Decisional style, sleepiness, and online responsiveness.

As sleep problems can impair quality of work, an online questionnaire was used to examine relationships between sleepiness and decision making while obtaining unobtrusive indices of performance. Participants (N = 344) completed the Insomnia Severity Index, Epworth Sleepiness Scale, and the Melbourne Decision Making Questionnaire in a Qualtrics survey while reporting mobile phone use. Qualtrics recorded the time and the number of clicks required to complete each page of the survey. Multiple regression indicated that insomnia was associated with daytime sleepiness and Hypervigilance, and mobile phone use before bed. Participants with moderate sleepiness required a greater number of clicks to complete the questionnaire. Greater sleepiness was associated with longer times to complete these self-assessment tasks. Clinically significant sleepiness produces changes in performance that can be detected from online responsivity. As sleepy individuals can be appreciably and quantitatively slower in performing subjective self-assessment tasks, this argues for objective measures of sleepiness and automated interventions and the design of systems that allow better quality sleep.Practitioner summary: Work can require processing of electronic messages, but 24/7 accessibility increases workload, causes fatigue and potentially creates security risks. Although most studies use people's self-reports, this study monitors time and clicks required to complete self-assessment rating scales. Sleepiness affected online responsivity, decreasing online accuracy and increasing response times and hypervigilance.

Accuracy-sensitisation promotes the sharing of pro- (but not anti-) vaccine information.

OBJECTIVE: This study investigated (i) factors predicting the seeking and sharing of vaccinerelated information, and (ii) the effect of an accuracy-sensitisation prime on sharing intentions. Design:This was a preregistered online survey with 213 participants. Participants were randomly assigned to an intervention group (who were exposed to an accuracy-sensitisation prime) or a control group. DESIGN: This was a preregistered online survey with 213 participants. Participants were randomly assigned to an intervention group (who were exposed to an accuracy-sensitisation prime) or a control group. MAIN OUTCOME MEASURES: Measures included decision-making style, COVID-19 anxiety, and percentages of pro and anti-vaccine friends. We also measured preferences to seek pro or anti-vaccine-related information and sharing intentions with respect to this information. RESULTS: Compared with those seeking both pro and anti-vaccine information, participants seeking only pro-vaccine information had lower hypervigilance and buck-passing and higher COVID-19 anxiety. The likelihood of sharing anti-vaccine information was positively predicted by the percentage of one's anti-vaccine friends, the size of one's social network, and conservative political orientation. Conversely, the likelihood of sharing pro-vaccine information was positively predicted by the percentage of one's pro-vaccine friends, and liberal political orientation. Participants sensitised to accuracy were significantly more likely to share provaccine information; however, accuracy-sensitisation had no effect on anti-vaccine information sharing. CONCLUSIONS: Individuals who seek anti-vaccine information have a tendency towards disorganised and impulsive decision-making. Accuracy-sensitisation may prime people to internalise a norm promoting truth-sharing.

Incompatibility Influences Cursor Placement When Pointing to Images of Cups.

OBJECTIVE: As images are used within graphical user interfaces to signify menu selection, it is important to understand how image properties can influence cursor placement online. BACKGROUND: Objects have multiple dimensions that create potential ambiguity and Stroop-like confusions for the operator if a previously habitual response conflicts with the required response. METHODS: To examine the impact of compatibility and other contextual factors, 41 participants used a computer Mouse or touch screen to place the cursor upon images of full or empty cups that varied in size, and direction of handle. RESULTS: Cursor placements took longer using the Mouse than touch screen. Although participants were placing the cursor on images, the size of the cup, whether it was empty or full, and the handle orientation interacted in their effects upon response duration and cursor placement. The effects of cup size reversed for empty cups or those with incompatible handles. CONCLUSION: Context can influence cursor placement. Perceived spillability influenced precision requirements, and the cup handle can serve as target or a flanking distractor. APPLICATION: Image content can influence screen hotspots. As performance can change with cup spillability, this bodes well for attempts to detect intent from cursor trajectories.

High achievers, Schadenfreude and Gluckschmerz in New Zealanders and Chinese.

The willingness to support (or denigrate) high-profile individuals online was examined across cultures using the Tall Poppy Scale. A sample of 106 Chinese and 164 New Zealand Europeans answered an online questionnaire addressing their preference for high achievers to be rewarded or fail. Participants were asked whether they would vote to support reality TV contestants, and offered further information (about success or failure) on a debrief page. The Favour Reward scale predicted willingness to vote and support others. The Favour Fall subscale tended to predict time spent viewing achievement-related information on a debrief page. The Chinese sample did not prefer reward of high achievers, instead favoring their fall, but spent less time per click on the debrief page, suggesting they disliked recognizing individual achievement.

Remote detection of Cannabis-related impairments in performance?

RATIONALE: Researchers have traditionally studied the effects of psychoactive drugs such as Cannabis in controlled laboratory settings or relied on retrospective self-reports to measure impairment. However, advances in technology afford opportunities to conduct assessments remotely. OBJECTIVES: We considered whether objective click-stream data (time and number of clicks spent on a webpage) during an online survey could supplement self-reports of substance use problems. METHODS: The clickstream data of participants (n = 236) were examined as they completed an online study which included validated psychometric tests (Cannabis Use Disorders Identification Test-Revised, Grit-O, Kessler Psychological Distress Scale, and Brief Self Control Scale). Clickstream data were compared to self-reported Cannabis use. RESULTS: People reporting Cannabis use within the last 4 weeks required more time and more clicks to complete the online survey, and this was specifically associated with reported frequency of use, duration of impairment, and problems with memory and concentration. Longer amounts of time and more clicks on the online questionnaire were associated with more recent Cannabis use rather than demographic factors or stimulant use. CONCLUSIONS: These results imply clickstream data remotely detected indecision or other deficits associated with previous Cannabis use.

Understanding sexual activity while driving as a form of distracted driving.

Sexual activity while driving has been reported in emerging research. Sexual activity while driving is a form of distracted driving because it includes an individual (the driver) who deviates resources from the primary task (driving) towards a secondary task (sexual activity). However, most of our current knowledge about the range of sexual activities while driving is based on self-reported data or media reports. Thus, an in-depth understanding of sexual activities while driving and their interactions with non-sexual driving behaviours and vehicle control is missing. Additionally, there is limited information on the context of where sexual activities while driving occurs and the influence of factors such as the environment, the vehicle, interactions with other road users, and other in-vehicle distractions. To cover this gap, a content analysis of sexually explicit media (SEM) was conducted on a sample of 270 videos depicting real driving. We conducted descriptive analyses and used decision tree analysis to explore the association between sexual activities while driving and their interactions with non-sexual driving behaviours and vehicle control. The videos portrayed a naturalistic driving situation of a driver of a moving vehicle engaging in sexual activity. The results show that when engaging in sexual activity, drivers do not present safe vehicle control. Sexual activity imposes additional cognitive, physical, and visual demands on the driver, thereby decreasing safety. Similar to other distractions, drivers engaging in sexual activity while driving appear to mitigate risks. Concerning the potential for legal sanctions, it appears that drivers may attempt to conceal sexual activity by reducing their visible nudity and minimising interactions with other road users. Finally, mobile phones and cameras appear to interact with sexual activities while driving, by imposing potential restrictions on the range of sexual activities. Implications for policymakers and practitioners are discussed.

Therapeutic Targeting of Protein Disulfide Isomerase PDIA1 in Multiple Myeloma.

Multiple myeloma is a genetically complex hematologic neoplasia in which malignant plasma cells constantly operate at the maximum limit of their unfolded protein response (UPR) due to a high secretory burden of immunoglobulins and cytokines. The endoplasmic reticulum (ER) resident protein disulfide isomerase, PDIA1 is indispensable for maintaining structural integrity of cysteine-rich antibodies and cytokines that require accurate intramolecular disulfide bond arrangement. PDIA1 expression analysis from RNA-seq of multiple myeloma patients demonstrated an inverse relationship with survival in relapsed or refractory disease, supporting its critical role in myeloma persistence. Using a structure-guided medicinal chemistry approach, we developed a potent, orally bioavailable small molecule PDIA1 inhibitor CCF642-34. The inhibition of PDIA1 overwhelms the UPR in myeloma cells, resulting in their apoptotic cell death at doses that do not affect the normal CD34+ hematopoietic stem and progenitor cells. Bortezomib resistance leads to increased PDIA1 expression and thus CCF642-34 sensitivity, suggesting that proteasome inhibitor resistance leads to PDIA1 dependence for proteostasis and survival. CCF642-34 induces acute unresolvable UPR in myeloma cells, and oral treatment increased survival of mice in the syngeneic 5TGM1 model of myeloma. Results support development of CCF642-34 to selectively target the plasma cell program and overcome the treatment-refractory state in myeloma.

SAR insights into TET2 catalytic domain inhibition: Synthesis of 2-Hydroxy-4-Methylene-pentanedicarboxylates.

The TET (Ten-Eleven Translocation) dioxygenase enzyme family comprising 3 members, TET1-3, play key roles in DNA demethylation. These processes regulate transcription programs that determine cell lineage, survival, proliferation, and differentiation. The impetus for our investigations described here is derived from the need to develop illuminating small molecule probes for TET enzymes with cellular activity and specificity. The studies were done so in the context of the importance of TET2 in the hematopoietic system and the preponderance of loss of function somatic TET2 mutations in myeloid diseases. We have identified that 2-hydroxy-4-methylene-pentanedicarboxylic acid 2a reversibly competes with the co-substrate α-KG in the TET2 catalytic domain and inhibits the dioxygenase activity with an IC50 = 11.0 ± 0.9 µM at 10 µM α-KG in a cell free system and binds in the TET2 catalytic domain with Kd = 0.3 ± 0.12 µM.

A Therapeutic Strategy for Preferential Targeting of TET2 Mutant and TET-dioxygenase Deficient Cells in Myeloid Neoplasms.

TET2 is frequently mutated in myeloid neoplasms. Genetic TET2 deficiency leads to skewed myeloid differentiation and clonal expansion, but minimal residual TET activity is critical for survival of neoplastic progenitor and stem cells. Consistent with mutual exclusivity of TET2 and neomorphic IDH1/2 mutations, here we report that IDH1/2 mutant-derived 2-hydroxyglutarate is synthetically lethal to TET-dioxygenase deficient cells. In addition, a TET-selective small molecule inhibitor decreased cytosine hydroxymethylation and restricted clonal outgrowth of TET2 mutant, but not normal hematopoietic precursor cells in vitro and in vivo. While TET-inhibitor phenocopied somatic TET2 mutations, its pharmacologic effects on normal stem cells were, unlike mutations, reversible. Treatment with TET inhibitor suppressed the clonal evolution of TET2 mutant cells in murine models and TET2-mutated human leukemia xenografts. These results suggest that TET inhibitors may constitute a new class of targeted agents in TET2 mutant neoplasia.

Pharmacological polyamine catabolism upregulation with methionine salvage pathway inhibition as an effective prostate cancer therapy.

Prostatic luminal epithelial cells secrete high levels of acetylated polyamines into the prostatic lumen, sensitizing them to perturbations of connected metabolic pathways. Enhanced flux is driven by spermidine/spermine N1-acetyltransferase (SSAT) activity, which acetylates polyamines leading to their secretion and drives biosynthetic demand. The methionine salvage pathway recycles one-carbon units lost to polyamine biosynthesis to the methionine cycle to overcome stress. Prostate cancer (CaP) relies on methylthioadenosine phosphorylase (MTAP), the rate-limiting enzyme, to relieve strain. Here, we show that inhibition of MTAP alongside SSAT upregulation is synergistic in androgen sensitive and castration recurrent CaP models in vitro and in vivo. The combination treatment increases apoptosis in radical prostatectomy ex vivo explant samples. This unique high metabolic flux through polyamine biosynthesis and connected one carbon metabolism in CaP creates a metabolic dependency. Enhancing this flux while simultaneously targeting this dependency in prostate cancer results in an effective therapeutic approach potentially translatable to the clinic.

Reactions to ideal body shapes.

Difficult-to-attain beauty standards that are promulgated by the media could contribute to body dissatisfaction, but their potential impact upon body image remains unclear. The present study examined reactions to thin-ideal and muscular-ideal images, and examined the effects of ideal image exposure on preferred body shape and time spent deliberating about ideal shape. In a 2 × 2 experimental design, 200 Internet users completed the Kessler psychological distress scale (K10) and were randomly assigned to view idealistic body images or houses (and rated them on semantic differential dimensions). Females viewed thin ideal images and males viewed muscular ideal images, while the control groups viewed images of houses. Between group measures analysis of variance revealed women reacted negatively to thinspirational images. Women were more driven for thinness and idealized a thinner shape for the female body than men. Psychologically distressed participants had a stronger drive for thinness and greater body dissatisfaction compared to low-distress participants. In addition, although beauty ideal imagery had no significant impact on males, females spent more time in choosing ideal body figure. Viewing thin bodies for females created a trend toward desiring a slimmer figure, as well as increased preoccupation with size as they spent more time deliberating over a photorealistic figure rating scale. Therefore, exposure to thinspiration promotes dissatisfaction with self and leads women to dwell more upon their body image.

Cannabis, Decision-Making, and Online Assistance Seeking.

BACKGROUND AND OBJECTIVES: Maladaptive decision-making strategies could contribute to cannabis-related problems, as some individuals may neither select safe patterns of cannabis use, nor seek treatment. METHODS: To explore decision-making styles and their relationship to cannabis-related harm, 153 respondents completed the Cannabis Use Disorders Identification Test-Revised (CUDIT-R), the Melbourne Decision Making Questionnaire (MDMQ), and answered questions about their willingness to seek online: (1) further information or (2) treatment for cannabis-related issues. RESULTS: Multiple regression considered relationships between problematic cannabis use, decision-making style, and cannabis use within the past month. Subscales of the CUDIT-R revealed that: (1) hazardous use was associated with higher hypervigilance and higher decisional self-esteem; (2) dependence symptoms were associated with lower vigilance and higher procrastination; and (3) harmful use was associated with higher procrastination. People with symptoms of CUD were less likely to seek further help or support online if prone to procrastination or buckpasssing. DISCUSSION AND CONCLUSIONS: Decisional style influenced cannabis use and symptoms. Those people with cannabis-related problems that did not seek online assistance were defensively avoidant. SCIENTIFIC SIGNIFICANCE: Procrastination is a feature of problematic cannabis use. Online offers of assistance may be ignored by defensively avoidant CUD clients. (Am J Addict 2019;00:1-7).

Sleep- and Wake-Promoting Drugs: Where Are They Being Sourced, and What Is Their Impact?

Background: Recent decades have seen both an increased number of shift workers in order to deliver services 24/7, and increased potential for social interactions at all hours of the day. People have sought to engage in strategies, which either promote vigilance or facilitate sleep, with the use of sleep- and wake-promoting drugs representing one strategy. Methods: We investigated use of sleep- and wake-promoting drugs in participants (n = 377) who completed a survey investigating the type and source of sleep- and wake-promoting drugs, and their impact on sleep and performance outcomes. Results: The most commonly reported wake-promoting drugs were amphetamine and dextroamphetamin salts, modafinil, and illicit substances including methamphetamine and cocaine, while the most commonly reported sleep-promoting drugs were benzodiazepines and antihistamines. Use of a sleep-promoting drug in the past month was associated with higher odds of having poorer sleep quality (OR = 3.15) and moderate-high insomnia (OR = 3.30), while use of a wake-promoting drug was associated with poor sleep quality (OR = 3.76), or making a fatigue-related error (OR = 2.65). Conclusions: These findings represent novel data on the use and source of sleep- and wake-promoting- drugs, and suggest that despite their use, poor sleep and performance outcomes persist, likely representing individuals struggling to keep up with the 24/7 world.

Problematic Use of Mobile Phones in Australia Is It Getting Worse?

Rapid technological innovations over the past few years have led to dramatic changes in today's mobile phone technology. While such changes can improve the quality of life of its users, problematic mobile phone use can result in its users experiencing a range of negative outcomes such as anxiety or, in some cases, engagement in unsafe behaviors with serious health and safety implications such as mobile phone distracted driving. The aims of the present study are two-fold. First, this study investigated the current problem mobile phone use in Australia and its potential implications for road safety. Second, based on the changing nature and pervasiveness of mobile phones in Australian society, this study compared data from 2005 with data collected in 2018 to identify trends in problem mobile phone use in Australia. As predicted, the results demonstrated that problem mobile phone use in Australia increased from the first data collected in 2005. In addition, meaningful differences were found between gender and age groups in this study, with females and users in the 18-25 year-old age group showing higher mean Mobile Phone Problem Use Scale (MPPUS) scores. Additionally, problematic mobile phone use was linked with mobile phone use while driving. Specifically, participants who reported high levels of problem mobile phone use, also reported handheld and hands-free mobile phone use while driving.

Instances of online suicide, the law and potential solutions.

To understand the social and legal issues posed by suicide-related communications over the Internet (messages of threatened suicide and advocated suicide), this article examines a selection of cases involving different types of online baiting and harassment that illustrate different legal and technological issues. The anonymity afforded by computer-mediated communication allows bullies to harass vulnerable individuals and leak (disclose) their personal information. Computer mediation of communication potentially diffuses responsibility; imposes a temporal asynchrony between signified intent and audience response; and reduces the empathy that might motivate observers or witnesses to intervene and render assistance, factors that make online baiting a serious social, legal and technological problem. Potential actions (both legal and technological) for addressing this problem are outlined.

Risky Alcohol Consumption and Online Activity Levels.

University students engage in risky patterns of alcohol consumption, which may affect their health and performance at university. This study provides a novel analysis which tracked students' interaction with online course materials over time, and examined associations between online activity and alcohol related harm (as indicated by the Alcohol Use Disorders Identification Test). Study 1 tracked 63 undergraduate psychology students in the second half of a semester and found risky drinking behaviors were marginally related to reductions in online study activity. Study 2 tracked 88 undergraduate psychology students in the first half of a semester. Risky drinking behaviors were associated with less online activity after midday. Students reporting more alcohol related harm were less likely to login between 7 pm and midnight, and between 1 am and 6 am. This study demonstrates a potential sensitivity of online activity levels to alcohol use.

Cannabis, alcohol use, psychological distress, and decision-making style.

INTRODUCTION: There have been suggestions of hypofrontality in cannabis users. To understand cannabis-related differences in decisional processes, Janis and Mann's conflict model of decision making was applied to recreational cannabis smokers who varied in their alcohol use and level of psychological distress. METHOD: An online sample of recreational substance users (114 male, 119 female) completed the Melbourne Decision Making Questionnaire, the Alcohol Use Disorders Identification Test (AUDIT), Kessler's Psychological Distress Scale (K10), and the Severity of Dependence Scale (SDS) for cannabis. RESULTS: Multivariate analysis of variance examined self-reported decision-making styles as a function of gender, recent cannabis use, risky alcohol consumption, and levels of psychological distress. Psychological distress was associated with lower decisional self-esteem and higher levels of procrastination and buck-passing. There were gender differences associated with cannabis use. Female cannabis users reported higher levels of hypervigilance, while male cannabis users reported lower levels of buck-passing. CONCLUSIONS: Although there was little indication of an avoidant decisional style in cannabis users, the results suggest that cannabis affects decisional processes, contributing to panic in females and impulsivity in males.

Buried Hydrogen Bond Interactions Contribute to the High Potency of Complement Factor D Inhibitors.

Aberrant activation of the complement system is associated with diseases, including paroxysmal nocturnal hemoglobinuria and age-related macular degeneration. Complement factor D is the rate-limiting enzyme for activating the alternative pathway in the complement system. Recent development led to a class of potent amide containing pyrrolidine derived factor D inhibitors. Here, we used biochemical enzymatic and biolayer interferometry assays to demonstrate that the amide group improves the inhibitor potency by more than 80-fold. Our crystal structures revealed buried hydrogen bond interactions are important. Molecular orbital analysis from quantum chemistry calculations dissects the chemical groups participating in these interactions. Free energy calculation supports the differential contributions of the amide group to the binding affinities of these inhibitors. Cell-based hemolysis assay confirmed these compounds inhibit factor D mediated complement activation via the alternative pathway. Our study highlights the important interactions contributing to the high potency of factor D inhibitors reported recently.

Dynamic Selective Exposure during Decision-Making.

To understand dynamic changes in the likelihood that people would access and selectively expose themselves to information online, the present study examined the checking of account balances during simulated gambling. Sixteen participants played 120 hands of computer Blackjack for points, at higher or lower levels of risk (different point multipliers), and after each win or loss the computer recorded if participants checked their account balances. There were individual differences in checking rates. Participants who were more likely to check balances exhibited a selectivity of exposure to decision consonant information after a win at low risk. Although it was expected that people would seek to maintain positive mood, data were better explained in terms of Cognitive Dissonance. The effects of Cognitive Dissonance are liable to extend beyond single static decisions into dynamic online environments.

Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma.

Multiple myeloma cells secrete more disulfide bond-rich proteins than any other mammalian cell. Thus, inhibition of protein disulfide isomerases (PDI) required for protein folding in the endoplasmic reticulum (ER) should increase ER stress beyond repair in this incurable cancer. Here, we report the mechanistically unbiased discovery of a novel PDI-inhibiting compound with antimyeloma activity. We screened a 30,355 small-molecule library using a multilayered multiple myeloma cell-based cytotoxicity assay that modeled disease niche, normal liver, kidney, and bone marrow. CCF642, a bone marrow-sparing compound, exhibited a submicromolar IC50 in 10 of 10 multiple myeloma cell lines. An active biotinylated analog of CCF642 defined binding to the PDI isoenzymes A1, A3, and A4 in MM cells. In vitro, CCF642 inhibited PDI reductase activity about 100-fold more potently than the structurally distinct established inhibitors PACMA 31 and LOC14. Computational modeling suggested a novel covalent binding mode in active-site CGHCK motifs. Remarkably, without any further chemistry optimization, CCF642 displayed potent efficacy in an aggressive syngeneic mouse model of multiple myeloma and prolonged the lifespan of C57BL/KaLwRij mice engrafted with 5TGM1-luc myeloma, an effect comparable to the first-line multiple myeloma therapeutic bortezomib. Consistent with PDI inhibition, CCF642 caused acute ER stress in multiple myeloma cells accompanied by apoptosis-inducing calcium release. Overall, our results provide an illustration of the utility of simple in vivo simulations as part of a drug discovery effort, along with a sound preclinical rationale to develop a new small-molecule therapeutic to treat multiple myeloma. Cancer Res; 76(11); 3340-50. ©2016 AACR.