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The symptoms of autism spectrum disorder are conceptualized to alter the quality of parent–children interactions, exposure to social learning exchanges, and ultimately the course of child development. There is evidence that modifying the procedures of Pivotal Response Treatment (PRT) to explicitly target social motivation enhances child engagement and parent–child synchrony in moment-by-moment exchanges. However, it is unclear if these within session improvements ultimately yield favorable developmental outcomes over time. The current investigation presents feasibility, utility, and preliminary efficacy data of a pilot randomized clinical trial (RCT) of a Pivotal Response Intervention for Social Motivation (PRISM) model. Data on participant factors, treatment protocol acceptability, and outcome variance and effect size are highly favorable and support the pursuit of a future, large scale RCT.

The designs of clinical trials of drugs for rare diseases are challenged by health technology assessment organisations and payers. Phase II pivotal studies, single-arm or open-label designs, the extensive use of non-final endpoints, and the limited use of patient-reported outcomes (PROs) are the main points of contention. The evidence on the actual design of these trials is limited, but corroborates the concerns of the above. Our aim is to scrutinise whether the design of pivotal studies of drugs for rare diseases to be launched into the Italian market by 2026 present similar issues. The drugs and the relevant pivotal studies were retrieved from Biomedtracker and US and European clinical trial databases. We identified 154 new drugs for rare diseases. Single-arm designs account for 36% of trials. Almost 50% of randomised control trials (RCTs) are designed using an active comparator and 61% are double-blinded. Primary endpoints are mostly (82%) surrogate. A total of 59% of studies include PROs. Our findings were partially expected (e.g., extensive use of surrogate endpoints) and partially not (e.g., RCTs and an active comparator), considering previous studies on the same topic. Having more head-to-head studies may reduce uncertainty concerning evidence at market launch, but different issues persist, including the still limited role of PROs.

We study how the diffusion of being pivotal affects immoral outcomes. In our main experiment, subjects decide about agreeing to kill mice and receiving money versus objecting to the killing and foregoing the monetary amount. In a baseline condition, subjects decide individually about the life of one mouse. In the main treatment, subjects are organized into groups of eight and decide simultaneously. Eight mice are killed if at least one subject opts for killing. The fraction of subjects agreeing to kill is significantly higher in the main condition compared with the baseline condition. In a second experiment, we run the same baseline and main conditions but use a charity context and additionally study sequential decision-making. We replicate our finding from the mouse paradigm. We further show that the observed effects increase with experience, i.e., when we repeat the experiment for a second time. For both experiments, we elicit beliefs about being pivotal, which we validate in a treatment with non-involved observers. We show that beliefs are a main driver of our results.

The social validity of autism behavioral intervention has been questioned. Naturalistic Developmental Behavioral Interventions (NDBIs) attempt to address some concerns, but it is unclear whether autistic people consider NDBIs socially valid. Social validity of an NDBI, Pivotal Response Treatment (PRT), was investigated through autistic adults commenting on videos of autistic children receiving PRT. Qualitative coding of responses generated three themes: respect for individuals; assessment of intervention implementation; and socioemotional considerations. Although video brevity limits the scope of the present study’s conclusions, participants highlighted PRT components that appeared socially valid (e.g., reinforcing attempts, following the child’s lead) and aspects appearing invalid (e.g., overemphasis on spoken language). Therefore, adjustments appear necessary for PRT to be fully acceptable to the autistic community.

The discovery that subanesthetic doses of (R, S)-ketamine (ketamine) and (S)-ketamine (esketamine) rapidly induce antidepressant effects and promote sustained actions following drug clearance in depressed patients who are treatment-resistant to other therapies has resulted in a paradigm shift in the conceptualization of how rapidly and effectively depression can be treated. Consequently, the mechanism(s) that next generation antidepressants may engage to improve pathophysiology and resultant symptomology are being reconceptualized. Impaired excitatory glutamatergic synapses in mood-regulating circuits are likely a substantial contributor to the pathophysiology of depression. Metaplasticity is the process of regulating future capacity for plasticity by priming neurons with a stimulation that alters later neuronal plasticity responses. Accordingly, the development of treatment modalities that specifically modulate the duration, direction, or magnitude of glutamatergic synaptic plasticity events such as long-term potentiation (LTP), defined here as metaplastogens, may be an effective approach to reverse the pathophysiology underlying depression and improve depression symptoms. We review evidence that the initiating mechanisms of pharmacologically diverse rapid-acting antidepressants (i.e., ketamine mimetics) converge on consistent downstream molecular mediators that facilitate the expression/maintenance of increased synaptic strength and resultant persisting antidepressant effects. Specifically, while the initiating mechanisms of these therapies may differ (e.g., cell type-specificity, N-methyl-D-aspartate receptor (NMDAR) subtype-selective inhibition vs activation, metabotropic glutamate receptor 2/3 antagonism, AMPA receptor potentiation, 5-HT receptor-activating psychedelics, etc.), the sustained therapeutic mechanisms of putative rapid-acting antidepressants will be mediated, in part, by metaplastic effects that converge on consistent molecular mediators to enhance excitatory neurotransmission and altered capacity for synaptic plasticity. We conclude that the convergence of these therapeutic mechanisms provides the opportunity for metaplasticity processes to be harnessed as a druggable plasticity mechanism by next-generation therapeutics. Further, targeting metaplastic mechanisms presents therapeutic advantages including decreased dosing frequency and associated diminished adverse responses by eliminating the requirement for the drug to be continuously present.

Global climate change is expected to have major impacts on biodiversity. Sea turtles have temperature-dependent sex determination, and many populations produce highly femalebiased offspring sex ratios, a skew likely to increase further with global warming. We estimated the primary sex ratio at one of the world’s largest green turtle Chelonia mydas rookeries in Guinea-Bissau, West Africa, and explored its resilience to climate change. In 2013 and 2014, we deployed data loggers recording nest (n = 101) and sand (n = 30) temperatures, and identified hatchling sex by histological examination of gonads. A logistic curve was fitted to the data to allow predictions of sex ratio across habitats and through the nesting season. The population-specific pivotal temperature was 29.4°C, with both sexes produced within incubation temperatures from 27.6 to 31.4°C: the transitional range of temperatures (TRT). Primary sex ratio changed from maleto female-biased across relatively small temporal and spatial scales. Overall it was marginally female-biased, but we estimated an exceptionally high male hatchling production of 47.7% (95% CI: 36.7–58.3%) and 44.5% (95% CI: 33.8–55.4%) in 2013 and 2014, respectively. Both the temporal and spatial variation in incubation conditions and the wide range of the TRT suggest resilience and potential for adaptation to climate change if the present nesting habitat remains unchanged. These findings underline the importance of assessing site-specific parameters to understand populations’ responses to climate change, particularly with regard to identifying rookeries with high male hatchling production that may be key for the future conservation of sea turtles under projected global warming scenarios.

In the landscape of Covid-19 pandemic, people’s well-being, to some extent, can be affected through virtual reality tourism because it has the opportunity to enhance their level of well-being and destination recovery. To verify this empirically an investigation was conducted among people who used Quanjingke, the largest tourism-related virtual reality website in China, during the pandemic. The specific the aim of this paper is to prove the effectiveness of virtual reality tourism in promoting people’s subjective well-being. Hence, an integrated model with the constructs of peripheral attribute, core attribute and pivotal attribute, presence, perceived value, satisfaction, and subjective well-being was proposed and tested. The results indicate that attributes of virtual reality tourism have a positive effect on presence during virtual reality experiences, which positively influences perceived value. The values of virtual reality tourism perceived by tourists result in their satisfaction. Eventually, it was found that tourists’ subjective well-being is improved due to their satisfaction with virtual reality tourism. Practical suggestions are also provided based on the findings.

We study the feasibility and optimal design of presale crowdfunding contracts where participating consumers pay a premium above the future expected spot price and financially constrained entrepreneurs balance the potential product–market distortions introduced through presale crowdfunding against the cost of traditional external financing. Our analysis shows how such crowdfunding contracts enable the execution of projects that could not be otherwise undertaken and highlights novel interactions between the cost of capital, demand uncertainty, and production. Tighter financing constraints reduce the ability of the monopolist to extract surplus but, contrary to the usual result, may increase production. We evaluate how uncertainty and market size reduce the price-discriminating power of the monopolist and affect the optimal contract regime. Nevertheless, we show how such presale price-discriminating contracts are implementable even when the number of potential consumers is relatively high and their individual demand is stochastic. This paper was accepted by Gustavo Manso, finance.

Pivotal response treatment (PRT) is a promising intervention focused on improving social communication skills in children with autism spectrum disorder (ASD). Since robots potentially appeal to children with ASD and may contribute to their motivation for social interaction, this exploratory randomized controlled trial (RCT) was conducted comparing PRT (PRT and robot-assisted PRT) with treatment-as-usual (TAU). Seventy-three children (PRT: n = 25; PRT + robot: n = 25; TAU: n = 23) with ASD, aged 3–8 years were assessed at baseline, after 10 and 20 weeks of intervention, and at 3-month follow-up. There were no significant group differences on parent- and teacher-rated general social-communicative skills and blindly rated global functioning directly after treatment. However, at follow-up largest gains were observed in robot-assisted PRT compared to other groups. These results suggest that robot-assistance may contribute to intervention efficacy for children with ASD when using game scenarios for robot-child interaction during multiple sessions combined with motivational components of PRT. This trial is registered at https://www.trialregister.nl/trial/4487; NL4487/NTR4712 (2014-08-01).

This article presents an innovative sampling strategy, ordered moving extremes lower k -record ranked set sampling, designed to enhance parameter estimation and prediction for the generalized exponential distribution. By incorporating k -record values with random sample sizes, we develop maximum likelihood estimation, classical Bayes estimation, and empirical Bayes estimators, leveraging informative priors under balanced loss functions, including balanced squared error and balanced linear exponential. Additionally, we utilize the pivotal prediction method to construct prediction intervals for future observations under double type-II censoring. Extensive simulation studies demonstrate that our approach significantly improves estimation accuracy by achieving lower mean squared errors and reduced bias compared to conventional methods. The efficacy of the proposed sampling method is further validated through its application to real-world medical datasets, showcasing its practical utility in enhancing statistical inferences for lifetime data analysis. The key findings highlight that ordered moving extremes lower k -record ranked set sampling effectively balances efficiency and accuracy, making it particularly well-suited for reliability studies and survival analysis.