The parasite intraerythrocytic cycle and human circadian cycle are coupled during malaria infection.

During infections with the malaria parasites Plasmodium vivax, patients exhibit rhythmic fevers every 48 h. These fever cycles correspond with the time the parasites take to traverse the intraerythrocytic cycle (IEC). In other Plasmodium species that infect either humans or mice, the IEC is likely guided by a parasite-intrinsic clock [Rijo-Ferreiraet al., Science 368, 746-753 (2020); Smith et al., Science 368, 754-759 (2020)], suggesting that intrinsic clock mechanisms may be a fundamental feature of malaria parasites. Moreover, because Plasmodium cycle times are multiples of 24 h, the IECs may be coordinated with the host circadian clock(s). Such coordination could explain the synchronization of the parasite population in the host and enable alignment of IEC and circadian cycle phases. We utilized an ex vivo culture of whole blood from patients infected with P. vivax to examine the dynamics of the host circadian transcriptome and the parasite IEC transcriptome. Transcriptome dynamics revealed that the phases of the host circadian cycle and the parasite IEC are correlated across multiple patients, showing that the cycles are phase coupled. In mouse model systems, host-parasite cycle coupling appears to provide a selective advantage for the parasite. Thus, understanding how host and parasite cycles are coupled in humans could enable antimalarial therapies that disrupt this coupling.

The spatiotemporal gradient of intrusion errors in continuous outcome source memory: Source retrieval is affected by both guessing and intrusions.

Previous research has characterized source retrieval as a thresholded process, which fails on a proportion of trials and leads to guessing, as opposed to a continuous process, in which response precision varies across trials but is never zero. The thresholded view of source retrieval is largely based on the observation of heavy tailed distributions of response errors, thought to reflect a large proportion of "memoryless" trials. In this study, we investigate whether these errors might instead reflect systematic intrusions from other list items which can mimic source guessing. Using the circular diffusion model of decision making, which accounts for both response errors and RTs we found that intrusions account for some, but not all, errors in a continuous-report source memory task. We found that intrusion errors were more likely to come from items studied in nearby locations and times, and were well-described by a spatiotemporal gradient model, but not from semantically or perceptually similar cues. Our findings support a thresholded view of source retrieval but suggest that previous work has overestimated the proportion of guesses which have been conflated with intrusions.

"Reliable organisms from unreliable components" revisited: the linear drift, linear infinitesimal variance model of decision making.

Diffusion models of decision making, in which successive samples of noisy evidence are accumulated to decision criteria, provide a theoretical solution to von Neumann's (1956) problem of how to increase the reliability of neural computation in the presence of noise. I introduce and evaluate a new neurally-inspired dual diffusion model, the linear drift, linear infinitesimal variance (LDLIV) model, which embodies three features often thought to characterize neural mechanisms of decision making. The accumulating evidence is intrinsically positively-valued, saturates at high intensities, and is accumulated for each alternative separately. I present explicit integral-equation predictions for the response time distribution and choice probabilities for the LDLIV model and compare its performance on two benchmark sets of data to three other models: the standard diffusion model and two dual diffusion model composed of racing Wiener processes, one between absorbing and reflecting boundaries and one with absorbing boundaries only. The LDLIV model and the standard diffusion model performed similarly to one another, although the standard diffusion model is more parsimonious, and both performed appreciably better than the other two dual diffusion models. I argue that accumulation of noisy evidence by a diffusion process and drift rate variability are both expressions of how the cognitive system solves von Neumann's problem, by aggregating noisy representations over time and over elements of a neural population. I also argue that models that do not solve von Neumann's problem do not address the main theoretical question that historically motivated research in this area.

Diffusion theory of the antipodal "shadow" mode in continuous-outcome, coherent-motion decisions.

Continuous-outcome decisions, in which responses are made on continuous scales, are increasingly used to study perception and memory for stimulus attributes like color, orientation, and motion. This interest has led to the development of models of continuous-outcome decision processes like the circular diffusion model that predict joint distributions of decision outcomes and response times (RTs). We use the circular diffusion model and a new spherical generalization of it to model performance in a continuous-outcome version of the random-dot motion task. The task is a benchmark test of decision models because it yields bimodal distributions of decision outcomes: In addition to a peak or mode in the true direction of motion, there is a secondary, antipodal, mode at 180° to the true direction. Models like the circular diffusion model, in which evidence is accumulated by a single process, are thought to be unable to predict bimodality. We compared diffusion models for the continuous motion task in which evidence is accumulated in either a two-dimensional (2D) or a three-dimensional (3D) representational space. We found that performance was well described by a spherical (3D) diffusion model in which the drift rate encodes perceived motion direction and strength and the points on the bounding sphere representing the decision criterion are projected onto a 2D circle to make a response. A model with an antipodal component of drift rate and drift-rate variability successfully predicted bimodal distributions of decision outcomes and the joint distributions of decision outcomes and RT for individual participants. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Salience by competitive and recurrent interactions: Bridging neural spiking and computation in visual attention.

Decisions about where to move the eyes depend on neurons in frontal eye field (FEF). Movement neurons in FEF accumulate salience evidence derived from FEF visual neurons to select the location of a saccade target among distractors. How visual neurons achieve this salience representation is unknown. We present a neuro-computational model of target selection called salience by competitive and recurrent interactions (SCRI), based on the competitive interaction model of attentional selection and decision-making (Smith & Sewell, 2013). SCRI selects targets by synthesizing localization and identification information to yield a dynamically evolving representation of salience across the visual field. SCRI accounts for neural spiking of individual FEF visual neurons, explaining idiosyncratic differences in neural dynamics with specific parameters. Many visual neurons resolve the competition between search items through feedforward inhibition between signals representing different search items, some also require lateral inhibition, and many act as recurrent gates to modulate the incoming flow of information about stimulus identity. SCRI was tested further by using simulated spiking representations of visual salience as input to the gated accumulator model of FEF movement neurons (Purcell et al., 2010, 2012). Predicted saccade response times fit those observed for search arrays of different set sizes and different target-distractor similarities, and accumulator trajectories replicated movement neuron discharge rates. These findings offer new insights into visual decision-making through converging neuro-computational constraints and provide a novel computational account of the diversity of FEF visual neurons. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Modeling evidence accumulation decision processes using integral equations: Urgency-gating and collapsing boundaries.

Diffusion models of evidence accumulation have successfully accounted for the distributions of response times and choice probabilities from many experimental tasks, but recently their assumption that evidence is accumulated at a constant rate to constant decision boundaries has been challenged. One model assumes that decision-makers seek to optimize their performance by using decision boundaries that collapse over time. Another model assumes that evidence does not accumulate and is represented by a stationary distribution that is gated by an urgency signal to make a response. We present explicit, integral-equation expressions for the first-passage time distributions of the urgency-gating and collapsing-bounds models and use them to identify conditions under which the models are equivalent. We combine these expressions with a dynamic model of stimulus encoding that allows the effects of perceptual and decisional integration to be distinguished. We compare the resulting models to the standard diffusion model with variability in drift rates on data from three experimental paradigms in which stimulus information was either constant or changed over time. The standard diffusion model was the best model for tasks with constant stimulus information; the models with time-varying urgency or decision bounds performed similarly to the standard diffusion model on tasks with changing stimulus information. We found little support for the claim that evidence does not accumulate and attribute the good performance of the time-varying models on changing-stimulus tasks to their increased flexibility and not to their ability to account for systematic experimental effects. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Civilian-military malaria outbreak response in Thailand: an example of multi-stakeholder engagement for malaria elimination.

BACKGROUND: In April 2017, the Thai Ministry of Public Health (MoPH) was alerted to a potential malaria outbreak among civilians and military personnel in Sisaket Province, a highly forested area bordering Cambodia. The objective of this study was to present findings from the joint civilian-military outbreak response. METHODS: A mixed-methods approach was used to assess risk factors among cases reported during the 2017 Sisaket malaria outbreak. Routine malaria surveillance data from January 2013 to March 2018 obtained from public and military medical reporting systems and key informant interviews (KIIs) (n = 72) were used to develop hypotheses about potential factors contributing to the outbreak. Joint civilian-military response activities included entomological surveys, mass screen and treat (MSAT) and vector control campaigns, and scale-up of the "1-3-7" reactive case detection approach among civilians alongside a pilot "1-3-7" study conducted by the Royal Thai Army (RTA). RESULTS: Between May-July 2017, the monthly number of MoPH-reported cases surpassed the epidemic threshold. Outbreak cases detected through the MoPH mainly consisted of Thai males (87%), working as rubber tappers (62%) or military/border police (15%), and Plasmodium vivax infections (73%). Compared to cases from the previous year (May-July 2016), outbreak cases were more likely to be rubber tappers (OR = 14.89 [95% CI: 5.79-38.29]; p < 0.001) and infected with P. vivax (OR=2.32 [1.27-4.22]; p = 0.006). Themes from KIIs were congruent with findings from routine surveillance data. Though limited risk factor information was available from military cases, findings from RTA's "1-3-7" study indicated transmission was likely occurring outside military bases. Data from entomological surveys and MSAT campaigns support this hypothesis, as vectors were mostly exophagic and parasite prevalence from MSAT campaigns was very low (range: 0-0.7% by PCR/microscopy). CONCLUSIONS: In 2017, an outbreak of mainly P. vivax occurred in Sisaket Province, affecting mainly military and rubber tappers. Vector control use was limited to the home/military barracks, indicating that additional interventions were needed during high-risk forest travel periods. Importantly, this outbreak catalyzed joint civilian-military collaborations and integration of the RTA into the national malaria elimination strategy (NMES). The Sisaket outbreak response serves as an example of how civilian and military public health systems can collaborate to advance national malaria elimination goals in Southeast Asia and beyond.

Estimating systematic and random sources of variability in perceptual decision-making: A reply to Evans, Tillman, & Wagenmakers (2020).

Ratcliff, Voskuilen, and McKoon (2018) presented data and model-based analyses that provided strong evidence for across-trial variability in evidence entering the decision process in several perceptual tasks. They did this using a double-pass procedure in which exactly the same stimuli are presented on two widely-separated trials. If there were only random variability (i.e., the first and second presentations of a stimulus were independent), then the agreement in the choice made on the two trials would be a function of accuracy: as accuracy increases from chance to 100% correct, then the probability of agreement increases. In the experiments, agreement was greater than that predicted from independence which means that there was systematic variability in items from trial to trial. Evans et al. (2020) criticized this by arguing that because of possible tradeoffs among parameters, the evidence did not support two sources of across-trial variability, but rather the results could be explained by only a systematic (item) component of variability. However, their own analysis showed that parameter estimates were accurate enough to support identification of the two sources of variability. We present a new analysis of possible sources of across-trial variability in evidence and show that systematic variability can be estimated from accuracy-agreement functions with a functional form that depends on only two diffusion model parameters. We also point out that size of the estimates of these two sources are model-dependent. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Plasmodium falciparum phenotypic and genotypic resistance profile during the emergence of Piperaquine resistance in Northeastern Thailand.

Malaria remains a public health problem in Thailand, especially along its borders where highly mobile populations can contribute to persistent transmission. This study aimed to determine resistant genotypes and phenotypes of 112 Plasmodium falciparum isolates from patients along the Thai-Cambodia border during 2013-2015. The majority of parasites harbored a pfmdr1-Y184F mutation. A single pfmdr1 copy number had CVIET haplotype of amino acids 72-76 of pfcrt and no pfcytb mutations. All isolates had a single pfk13 point mutation (R539T, R539I, or C580Y), and increased % survival in the ring-stage survival assay (except for R539I). Multiple copies of pfpm2 and pfcrt-F145I were detected in 2014 (12.8%) and increased to 30.4% in 2015. Parasites containing either multiple pfpm2 copies with and without pfcrt-F145I or a single pfpm2 copy with pfcrt-F145I exhibited elevated IC90 values of piperaquine. Collectively, the emergence of these resistance patterns in Thailand near Cambodia border mirrored the reports of dihydroartemisinin-piperaquine treatment failures in the adjacent province of Cambodia, Oddar Meanchey, suggesting a migration of parasites across the border. As malaria elimination efforts ramp up in Southeast Asia, host nations militaries and other groups in border regions need to coordinate the proposed interventions.

Distribution and Temporal Dynamics of Plasmodium falciparum Chloroquine Resistance Transporter Mutations Associated With Piperaquine Resistance in Northern Cambodia.

BACKGROUND: Newly emerged mutations within the Plasmodium falciparum chloroquine resistance transporter (PfCRT) can confer piperaquine resistance in the absence of amplified plasmepsin II (pfpm2). In this study, we estimated the prevalence of co-circulating piperaquine resistance mutations in P. falciparum isolates collected in northern Cambodia from 2009 to 2017. METHODS: The sequence of pfcrt was determined for 410 P. falciparum isolates using PacBio amplicon sequencing or whole genome sequencing. Quantitative polymerase chain reaction was used to estimate pfpm2 and pfmdr1 copy number. RESULTS: Newly emerged PfCRT mutations increased in prevalence after the change to dihydroartemisinin-piperaquine in 2010, with >98% of parasites harboring these mutations by 2017. After 2014, the prevalence of PfCRT F145I declined, being outcompeted by parasites with less resistant, but more fit PfCRT alleles. After the change to artesunate-mefloquine, the prevalence of parasites with amplified pfpm2 decreased, with nearly half of piperaquine-resistant PfCRT mutants having single-copy pfpm2. CONCLUSIONS: The large proportion of PfCRT mutants that lack pfpm2 amplification emphasizes the importance of including PfCRT mutations as part of molecular surveillance for piperaquine resistance in this region. Likewise, it is critical to monitor for amplified pfmdr1 in these PfCRT mutants, as increased mefloquine pressure could lead to mutants resistant to both drugs.

A circular diffusion model of continuous-outcome source memory retrieval: Contrasting continuous and threshold accounts.

A circular analogue of the diffusion model adapted for continuous response tasks is applied to a continuous-outcome source memory task. In contrast to existing models of source retrieval that attribute all of the variability in responding to memory, the circular diffusion model decomposes noise into variability arising from memory and from decision processes. We compared three models: (1) a single diffusion process with trial-to-trial variability in drift rate, (2) a mixture of two diffusion processes, one with positive drift that does not vary from trial-to-trial, and a second zero-drift process that represents discrete guessing, and (3) a hybrid model that mixed positive and zero-drift processes with trial-to-trial variability in the positive drift process. Comparison of model fits to joint response error and response-time (RT) data suggest that a memory strength threshold under which no information is retrieved appears to underlie responding in a continuous-report source memory task. Additionally, we also conditioned participants' source responding on their confidence in an old/new recognition task, ruling out the possibility that participant guessing was only due to unrecognized items. Overall, our findings support an all-or-none or some-or none view of source memory retrieval and pose a challenge to continuous models of source memory.

A single, simple, statistical mechanism explains resource distribution and temporal updating in visual short-term memory.

Investigations into the way that information is held and integrated within the visual system provides some basis for understanding how visual information is represented and processed. Just over sixty years ago, Swets, Shipley, McKey, and Green (1959) demonstrated that performance within an auditory detection task increases as a function of the square root of the number of stimulus observation intervals, following the predictions of basic sampling theory, indicating the efficient perceptual integration of stimulus information. This principle of observer performance contingent on a constant rate of stimulus sampling also forms the basis of the sample-size model (Palmer, 1990; Sewell, Lilburn, & Smith, 2014) which seeks to provide an account of how memory resources might be divided among item representations in visual short-term memory (VSTM). In this article, we combine the multiple observations paradigm of Swets and colleagues with the VSTM paradigm of Sewell and colleagues and show that the sample-size relationship accounts for both the increase in performance with the number of presentation intervals and the way that performance changes as a function of the number of items in memory. The model provides an account of both the overall information limit of VSTM and an account of the dynamics of that limit, demonstrating not only that observers can selectively update specific representations in memory but that performance in this task is accounted for by a simple statistical constraint. We discuss the implications for models of VSTM capacity and architecture generally, focusing on the implications for objecthood and the characteristics of encoding to and retrieval from memory.

Piperaquine resistant Cambodian Plasmodium falciparum clinical isolates: in vitro genotypic and phenotypic characterization.

BACKGROUND: High rates of dihydroartemisinin-piperaquine (DHA-PPQ) treatment failures have been documented for uncomplicated Plasmodium falciparum in Cambodia. The genetic markers plasmepsin 2 (pfpm2), exonuclease (pfexo) and chloroquine resistance transporter (pfcrt) genes are associated with PPQ resistance and are used for monitoring the prevalence of drug resistance and guiding malaria drug treatment policy. METHODS: To examine the relative contribution of each marker to PPQ resistance, in vitro culture and the PPQ survival assay were performed on seventeen P. falciparum isolates from northern Cambodia, and the presence of E415G-Exo and pfcrt mutations (T93S, H97Y, F145I, I218F, M343L, C350R, and G353V) as well as pfpm2 copy number polymorphisms were determined. Parasites were then cloned by limiting dilution and the cloned parasites were tested for drug susceptibility. Isobolographic analysis of several drug combinations for standard clones and newly cloned P. falciparum Cambodian isolates was also determined. RESULTS: The characterization of culture-adapted isolates revealed that the presence of novel pfcrt mutations (T93S, H97Y, F145I, and I218F) with E415G-Exo mutation can confer PPQ-resistance, in the absence of pfpm2 amplification. In vitro testing of PPQ resistant parasites demonstrated a bimodal dose-response, the existence of a swollen digestive vacuole phenotype, and an increased susceptibility to quinine, chloroquine, mefloquine and lumefantrine. To further characterize drug sensitivity, parental parasites were cloned in which a clonal line, 14-B5, was identified as sensitive to artemisinin and piperaquine, but resistant to chloroquine. Assessment of the clone against a panel of drug combinations revealed antagonistic activity for six different drug combinations. However, mefloquine-proguanil and atovaquone-proguanil combinations revealed synergistic antimalarial activity. CONCLUSIONS: Surveillance for PPQ resistance in regions relying on DHA-PPQ as the first-line treatment is dependent on the monitoring of molecular markers of drug resistance. P. falciparum harbouring novel pfcrt mutations with E415G-exo mutations displayed PPQ resistant phenotype. The presence of pfpm2 amplification was not required to render parasites PPQ resistant suggesting that the increase in pfpm2 copy number alone is not the sole modulator of PPQ resistance. Genetic background of circulating field isolates appear to play a role in drug susceptibility and biological responses induced by drug combinations. The use of latest field isolates may be necessary for assessment of relevant drug combinations against P. falciparum strains and when down-selecting novel drug candidates.

Safety, Pharmacokinetics, and Activity of High-Dose Ivermectin and Chloroquine against the Liver Stage of Plasmodium cynomolgi Infection in Rhesus Macaques.

Previously, ivermectin (1 to 10 mg/kg of body weight) was shown to inhibit the liver-stage development of Plasmodium berghei in orally dosed mice. Here, ivermectin showed inhibition of the in vitro development of Plasmodium cynomolgi schizonts (50% inhibitory concentration [IC50], 10.42 µM) and hypnozoites (IC50, 29.24 µM) in primary macaque hepatocytes when administered as a high dose prophylactically but not when administered in radical cure mode. The safety, pharmacokinetics, and efficacy of oral ivermectin (0.3, 0.6, and 1.2 mg/kg) with and without chloroquine (10 mg/kg) administered for 7 consecutive days were evaluated for prophylaxis or radical cure of P. cynomolgi liver stages in rhesus macaques. No inhibition or delay to blood-stage P. cynomolgi parasitemia was observed at any ivermectin dose (0.3, 0.6, and 1.2 mg/kg). Ivermectin (0.6 and 1.2 mg/kg) and chloroquine (10 mg/kg) in combination were well-tolerated with no adverse events and no significant pharmacokinetic drug-drug interactions observed. Repeated daily ivermectin administration for 7 days did not inhibit ivermectin bioavailability. It was recently demonstrated that both ivermectin and chloroquine inhibit replication of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro Further ivermectin and chloroquine trials in humans are warranted to evaluate their role in Plasmodium vivax control and as adjunctive therapies against COVID-19 infections.

Vision for the blind: visual psychophysics and blinded inference for decision models.

Evidence accumulation models like the diffusion model are increasingly used by researchers to identify the contributions of sensory and decisional factors to the speed and accuracy of decision-making. Drift rates, decision criteria, and nondecision times estimated from such models provide meaningful estimates of the quality of evidence in the stimulus, the bias and caution in the decision process, and the duration of nondecision processes. Recently, Dutilh et al. (Psychonomic Bulletin & Review 26, 1051-1069, 2019) carried out a large-scale, blinded validation study of decision models using the random dot motion (RDM) task. They found that the parameters of the diffusion model were generally well recovered, but there was a pervasive failure of selective influence, such that manipulations of evidence quality, decision bias, and caution also affected estimated nondecision times. This failure casts doubt on the psychometric validity of such estimates. Here we argue that the RDM task has unusual perceptual characteristics that may be better described by a model in which drift and diffusion rates increase over time rather than turn on abruptly. We reanalyze the Dutilh et al. data using models with abrupt and continuous-onset drift and diffusion rates and find that the continuous-onset model provides a better overall fit and more meaningful parameter estimates, which accord with the known psychophysical properties of the RDM task. We argue that further selective influence studies that fail to take into account the visual properties of the evidence entering the decision process are likely to be unproductive.

Prevalence of CYP2D6 Genotypes and Predicted Phenotypes in a Cohort of Cambodians at High Risk for Infections with Plasmodium vivax.

Clinical failure of primaquine (PQ) has been demonstrated in people with CYP450 2D6 genetic polymorphisms that result in reduced or no enzyme activity. The distribution of CYP2D6 genotypes and predicted phenotypes in the Cambodian population is not well described. Surveys in other Asian countries have shown an approximate 50% prevalence of the reduced activity CYP2D6 allele *10, which could translate into increased risk of PQ radical cure failure and repeated relapses, making interruption of transmission and malaria elimination difficult to achieve. We determined CYP2D6 genotypes from 96 volunteers from Oddor Meanchey Province, Cambodia, an area endemic for Plasmodium vivax. We found a 54.2% frequency of the *10 allele, but in approximately half of our subjects, it was paired with a normal activity allele, either *1 or *2. The prevalence of *5, a null allele, was 9.4%. Overall predicted phenotype percentages were normal metabolizers, 46%; intermediate metabolizers, 52%; and poor metabolizers, 1%.

A diffusion model analysis of target detection in near-threshold visual search.

When searching for a target briefly presented among distractors how do people combine information across display locations to make a decision and how does the quality of the evidence entering the decision process vary with the type of items in the display? Research on accuracy in near-threshold visual search has had difficulty in distinguishing between models that make similar predictions about accuracy but make different assumptions about the underlying psychological processes. We used the diffusion model to analyse response times and accuracy data from four near-threshold search tasks which showed striking asymmetries between response-time distributions on target-present and target-absent trials. We found that performance was better explained by a model in which evidence was accumulated in parallel about each stimulus separately than one in which the evidence was pooled into a single decision process. We found that as contrast increased, the quality of the evidence entering the decision process about targets was markedly stronger than the evidence about nontargets. The overall pattern of evidence strength for stimuli on target-present and target-absent trials was consistent with a fixed-capacity memory system in which early visual processes assigned resources preferentially to targets over nontargets. The asymmetry was somewhat reduced in a letter-digit discrimination task that used heterogeneous targets and distractors, likely because heterogeneity reduces the efficiency of the preattentive filtering processes.

Modeling continuous outcome color decisions with the circular diffusion model: Metric and categorical properties.

The circular diffusion model is extended to provide a theory of the speed and accuracy of continuous outcome color decisions and used to characterize eye-movement decisions about the hues of noisy color patches in an isoluminant, equidiscriminability color space. Heavy-tailed distributions of decision outcomes were found with high levels of chromatic noise, similar to those found in visual working memory studies with high memory loads. Decision times were longer for less accurate decisions, in agreement with the slow error property typically found in difficult 2-choice tasks. Decision times were shorter, and responses were more accurate in parts of the space corresponding to nameable color categories, although the number and locations of the categories varied among participants. We show that these findings can be predicted by a theory of across-trial variability in the quality of the evidence entering the decision process, represented mathematically by the drift rate of the diffusion process. The heavy-tailed distributions of decision outcomes and the slow-error pattern can be predicted by either of 2 models of drift rate. One model is based on encoding failures and the other is based on a nonlinear transformation of the stimulus space. Both models predict highly inaccurate stimulus representations on some trials, leading to heavy-tailed distributions and slow errors. The color-category effects were successfully modeled as stimulus biases in a similarity-choice framework, in which the drift rate is the vector sum of the encoded metric and categorical representations of the stimulus. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Determination of Cytochrome P450 Isoenzyme 2D6 (CYP2D6) Genotypes and Pharmacogenomic Impact on Primaquine Metabolism in an Active-Duty US Military Population.

BACKGROUND: Plasmodium vivax malaria requires a 2-week course of primaquine (PQ) for radical cure. Evidence suggests that the hepatic isoenzyme cytochrome P450 2D6 (CYP2D6) is the key enzyme required to convert PQ into its active metabolite. METHODS: CYP2D6 genotypes and phenotypes of 550 service personnel were determined, and the pharmacokinetics (PK) of a 30-mg oral dose of PQ was measured in 45 volunteers. Blood and urine samples were collected, with PQ and metabolites were measured using ultraperformance liquid chromatography with mass spectrometry. RESULTS: Seventy-six CYP2D6 genotypes were characterized for 530 service personnel. Of the 515 personnel for whom a single phenotype was predicted, 58% had a normal metabolizer (NM) phenotype, 35% had an intermediate metabolizer (IM) phenotype, 5% had a poor metabolizer (PM) phenotype, and 2% had an ultrametabolizer phenotype. The median PQ area under the concentration time curve from 0 to ∞ was lower for the NM phenotype as compared to the IM or PM phenotypes. The novel 5,6-ortho-quinone was detected in urine but not plasma from all personnel with the NM phenotype. CONCLUSION: The plasma PK profile suggests PQ metabolism is decreased in personnel with the IM or PM phenotypes as compared to those with the NM phenotype. The finding of 5,6-ortho-quinone, the stable surrogate for the unstable 5-hydroxyprimaquine metabolite, almost exclusively in personnel with the NM phenotype, compared with sporadic or no production in those with the IM or PM phenotypes, provides further evidence for the role of CYP2D6 in radical cure. CLINICAL TRIALS REGISTRATION: NCT02960568.