control (standard dosing) group received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to routine clinical practice. The primary outcome measure was the percentage of time in the therapeutic range of 2.0 to 3.0 for the international normalized ratio (INR) during the first 12 weeks after warfarin initiation. RESULTS: A total of 455 patients were recruited, with 227 randomly assigned to the genotype-guided group and 228 assigned to the control group. The mean percentage of time in the therapeutic range was 67.4% in the genotype-guided group as compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% confidence interval, 3.3 to 10.6; P<0.001). There were significantly fewer incidences of excessive anticoagulation (INR ≥4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001). CONCLUSIONS: Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy. (Funded by the European Commission Seventh Framework Programme and others; ClinicalTrials.gov number, NCT01119300.).