Embracing neurodiversity in doll play: Investigating neural and language correlates of doll play in a neurodiverse sample.

Doll play may provide opportunities for children to rehearse social interactions, even when playing alone. Previous research has found that the posterior superior temporal sulcus (pSTS) was more engaged when children played with dolls alone, compared to playing with tablet games alone. Children's use of internal state language (ISL) about others was also associated with pSTS activity. As differences in social cognition are frequently observed in autistic people, we were interested in the brain and language correlates of doll play in children with varying levels of autistic traits. We investigated children's (N = 57, mean age = 6.72, SD = 1.53) use of ISL and their pSTS brain activity using functional near-infrared spectroscopy (fNIRS) as they played with dolls and tablet games, both alone and with a social partner. We also investigated whether there were any effects of autistic traits using the parent-report Autism Spectrum Quotient-Children's Version (AQ-Child). We found that the left pSTS was engaged more as children played with dolls or a tablet with a partner, and when playing with dolls alone, compared to when playing with a tablet alone. Relations between language and neural correlates of social processing were distinct based on the degree of autistic traits. For children with fewer autistic traits, greater pSTS activity was associated with using ISL about others. For children with more autistic traits, greater pSTS activity was associated with experimenter talk during solo play. These divergent pathways highlight the importance of embracing neurodiversity in children's play patterns to best support their development through play.

The Metabolism of Lufotrelvir, a Prodrug Investigated for the Treatment of SARS-COV2 in Humans Following Intravenous Administration.

The metabolism of lufotrelvir, a novel phosphate prodrug of PF-00835231 for the treatment of COVID-19, was evaluated in healthy human volunteers and clinical trial participants with COVID-19 following intravenous infusion. The prodrug was completely converted to PF-00835231 that was subsequently cleared by hydrolysis, hydroxylation, ketoreduction, epimerization, renal clearance, and secretion into the feces. The main circulating metabolite was a hydrolysis product (M7) that was present at concentrations greater than PF-00835231, and this was consistent between healthy volunteers and participants with COVID-19. On administration of [14C]lufotrelvir, only 63% of the dose was obtained in excreta over 10 days and total drug-related material demonstrated a prolonged terminal phase half-life in plasma. A considerable portion of the labeled material was unextractable from fecal homogenate and plasma. The position of the carbon-14 atom in the labeled material was at a leucine carbonyl, and pronase digestion of the pellet derived from extraction of the fecal homogenate showed that [14C]leucine was released. SIGNIFICANCE STATEMENT: Lufotrelvir is an experimental phosphate prodrug intravenous therapy investigated for the potential treatment of COVID-19 in a hospital setting. The overall metabolism of lufotrelvir was determined in human healthy volunteers and clinical trial participants with COVID-19. Conversion of the phosphate prodrug to the active drug PF-00835231 was complete and the subsequent metabolic clearance of the active drug was largely via amide bond hydrolysis. Substantial drug-related material was not recovered due to loss of the carbon-14 label to endogenous metabolism.

Etiology of problem gambling in Canada.

OBJECTIVE: To conduct a large-scale national cohort study to identify the current etiological risk factors for problem gambling in Canada. METHOD: A cohort of 10,119 Canadian gamblers completed a comprehensive self-administered online questionnaire in 2018 and were reassessed in 2019. At baseline, the sample contained 1,388 at-risk gamblers, 1,346 problem gamblers, and 2,710 with a major DSM-5 mental health disorder. A total of 108 independent variables (IVs) were available for analysis, as well as the self-report of perceived causes of gambling-related problems for 1,261 individuals. RESULTS: The strongest multivariate predictors of current and future problem gambling were "gambling-related" variables (i.e., current and past problem gambling, intensive gambling involvement, playing electronic gambling machines (EGMs), gambling fallacies, socializing with other people having gambling-related problems, and family history of having gambling-related problems). Beyond gambling-related variables, greater impulsivity and lower household income were robustly predictive. Thirteen additional variables were either concurrently or prospectively predictive, but not both. In contrast to the many different quantitative predictors, self-reported causes tended to be singular and psychologically oriented (i.e., desire to win money, boredom, stress, poor self-control). CONCLUSIONS: The predictors of problematic gambling in the present study are very similar to the predictors identified in prior international longitudinal and cross-sectional research. This implies core cross-cultural risk factors, with gambling-related variables and impulsivity being most important, and comorbidities and demographic variables having more modest contributions. The additional value of the present results is that they comprehensively identify the relative importance of all known etiologically relevant variables within a current Canadian context. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Problem gambling severity, gambling behavior, substance use, and mental health in gamblers who do and do not use cannabis: Evidence from a Canadian national sample.

INTRODUCTION: Cannabis use frequently co-occurs with gambling, and evidence indicates that both acute and chronic cannabis use may influence gambling behavior. The primary aim of the present study was to further contribute to the literature on this relationship by examining data collected from a Canadian national study of gambling. METHODS: Respondents consisted of 10,054 Canadian gamblers recruited from Leger Opinion's (LEO) online panel. In this study, gamblers who used cannabis were compared with non-users across a number of gambling as well as demographic and mental health variables. RESULTS: Of the total sample, 25.4 % reported past 12-month cannabis use. Among the 2,553 cannabis-users, 21.3 % reported daily use, and 69.9 % reported using once a month or more. A total of 56.2 % indicated they had used cannabis while gambling in the past 12 months. Bivariate analysis found significant differences between cannabis use and non-use on numerous demographic, mental health, and gambling-related variables. Individuals with greater problem gambling severity scores, more hours gambling, and a larger range of gambling activities were more likely to endorse using cannabis. Hierarchical logistic regression revealed that tobacco use, and having experienced significant child abuse were predictors of cannabis use. Non-use of cannabis was associated with older age, less engagement in online gambling, and being less likely to consume alcohol. CONCLUSION: The present findings both corroborate previous studies and expand upon the relationship between cannabis and gambling.

Harm Minimization Training, Knowledge, and Behaviour of Canadian Casino Employees.

Casino employees regularly interact with problem and at-risk gamblers and thus have considerable potential to both prevent and reduce gambling-related harm. While harm minimization (HM) and responsible gambling (RG) are routinely espoused by the casino industry, the actual level of employee HM/RG training, knowledge, and behaviour is unknown. The present study investigated this issue in the Canadian context by examining employee surveys collected by the RG Check accreditation program (8,262 surveys from 78 Canadian casinos/racinos collected between 2011 and 2020). These surveys revealed that almost all casino employees receive HM/RG training, but the amount of training tends to be quite limited (one hour) except for supervisors, managers, and security personnel. Basic HM/RG knowledge among all employees appears adequate, although their understanding of probability is incomplete. The most important consideration is whether this training and knowledge translates into meaningful HM/RG behaviour towards patrons. The large majority of employees (83.1%) report engaging in at least one HM/RG interaction with a patron at some point during the course of their employment (median length of 4 to 9 years), with security personnel reporting the highest rates. However, the frequency, nature, and impact of these interactions is unknown.

Making Change: Attempts to Reduce or Stop Gambling in a General Population Sample of People Who Gamble.

Objective: This study examined past year attempts to reduce or quit gambling among people who gamble generally and those with gambling problems specifically. Methods: Regular gamblers recruited from an online panel (N = 10,054) completed a survey of gambling, mental health and substance use comorbidity and attempts to reduce or quit gambling. The sample was weighted to match the gambling and demographic profile for the same subsample (i.e., past month gamblers) in a recent Canadian national survey. Results: 5.7% reported that they tried to cutback or stop gambling in the past year. As predicted, individuals making a change attempt had greater levels of problem gambling severity and were more likely to have a gambling problem. Of individuals with problem gambling, 59.8% made a change attempt. Of those, 90.2% indicated that they did this primarily on their own, and 7.7% accessed formal or informal treatment. Most people attempting self- change indicated that this was a personal preference (55%) but about a third reported feeling too ashamed to seek help. Over a third (31%) reported that their attempt was successful. Of the small group of people accessing treatment, 39% described it as helpful. Conclusions: Whereas gambling treatment-seeking rates are low, rates of self-change attempts are high. The public health challenge is to promote self-change efforts among people beginning to experience gambling problems, facilitate success at self-change by providing accessible support for use of successful strategies, and provide seamless bridges to a range of other treatments when desired or required.

Indigenous Gambling and Problem Gambling in Canada.

The present study provides a profile of Canadian Indigenous gambling and problem gambling using the 2018 Canadian Community Health Survey (CCHS) (n = 23,952 adults; 1,324 Indigenous) and an online panel survey of 10,199 gamblers (n = 589 Indigenous). The relative popularity of different types of gambling was similar between Indigenous and non-Indigenous samples. However, there was higher Indigenous participation in electronic gambling machines (EGMs), bingo, instant lotteries, overall gambling and a higher rate of problem gambling (2.0% versus 0.5%). Variables predictive of Indigenous problem gambling were EGM participation, gambling fallacies, having a mental or substance use disorder, sports betting, and male gender. Compared to non-Indigenous problem gamblers, Indigenous problem gamblers had higher substance use and lower impulsivity. In general, variables predictive of Indigenous problem gambling were the same ones predictive of problem gambling in all populations, with elevated Indigenous problem gambling rates primarily being due to elevated rates of these generic risk factors. Many of these risk factors are modifiable. Particular consideration should be given to reducing the disproportionate concentration of EGMs in geographic areas having the highest concentration of Indigenous people and ameliorating the disadvantageous social conditions in this population that are conducive to mental health and substance use problems.

Gambling in Canada During the COVID Lockdown: Prospective National Survey.

The current study investigated the impact of the COVID pandemic lockdown on gambling and problem gambling in Canada. The AGRI National Project's online panel participants (N = 3449) provided baseline gambling data 6 months prior to the pandemic. Re-surveying this sample during the lockdown provided an opportunity to make quantitative comparisons of the changes. Nearly one-third of gamblers reported ceasing gambling altogether during the lockdown. For the continuing gamblers, quantitative data indicated significant decreases in gambling frequency, time spent in gambling sessions, money spent, and the number of game types played. Qualitative perceptions of changes in gambling were examined and the accuracy of these reports were not closely aligned with actual changes in gambling. Gambling platform was the only gambling engagement metric where increases were found with ~ 17% of the gambling sample migrating to online gambling during the lockdown. Although problem gambling within the sample generally declined, consistent with previous literature, it was also found that gambling online-among other biopsychosocial factors-was a significant predictor for classification as a problem gambler during the lockdown. COVID-specific influences on health, employment, leisure time and social isolation were moderately associated with problem gambling scores but were not independent predictors of changes in gambling engagement during lockdown. Future studies are required to assess if the pandemic related changes in gambling evidenced in this study remain stable, or if engagement reverts to pre-pandemic levels when the pandemic response allows for the re-opening of land-based gambling venues.

Responsible Gambling in Canada: An Analysis of the RG Check Patron Surveys.

This study analyzed the Responsible Gambling Check patron survey data from Canadian casinos and racinos collected from 2011-2019 (18,580 patrons and 75 venues). The results indicated increasing awareness and use over time of harm minimization tools among more frequent patrons. Despite these promising trends, it is concerning that a substantial percentage of gamblers are still unaware of the harm minimization tools available. Further, the actual impact of this awareness on responsible gambling behaviour is largely unknown. We suggest greater efforts are needed nation-wide to promote the awareness, utilization, and evaluation of these harm minimization tools.

Optical-Frequency Magnetic Polarizability in a Layered Semiconductor.

The optical response of crystals is most commonly attributed to electric dipole interactions between light and matter. Although metamaterials support "artificial" magnetic resonances supported by mesoscale structuring, there are no naturally occurring materials known to exhibit a nonzero optical-frequency magnetic polarizability. Here, we experimentally demonstrate and quantify a naturally occurring nonzero magnetic polarizability in a layered semiconductor system: two-dimensional (Ruddlesden-Popper phase) hybrid organic-inorganic perovskites. These results demonstrate the only known material with an optical-frequency permeability that differs appreciably from vacuum, informing future efforts to find, synthesize, or exploit atomic-scale optical magnetism for novel optical phenomena such as negative index of refraction and electromagnetic cloaking.

Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19.

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.

Conformational changes in twitchin kinase in vivo revealed by FRET imaging of freely moving C. elegans.

The force-induced unfolding and refolding of proteins is speculated to be a key mechanism in the sensing and transduction of mechanical signals in the living cell. Yet, little evidence has been gathered for its existence in vivo. Prominently, stretch-induced unfolding is postulated to be the activation mechanism of the twitchin/titin family of autoinhibited sarcomeric kinases linked to the mechanical stress response of muscle. To test the occurrence of mechanical kinase activation in living working muscle, we generated transgenic Caenorhabditis elegans expressing twitchin containing FRET moieties flanking the kinase domain and developed a quantitative technique for extracting FRET signals in freely moving C. elegans, using tracking and simultaneous imaging of animals in three channels (donor fluorescence, acceptor fluorescence, and transmitted light). Computer vision algorithms were used to extract fluorescence signals and muscle contraction states in each frame, in order to obtain fluorescence and body curvature measurements with spatial and temporal precision in vivo. The data revealed statistically significant periodic changes in FRET signals during muscle activity, consistent with a periodic change in the conformation of twitchin kinase. We conclude that stretch-unfolding of twitchin kinase occurs in the active muscle, whereby mechanical activity titrates the signaling pathway of this cytoskeletal kinase. We anticipate that the methods we have developed here could be applied to obtaining in vivo evidence for force-induced conformational changes or elastic behavior of other proteins not only in C. elegans but in other animals in which there is optical transparency (e.g., zebrafish).

Discovery and evaluation of non-basic small molecule modulators of the atypical chemokine receptor CXCR7.

The atypical chemokine receptor C-X-C chemokine receptor type 7 (CXCR7) is an attractive therapeutic target for a variety of cardiac and immunological diseases. As a strategy to mitigate known risks associated with the development of higher molecular weight, basic compounds, a series of pyrrolidinyl-azolopyrazines were identified as promising small-molecule CXCR7 modulators. Using a highly enabled parallel medicinal chemistry strategy, structure-activity relationship studies geared towards a reduction in lipophilicity and incorporation of saturated heterocycles led to the identification of representative tool compound 20. Notably, compound 20 maintained good potency against CXCR7 with a suitable balance of physicochemical properties to support in vivo pharmacokinetic studies.

The impact of COVID-19 on gambling and gambling disorder: emerging data.

PURPOSE OF REVIEW: The lockdown response to the COVID-19 pandemic has significantly impacted commercial gambling in many jurisdictions around the world. The goal of this review is to systematically identify and describe the survey data and findings to date examining the effect on individual gambling and gambling disorder. RECENT FINDINGS: Of the 17 publications meeting inclusion criteria, the majority reported cross-sectional assessments (n = 11, 65%) and remainder were longitudinal in that they had earlier gambling data for participants (n = 6, 35%). Not surprisingly given the closure of land-based gambling, an overall reduction in gambling frequency and expenditure was reported in all studies. The estimate of the proportion of participants in both the general population and the population that gambles who increased overall gambling or online gambling was variable. The most consistent correlates of increased gambling during the lockdown were increased problem gambling severity, younger age groups, and being male. SUMMARY: These results suggest that the impacts of the COVID-19 pandemic on gambling and problematic gambling are diverse - possibly causing a reduction in current or future problems in some, but also promoting increased problematic gambling in others. The longer-term implications of both the reduction in overall gambling, and the increase in some vulnerable groups are unclear, and requires assessment in subsequent follow-up studies. However, in the short term, individuals with existing gambling problems should be recognized as a vulnerable group.

Roles of ATM and ATR in DNA double strand breaks and replication stress.

The maintenance of genome integrity is critical for the faithful replication of the genome during cell division and for protecting cells from accumulation of DNA damage, which if left unrepaired leads to a loss of genetic information, a breakdown in cell function and ultimately cell death and cancer. ATM and ATR are master kinases that are integral to homologous recombination-mediated repair of double strand breaks and preventing accumulation of dangerous DNA structures and genome instability during replication stress. While the roles of ATM and ATR are heavily intertwined in response to double strand breaks, their roles diverge in the response to replication stress. This review summarises our understanding of the players and their mode of actions in recruitment, activation and activity of ATM and ATR in response to DNA damage and replication stress and discusses how controlling localisation of these kinases and their activators allows them to orchestrate a stress-specific response.

Predictors of gambling and problem gambling in Canada.

OBJECTIVES: The purpose of this study is to provide an updated profile of gamblers and problem gamblers in Canada and to identify characteristics most strongly associated with problem gambling. METHODS: An assessment of gambling participation and problem gambling was included in the 2018 Canadian Community Health Survey and administered to 23,952 individuals 18 years and older. Descriptive statistics provided a demographic profile for each type of gambling involvement as well as category of gambler (non-gambler, non-problem gambler, at-risk gambler, problem gambler). A logistic regression identified characteristics that best distinguished problem from non-problem gamblers. RESULTS: Gambling participation and problem gambling both varied as a function of gender, income, educational attainment, and race/ethnicity. However, multivariate analysis identified electronic gambling machine (EGM) participation to be the primary predictor of problem gambling status, with race/ethnicity, presence of a mood disorder, male gender, casino table game participation, older age, a greater level of smoking, participation in speculative financial activity, instant lottery participation, lower household income, and lottery or raffle ticket participation providing additional predictive power. Provincial EGM density and EGM participation rates are also very strong predictors of provincial rates of at-risk and problem gambling. CONCLUSION: Problem gambling has a biopsychosocial etiology, determined by personal vulnerability factors combined with the presence of riskier types of gambling such as EGMs. Effective prevention requires a multifaceted approach, but constraints on the availability and operation of EGMs would likely have the greatest single public health benefit.

RéSUMé: OBJECTIFS: Présenter un profil actualisé des joueurs et des joueurs pathologiques au Canada et cerner les caractéristiques les plus fortement associées au jeu pathologique. MéTHODE: Une évaluation de la participation au jeu de hasard et du jeu pathologique figurant dans l'Enquête sur la santé dans les collectivités canadiennes de 2018 a été administrée à 23 952 personnes de 18 ans et plus. Le profil démographique de chaque type de participation au jeu de hasard et la catégorie de joueur (non-joueur, joueur non pathologique, joueur à risque, joueur pathologique) ont été établis par statistique descriptive. Une régression logistique a permis de cerner les caractéristiques qui distinguaient le mieux les joueurs pathologiques des joueurs non pathologiques. RéSULTATS: La participation au jeu de hasard et le jeu pathologique variaient tous les deux en fonction du sexe, du revenu, du niveau d'instruction et de la race/l'ethnicité. L'analyse multivariée a cependant déterminé que l'utilisation d'appareils électroniques de jeu (AÉJ) était la principale variable prédictive du jeu pathologique, et que la race/l'ethnicité, la présence d'un trouble de l'humeur, le sexe masculin, la participation aux jeux de table dans les casinos, l'âge avancé, le tabagisme important, la participation à des activités financières spéculatives, la participation aux loteries instantanées, le faible revenu du ménage et l'achat de billets de loterie ou de tirage au sort amélioraient le pouvoir de prédiction. La densité provinciale des AÉJ et les taux d'utilisation des AÉJ étaient aussi de très fortes variables prédictives des taux provinciaux de jeu à risque et de jeu pathologique. CONCLUSION: Le jeu pathologique présente une étiologie biopsychosociale déterminée par des facteurs de vulnérabilité personnels combinés à la présence de types de jeu de hasard plus risqués, comme les AÉJ. Une prévention efficace nécessite une démarche pluridimensionnelle, mais l'imposition de limites à la disponibilité et à l'utilisation des AÉJ serait probablement la solution la plus avantageuse sur le plan de la santé publique.

Gambling and Problem Gambling in Canada in 2018: Prevalence and Changes Since 2002.

OBJECTIVE: The purpose of this study was to provide an updated profile of gambling and problem gambling in Canada and to examine how the rates and pattern of participation compare to 2002. METHOD: An assessment of gambling and problem gambling was included in the 2018 Canadian Community Health Survey and administered to 24,982 individuals aged 15 and older. The present analyses selected for adults (18+). RESULTS: A total of 66.2% of people reported engaging in some type of gambling in 2018, primarily lottery and/or raffle tickets, the only type in which the majority of Canadians participate. There are some significant interprovincial differences, with perhaps the most important one being the higher rate of electronic gambling machine (EGM) participation in Manitoba and Saskatchewan. The overall pattern of gambling in 2018 is very similar to 2002, although participation is generally much lower in 2018, particularly for EGMs and bingo. Only 0.6% of the population were identified as problem gamblers in 2018, with an additional 2.7% being at-risk gamblers. There is no significant interprovincial variation in problem gambling rates. The interprovincial pattern of problem gambling in 2018 is also very similar to what was found in 2002 with the main difference being a 45% decrease in the overall prevalence of problem gambling. CONCLUSIONS: Gambling and problem gambling have both decreased in Canada from 2002 to 2018 although the provincial patterns are quite similar between the 2 time periods. Several mechanisms have likely collectively contributed to these declines. Decreases have also been reported in several other Western countries in recent years and have occurred despite the expansion of legal gambling opportunities, suggesting a degree of inoculation or adaptation in large parts of the population.

When It HIITs, You Feel No Pain: Psychological and Psychophysiological Effects of Respite-Active Music in High-Intensity Interval Training.

The authors investigated the effects of respite-active music (i.e., music used for active recovery in between high-intensity exercise bouts) on psychological and psychophysiological outcomes. Participants (N = 24) made four laboratory visits for a habituation, medium- and fast-tempo music conditions, and a no-music control. A high-intensity interval-training protocol comprising 8 × 60-s exercise bouts at 100% Wmax with 90-s active recovery was administered. Measures were taken at the end of exercise bouts and recovery periods (rating of perceived exertion [RPE], state attention, and core affect) and then upon cessation of the protocol (enjoyment and remembered pleasure). Heart rate was measured throughout. Medium-tempo music enhanced affective valence during exercise and recovery, while both music conditions increased dissociation (only during recovery), enjoyment, and remembered pleasure relative to control. Medium-tempo music lowered RPE relative to control, but the heart rate results were inconclusive. As predicted, medium-tempo music, in particular, had a meaningful effect on a range of psychological outcomes.

Discovery of a Novel Inhibitor of Coronavirus 3CL Protease for the Potential Treatment of COVID-19.

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. The designed phosphate prodrug PF-07304814 is metabolized to PF-00835321 which is a potent inhibitor in vitro of the coronavirus family 3CL pro, with selectivity over human host protease targets. Furthermore, PF-00835231 exhibits potent in vitro antiviral activity against SARS-CoV-2 as a single agent and it is additive/synergistic in combination with remdesivir. We present the ADME, safety, in vitro , and in vivo antiviral activity data that supports the clinical evaluation of this compound as a potential COVID-19 treatment.