Did people really drink bleach to prevent COVID-19? A guide for protecting survey data against problematic respondents.

Survey respondents who are non-attentive, respond randomly, or misrepresent who they are can impact the outcomes of surveys. Prior findings reported by the CDC have suggested that people engaged in highly dangerous cleaning practices during the COVID-19 pandemic, including ingesting household cleaners such as bleach. In our attempts to replicate the CDC's results, we found that 100% of reported ingestion of household cleaners are made by problematic respondents. Once inattentive, acquiescent, and careless respondents are removed from the sample, we find no evidence that people ingested cleaning products to prevent a COVID-19 infection. These findings have important implications for public health and medical survey research, as well as for best practices for avoiding problematic respondents in all survey research conducted online.

Is it ethical to use Mechanical Turk for behavioral research? Relevant data from a representative survey of MTurk participants and wages.

To understand human behavior, social scientists need people and data. In the last decade, Amazon's Mechanical Turk (MTurk) emerged as a flexible, affordable, and reliable source of human participants and was widely adopted by academics. Yet despite MTurk's utility, some have questioned whether researchers should continue using the platform on ethical grounds. The brunt of their concern is that people on MTurk are financially insecure, subject to abuse, and earn inhumane wages. We investigated these issues with two representative probability surveys of the U.S. MTurk population (N = 4094). The surveys revealed: (1) the financial situation of people on MTurk mirrors the general population, (2) most participants do not find MTurk stressful or requesters abusive, and (3) MTurk offers flexibility and benefits that most people value above other options for work. People reported it is possible to earn more than $10 per hour and said they would not trade the flexibility of MTurk for less than $25 per hour. Altogether, our data are important for assessing whether MTurk is an ethical place for research.

A phase I, first-in-human study of TAK-164, an antibody-drug conjugate, in patients with advanced gastrointestinal cancers expressing guanylyl cyclase C.

PURPOSE: Guanylyl cyclase C (GCC) is highly expressed in several gastrointestinal malignancies and preclinical studies suggest that it is a promising target for antibody-based therapeutics. This phase I trial assessed the safety and tolerability of TAK-164, an investigational, anti-GCC antibody-drug conjugate (NCT03449030). METHODS: Thirty-one patients with GCC-positive, advanced gastrointestinal cancers received intravenous TAK-164 on day 1 of 21-day cycles. Dose escalation proceeded based on cycle 1 safety data via a Bayesian model. RESULTS: Median age was 58 years (range 32-72), 25 patients (80.6%) had colorectal carcinoma, and median number of prior therapies was four. No dose-limiting toxicities (DLTs) were reported during cycle 1 DLT evaluation period. After cycle 2 dosing, 3 patients reported dose-limiting treatment-emergent adverse events (TEAEs): grade 3 pyrexia and grade 5 hepatic failure (0.19 mg/kg), grade 4 hepatic failure and platelet count decreased (0.25 mg/kg), grade 3 nausea, grade 4 platelet and neutrophil count decreased (0.25 mg/kg). The recommended phase II dose (RP2D) was 0.064 mg/kg. Common TAK-164-related TEAEs included platelet count decreased (58.1%), fatigue (38.7%), and anemia (32.3%). There was a dose-dependent increase in TAK-164 exposure over the range, 0.032-0.25 mg/kg. TAK-164 half-life ranged from 63.5 to 159 h. One patient (0.008 mg/kg) with high baseline GCC expression had an unconfirmed partial response. CONCLUSIONS: TAK-164 appeared to have a manageable safety profile at 0.064 mg/kg. Hepatic toxicity was identified as a potential risk. The RP2D of 0.064 mg/kg was considered insufficient to derive clinical benefit; there are no plans for further clinical development. CLINICAL TRIAL REGISTRATION: NCT03449030.

Evaluating CloudResearch's Approved Group as a solution for problematic data quality on MTurk.

Maintaining data quality on Amazon Mechanical Turk (MTurk) has always been a concern for researchers. These concerns have grown recently due to the bot crisis of 2018 and observations that past safeguards of data quality (e.g., approval ratings of 95%) no longer work. To address data quality concerns, CloudResearch, a third-party website that interfaces with MTurk, has assessed ~165,000 MTurkers and categorized them into those that provide high- (~100,000, Approved) and low- (~65,000, Blocked) quality data. Here, we examined the predictive validity of CloudResearch's vetting. In a pre-registered study, participants (N = 900) from the Approved and Blocked groups, along with a Standard MTurk sample (95% HIT acceptance ratio, 100+ completed HITs), completed an array of data-quality measures. Across several indices, Approved participants (i) identified the content of images more accurately, (ii) answered more reading comprehension questions correctly, (iii) responded to reversed coded items more consistently, (iv) passed a greater number of attention checks, (v) self-reported less cheating and actually left the survey window less often on easily Googleable questions, (vi) replicated classic psychology experimental effects more reliably, and (vii) answered AI-stumping questions more accurately than Blocked participants, who performed at chance on multiple outcomes. Data quality of the Standard sample was generally in between the Approved and Blocked groups. We discuss how MTurk's Approval Rating system is no longer an effective data-quality control, and we discuss the advantages afforded by using the Approved group for scientific studies on MTurk.

Do you know the Wooly Bully? Testing era-based knowledge to verify participant age online.

People in online studies sometimes misrepresent themselves. Regardless of their motive for doing so, participant misrepresentation threatens the validity of research. Here, we propose and evaluate a way to verify the age of online respondents: a test of era-based knowledge. Across six studies (N = 1543), participants of various ages completed an age verification instrument. The instrument assessed familiarity with cultural phenomena (e.g., songs and TV shows) from decades past and present. We consistently found that our instrument discriminated between people of different ages. In Studies 1a and 1b, self-reported age correlated strongly with performance on the instrument (mean r = .8). In Study 2, the instrument reliably detected imposters who we knew were misrepresenting their age. For impostors, self-reported age did not correlate with performance on the instrument (r = .077). Finally, in Studies 3a, 3b, and 3c, the instrument remained robust with African Americans, people from low educational backgrounds, and recent immigrants to the United States. Thus, our instrument shows promise for verifying the age of online respondents, and, as we discuss, our approach of assessing "insider knowledge" holds great promise for verifying other identities within online studies.

Paranoia and belief updating during the COVID-19 crisis.

The COVID-19 pandemic has made the world seem less predictable. Such crises can lead people to feel that others are a threat. Here, we show that the initial phase of the pandemic in 2020 increased individuals' paranoia and made their belief updating more erratic. A proactive lockdown made people's belief updating less capricious. However, state-mandated mask-wearing increased paranoia and induced more erratic behaviour. This was most evident in states where adherence to mask-wearing rules was poor but where rule following is typically more common. Computational analyses of participant behaviour suggested that people with higher paranoia expected the task to be more unstable. People who were more paranoid endorsed conspiracies about mask-wearing and potential vaccines and the QAnon conspiracy theories. These beliefs were associated with erratic task behaviour and changed priors. Taken together, we found that real-world uncertainty increases paranoia and influences laboratory task behaviour.

Paranoia and belief updating during a crisis.

The 2019 coronavirus (COVID-19) pandemic has made the world seem unpredictable. During such crises we can experience concerns that others might be against us, culminating perhaps in paranoid conspiracy theories. Here, we investigate paranoia and belief updating in an online sample (N=1,010) in the United States of America (U.S.A). We demonstrate the pandemic increased individuals' self-rated paranoia and rendered their task-based belief updating more erratic. Local lockdown and reopening policies, as well as culture more broadly, markedly influenced participants' belief-updating: an early and sustained lockdown rendered people's belief updating less capricious. Masks are clearly an effective public health measure against COVID-19. However, state-mandated mask wearing increased paranoia and induced more erratic behaviour. Remarkably, this was most evident in those states where adherence to mask wearing rules was poor but where rule following is typically more common. This paranoia may explain the lack of compliance with this simple and effective countermeasure. Computational analyses of participant behaviour suggested that people with higher paranoia expected the task to be more unstable, but at the same time predicted more rewards. In a follow-up study we found people who were more paranoid endorsed conspiracies about mask-wearing and potential vaccines - again, mask attitude and conspiratorial beliefs were associated with erratic task behaviour and changed priors. Future public health responses to the pandemic might leverage these observations, mollifying paranoia and increasing adherence by tempering people's expectations of other's behaviour, and the environment more broadly, and reinforcing compliance.

Target-Mediated Drug Disposition Pharmacokinetic/Pharmacodynamic Model-Informed Dose Selection for the First-in-Human Study of AVB-S6-500.

AVB-S6-500 neutralized growth arrest-specific 6 (GAS6) protein and effectively inhibited AXL signaling in preclinical cancer models. A target-mediated drug disposition (TMDD) pharmacokinetic/pharmacodynamic (PK/PD) model was used to select first-in-human (FIH) doses for AVB-S6-500 based on predicted target (GAS6) suppression in the clinic. The effect of TMDD on AVB-S6-500 clearance was incorporated into a standard two-compartment model, providing parallel linear and nonlinear clearance. Observed AVB-S6-500 and GAS6 concentration data in cynomolgus monkeys and relevant interspecies differences were used to predict the PK (serum concentration)/PD (GAS6 suppression) relationship in humans. Human exposure and GAS6 suppression were simulated for the proposed FIH doses of 1, 2.5, 5, and 10 mg/kg. A dose of 1 mg/kg was selected to target GAS6 suppression for 2 weeks in the initial healthy volunteer study. The cynomolgus monkey:human ratios for the highest proposed FIH dose were anticipated to yield more than a 10-fold margin to the nonclinical no observed adverse event level while maintaining > 90% GAS6 suppression. In human subjects, the first dose (1 mg/kg) model-projected and clinically observed maximal concentration (Cmax ) was within 10% of predicted; repeat dosing at 5 mg/kg was within 1% (Cmax ) and 45% (area under the serum concentration-time curve from time 0 to end of dosing interval) of predicted. Predicted GAS6 suppression duration of 14 days was accurate for the 1 mg/kg dose. A PK/PD model expedited clinical development of AVB-S6-500, minimized exposure of patients with cancer to subtherapeutic doses, and rationally guided the optimal dosing in patients.

Tapped out or barely tapped? Recommendations for how to harness the vast and largely unused potential of the Mechanical Turk participant pool.

Mechanical Turk (MTurk) is a common source of research participants within the academic community. Despite MTurk's utility and benefits over traditional subject pools some researchers have questioned whether it is sustainable. Specifically, some have asked whether MTurk workers are too familiar with manipulations and measures common in the social sciences, the result of many researchers relying on the same small participant pool. Here, we show that concerns about non-naivete on MTurk are due less to the MTurk platform itself and more to the way researchers use the platform. Specifically, we find that there are at least 250,000 MTurk workers worldwide and that a large majority of US workers are new to the platform each year and therefore relatively inexperienced as research participants. We describe how inexperienced workers are excluded from studies, in part, because of the worker reputation qualifications researchers commonly use. Then, we propose and evaluate an alternative approach to sampling on MTurk that allows researchers to access inexperienced participants without sacrificing data quality. We recommend that in some cases researchers should limit the number of highly experienced workers allowed in their study by excluding these workers or by stratifying sample recruitment based on worker experience levels. We discuss the trade-offs of different sampling practices on MTurk and describe how the above sampling strategies can help researchers harness the vast and largely untapped potential of the Mechanical Turk participant pool.

Online panels in social science research: Expanding sampling methods beyond Mechanical Turk.

Amazon Mechanical Turk (MTurk) is widely used by behavioral scientists to recruit research participants. MTurk offers advantages over traditional student subject pools, but it also has important limitations. In particular, the MTurk population is small and potentially overused, and some groups of interest to behavioral scientists are underrepresented and difficult to recruit. Here we examined whether online research panels can avoid these limitations. Specifically, we compared sample composition, data quality (measured by effect sizes, internal reliability, and attention checks), and the non-naivete of participants recruited from MTurk and Prime Panels-an aggregate of online research panels. Prime Panels participants were more diverse in age, family composition, religiosity, education, and political attitudes. Prime Panels participants also reported less exposure to classic protocols and produced larger effect sizes, but only after screening out several participants who failed a screening task. We conclude that online research panels offer a unique opportunity for research, yet one with some important trade-offs.

The role of the equilibrative nucleoside transporter 1 on tissue and fetal distribution of ribavirin in the mouse.

Ribavirin is used for the treatment of hepatitis C virus (HCV) infection. The equilibrative nucleoside transporter 1 (ENT1) expressed in hepatocytes transports ribavirin into the liver, the site of efficacy of the drug. However, it is still unclear whether ENT1 plays a dominant role in the hepatic distribution of the drug in vivo. In addition, due to fetal toxicity, administration of ribavirin to pregnant women with HCV infection is contraindicated. ENT1 might play a role in the fetal distribution and therefore the fetal toxicity of ribavirin. The aim of the present study was to investigate the in vivo contribution of ENT1 to the tissue distribution of ribavirin. When compared with that in Ent1(+/+) mice, the ribavirin tissue to plasma concentration ratio (including phosphorylated metabolites) in Ent1(-/-) mice at 15 min and 6 h after intravenous [(3) H]-ribavirin (3 mg/kg) administration was consistently and significantly decreased in the liver and the pancreas. Likewise, when compared with the Ent1(+/+) mice, the fetal distribution of ribavirin at 15 min after administration was significantly reduced in Ent1(-/-) fetuses and placenta. In contrast, there was no significant difference between Ent1(+/+), Ent1(+/-) and Ent1(-/-) mice in the fetal or placental to maternal plasma ribavirin concentration ratio at 2 h after ribavirin administration. The findings in the present study suggest that ENT1 plays a pivotal role in the distribution of ribavirin into tissues including the liver and pancreas, but affects only the rate, but not the extent, of ribavirin distribution into the fetus. Copyright © 2016 John Wiley & Sons, Ltd.

Role of the equilibrative and concentrative nucleoside transporters in the intestinal absorption of the nucleoside drug, ribavirin, in wild-type and Ent1(-/-) mice.

Ribavirin is frontline treatment for hepatitis C virus infection. To determine the role of nucleoside transporters in the intestinal absorption of orally administered ribavirin, we perfused the intestines of Ent1(-/-) and wild-type mice, in situ, with [(3)H] ribavirin (20, 200, and 5000 µM) in the presence and absence of sodium. The decrease in luminal ribavirin concentration over 30 min was measured at 5 min intervals. Blood samples were collected approximately every 10 min. Ribavirin plus phosphorylated metabolite concentrations (hereafter referred to as ribavirin) were determined in tissue, blood, and plasma by HPLC fractionation and scintillation counting. There was no significant difference between wild-type and Ent1(-/-) mice in intestinal loss of ribavirin at any ribavirin concentration studied. Perfusions without sodium drastically reduced the intestinal loss of ribavirin in both wild-type and Ent1(-/-) mice. After 20 µM ribavirin perfusions, Ent1(-/-) intestinal tissue contained 8-fold greater ribavirin than wild-type mice (p < 0.01). Ribavirin concentrations in the wild-type intestinal tissue were 70-fold higher after 200 vs 20 µM perfusions (p < 0.001), indicating saturation of intestinal ribavirin efflux and possibly other processes as well. Ribavirin plasma concentrations were significantly higher in wild-type mice (2.7-fold) vs Ent1(-/-) mice at 30 min after the 20 µM perfusion (p < 0.01). These results suggest that, at lower intestinal concentrations of ribavirin, concentrative and equilibrative nucleoside transporters are important in the intestinal absorption of ribavirin. At higher intestinal concentrations, these transporters are saturated and other processes in the intestine (transport and/or metabolism) play an important role in the absorption of ribavirin.

The role of nucleoside transporters in the erythrocyte disposition and oral absorption of ribavirin in the wild-type and equilibrative nucleoside transporter 1-/- mice.

Ribavirin [1-(beta-d-ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide] is the treatment of choice for hepatitis C virus infection. Ribavirin is a substrate of several nucleoside transporters, including the equilibrative nucleoside transporter (Ent) and the concentrative nucleoside transporter 2. To determine the role of Ent1 in ribavirin absorption and erythrocyte distribution, we examined its pharmacokinetics in Ent1-null mice. After intravenous administration, we found that the erythrocyte area under the curve (AUC(0-12 h)) was reduced 3.05-fold along with 2.63-fold reduction of erythrocyte versus plasma AUC ratio in the Ent1(-/-) mice, whereas there was no significant difference in the plasma AUC(0-12 h) between Ent1(+/+) and Ent1(-/-) mice. After 48 h, we found a similar fraction of ribavirin or total radioactivity excreted in the urine between the Ent1(+/+) and Ent1(-/-) mice. After oral administration of three different doses, 0.024, 0.24, and 6.1 mg/kg, we found that the dose-normalized plasma AUC(0-12 h) of ribavirin was 69.7 +/- 12.0, 20.7 +/- 1.5, and 18.3 +/- 2.7 min/l, respectively, in the Ent1(+/+) mice and 18.9 +/- 2.8, 13.0 +/- 0.5, and 12.2 +/- 1.0 min/l, respectively, in the Ent1(-/-) mice. It is interesting that at the highest dose, the dose-normalized plasma AUC(0-30 min), AUC(0-12 h), and C(max) in the Ent1(+/+) mice were decreased 4.0-, 3.8-, and 3.4-fold, respectively, compared with the lowest dose, suggesting absorption was saturated at the highest dose we used. The dose-normalized plasma AUC(0-12 h) was 3.7- and 1.5-fold lower at the lowest and the highest dose, respectively, in the Ent1(-/-) mice compared with those of the Ent1(+/+) mice. Our findings indicate that Ent1 plays a significant role in the oral absorption and erythrocyte distribution of ribavirin.

The role of the equilibrative nucleoside transporter 1 (ENT1) in transport and metabolism of ribavirin by human and wild-type or Ent1-/- mouse erythrocytes.

The polar nucleoside drug ribavirin is front-line treatment for chronic hepatitis C virus infection. The human equilibrative nucleoside transporter (ENT) 1 transports ribavirin into erythrocytes where it is phosphorylated. These phosphorylated metabolites accumulate in the erythrocytes and produce dose-limiting hemolytic anemia. Here, we examined the in vitro and ex vivo transport and metabolism of ribavirin by erythrocytes isolated from humans and Ent1-null mice. Ribavirin (2.4 microM) uptake was significantly higher (1044 +/- 255 amol/microg/10 s) into erythrocytes from Ent1(+/+) mice compared with that from Ent1(-/-) mice (76.48 +/- 11.20 amol/microg/10 s). Our results showed a saturable (K(m) of 382 +/- 75.1 microM) transport of [(3)H]ribavirin into erythrocytes from Ent1(+/+) mice. We found that ribavirin concentration rapidly (within 60 s) reached equilibrium in erythrocytes using a time course of [(3)H]ribavirin transport (2.5 microM) and metabolism in mouse and human erythrocytes for 8 h. However, total radioactivity of ribavirin was predominantly attributed to the phosphorylated metabolites ribavirin monophosphate and ribavirin triphosphate. Our findings allow us to estimate ribavirin transport, diffusion, and metabolic clearance and to predict in vivo accumulation of ribavirin phosphates in erythrocytes of both mice and humans. Our modeling of ribavirin in erythrocytes on long-term administration of ribavirin suggests that the accumulation of ribavirin inside the cells is dependent on ENT1/Ent1 transport and the rates of intracellular phosphorylation and the degradation of the phosphorylated metabolites. We predict that Ent1(+/+) and Ent1(-/-) mice will serve as excellent models to investigate the contribution of Ent1 to the pharmacokinetics and toxicity of ribavirin in vivo.

Pharmacokinetics in drug discovery.

The aim of this current review is to summarize the present status of pharmacokinetics in Drug Discovery. The review is structured into four sections. The first section is a general overview of what we understand by pharmacokinetics and the different LADMET aspects: Liberation, Absorption, Distribution, Metabolism, Excretion, and Toxicity. The second section highlights the different computational or in silico approaches to estimate/predict one or several aspects of the pharmacokinetic profile of a discovery lead compound. The third section discusses the most commonly used in vitro methodologies. The fourth and last section examines the various approaches employed towards the pharmacokinetic assessment of discovery molecules; including all the LADME processes, discussing the different mathematical methodologies available to establish the PK profile of a test compound; what the main differences are and what should be the criteria for using one or another mathematical approach. The major conclusion of this review is that the use of the appropriate preclinical assays has a key role in the long-term viability of a pharmaceutical company since applying the right tools early in discovery will play a key role in determining the company's ability to discover novel safe and effective therapeutics to patients as quickly as possible.