Dopamine Alters the Effect of Brain Stimulation on Decision-Making.

Noninvasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS), show promise in treating a range of psychiatric and neurologic conditions. However, optimization of such applications requires a better understanding of how tDCS alters cognition and behavior. Existing evidence implicates dopamine in tDCS alterations of brain activity and plasticity; however, there is as yet no causal evidence for a role of dopamine in tDCS effects on cognition and behavior. Here, in a preregistered, double-blinded study, we examined how pharmacologically manipulating dopamine altered the effect of tDCS on the speed-accuracy trade-off, which taps ubiquitous strategic operations. Cathodal tDCS was delivered over the left prefrontal cortex and the superior medial frontal cortex before participants (N = 62, 24 males, 38 females) completed a dot-motion task, making judgments on the direction of a field of moving dots under instructions to emphasize speed, accuracy, or both. We leveraged computational modeling to uncover how our interventions altered latent decisional processes driving the speed-accuracy trade-off. We show that dopamine in combination with tDCS (but not tDCS alone nor dopamine alone) not only impaired decision accuracy but also impaired discriminability, which suggests that these manipulations altered the encoding or representation of discriminative evidence. This is, to the best of our knowledge, the first direct evidence implicating dopamine in the way tDCS affects cognition and behavior.SIGNIFICANCE STATEMENT tDCS can improve cognitive and behavioral impairments in clinical conditions; however, a better understanding of its mechanisms is required to optimize future clinical applications. Here, using a pharmacological approach to manipulate brain dopamine levels in healthy adults, we demonstrate a role for dopamine in the effects of tDCS in the speed-accuracy trade-off, a strategic cognitive process ubiquitous in many contexts. In doing so, we provide direct evidence implicating dopamine in the way tDCS affects cognition and behavior.

Individual Differences in Decision Strategy Relate to Neurochemical Excitability and Cortical Thickness.

The speed-accuracy trade-off (SAT), whereby faster decisions increase the likelihood of an error, reflects a cognitive strategy humans must engage in during the performance of almost all daily tasks. To date, computational modeling has implicated the latent decision variable of response caution (thresholds), the amount of evidence required for a decision to be made, in the SAT. Previous imaging has associated frontal regions, notably the left prefrontal cortex and the presupplementary motor area (pre-SMA), with the setting of such caution levels. In addition, causal brain stimulation studies, using transcranial direct current stimulation (tDCS), have indicated that while both of these regions are involved in the SAT, their role appears to be dissociable. tDCS efficacy to impact decision-making processes has previously been linked with neurochemical concentrations and cortical thickness of stimulated regions. However, to date, it is unknown whether these neurophysiological measures predict individual differences in the SAT, and brain stimulation effects on the SAT. Using ultra-high field (7T) imaging, here we report that instruction-based adjustments in caution are associated with both neurochemical excitability (the balance between GABA+ and glutamate) and cortical thickness across a range of frontal regions in both sexes. In addition, cortical thickness, but not neurochemical concentrations, was associated with the efficacy of left prefrontal and superior medial frontal cortex (SMFC) stimulation to modulate performance. Overall, our findings elucidate key neurophysiological predictors, frontal neural excitation, of individual differences in latent psychological processes and the efficacy of stimulation to modulate these.SIGNIFICANCE STATEMENT The speed-accuracy trade-off (SAT), faster decisions increase the likelihood of an error, reflects a cognitive strategy humans must engage in during most daily tasks. The SAT is often investigated by explicitly instructing participants to prioritize speed or accuracy when responding to stimuli. Using ultra-high field (7T) magnetic resonance imaging (MRI), we found that individual differences in the extent to which participants adjust their decision strategies with instruction related to neurochemical excitability (ratio of GABA+ to glutamate) and cortical thickness in the frontal cortex. Moreover, brain stimulation to the left prefrontal cortex and the superior medial frontal cortex (SMFC) modulated performance, with the efficacy specifically related to cortical thickness. This work sheds new light on the neurophysiological basis of decision strategies and brain stimulation.

Assessing the influence of dopamine and mindfulness on the formation of routines in visual search.

Given experience in cluttered but stable visual environments, our eye-movements form stereotyped routines that sample task-relevant locations, while not mixing-up routines between similar task-settings. Both dopamine signaling and mindfulness have been posited as factors that influence the formation of such routines, yet quantification of their impact remains to be tested in healthy humans. Over two sessions, participants searched through grids of doors to find hidden targets, using a gaze-contingent display. Within each session, door scenes appeared in either one of two colors, with each color signaling a differing set of likely target locations. We derived measures for how well target locations were learned (target-accuracy), how routine were sets of eye-movements (stereotypy), and the extent of interference between the two scenes (setting-accuracy). Participants completed two sessions, where they were administered either levodopa (dopamine precursor) or placebo (vitamin C), under double-blind counterbalanced conditions. Dopamine and trait mindfulness (assessed by questionnaire) interacted to influence both target-accuracy and stereotypy. Increasing dopamine improved accuracy and reduced stereotypy for high mindfulness scorers, but induced the opposite pattern for low mindfulness scorers. Dopamine also disrupted setting-accuracy invariant to mindfulness. Our findings show that mindfulness modulates the impact of dopamine on the target-accuracy and stereotypy of eye-movement routines, whereas increasing dopamine promotes interference between task-settings, regardless of mindfulness. These findings provide a link between non-human and human models regarding the influence of dopamine on the formation of task-relevant eye-movement routines and provide novel insights into behavior-trait factors that modulate the use of experience when building adaptive repertoires.

Clinical effectiveness of rehabilitation in ambulatory care for patients with persisting symptoms after COVID-19: a systematic review.

BACKGROUND: Lingering symptoms after acute COVID-19 present a major challenge to ambulatory care services. Since there are reservations regarding their optimal management, we aimed to collate all available evidence on the effects of rehabilitation treatments applicable in ambulatory care for these patients. METHODS: On 9 May 2022, we systematically searched articles in COVID-19 collections, Embase, MEDLINE, Cochrane Library, Web of Science, CINAHL, PsycArticles, PEDro, and EuropePMC. References were eligible if they reported on the clinical effectiveness of a rehabilitation therapy applicable in ambulatory care for adult patients with persisting symptoms continuing 4 weeks after the onset of COVID-19. The quality of the studies was evaluated using the CASP cohort study checklist and the Cochrane Risk of Bias Assessment Tool. Summary of Findings tables were constructed and the certainty of evidence was assessed using the GRADE framework. RESULTS: We included 38 studies comprising 2,790 participants. Physical training and breathing exercises may reduce fatigue, dyspnoea, and chest pain and may improve physical capacity and quality of life, but the evidence is very weak (based on 6 RCTs and 12 cohort studies). The evidence underpinning the effect of nutritional supplements on fatigue, dyspnoea, muscle pain, sensory function, psychological well-being, quality of life, and functional capacity is very poor (based on 4 RCTs). Also, the evidence-base is very weak about the effect of olfactory training on sensory function and quality of life (based on 4 RCTs and 3 cohort studies). Multidisciplinary treatment may have beneficial effects on fatigue, dyspnoea, physical capacity, pulmonary function, quality of life, return to daily life activities, and functional capacity, but the evidence is very weak (based on 5 cohort studies). The certainty of evidence is very low due to study limitations, inconsistency, indirectness, and imprecision. CONCLUSIONS: Physical training, breathing exercises, olfactory training and multidisciplinary treatment can be effective rehabilitation therapies for patients with persisting symptoms after COVID-19, still with high uncertainty regarding these effects. These findings can guide ambulatory care practitioners to treat these patients and should be incorporated in clinical practice guidelines. High-quality studies are needed to confirm our hypotheses and should report on adverse events.

Pornography consumption and sexual health among emerging adults from Malaysia: an observational study.

BACKGROUND: Despite the high prevalence, few studies have examined pornography consumption among emerging adults in Malaysia. The current study examined the attitudes, motivations, and behaviours related to pornography consumption and their association with sexual health. METHODS: Using a cross-sectional survey that was conducted online, a convenience sample of 319 Malaysians aged 18-30years (M =23.05, s.d.=2.55) reported their attitudes and behaviours related to pornography consumption, including the degree of problematic consumption, and completed measures of sexual health. These included sexual satisfaction, awareness of sexual feelings, sexual self-reflection, sexual assertiveness, embarrassment during partnered sex, and genital image. To capture pornography genre preferences, participants also reported the keywords that they typically use to search for pornography. These open-ended responses were thematically coded. RESULTS: Between 60 and 70% of participants reported positive attitudes toward pornography and 81.2% (N =259) reported lifetime intentional exposure to pornography. Gender differences were present in pornography consumption attitudes, motivations, preferences, and behaviours. Problematic pornography consumption, and not consumption frequency, was associated with poorer sexual satisfaction. Among women and not men, more frequent consumption was associated with more sexual self-reflection and positive feelings about their genitals. Sexual embarrassment was higher among women who consume pornography more problematically and among men who consumed pornography more frequently. CONCLUSIONS: Pornography consumption attitudes and behaviours appear rather universal. However, the benefits of pornography consumption frequency and disadvantages associated with problematic consumption appear to be more relevant for women's than men's sexual health, specifically sexual self-reflection, genital image, and sexual embarrassment.

Masturbation Among Malaysian Young Adults: Associated Sexual and Psychological Well-Being Outcomes.

Despite being a common sexual practice, not much is known about masturbation within the Malaysian context. The current study examined the masturbation practices of a convenience sample of Malaysian young adults, and how one's reported experience of masturbating and frequency of masturbation is associated with sexual and psychological well-being. Satisfaction with sex life, satisfaction with life, depression, anxiety, and stress were measured as outcome variables. Responses from 621 participants (M = 22.1 years, SD = 2.4 years) that were collected through an online questionnaire were analyzed. Results revealed that most participants (77.7%) had masturbated at least once in their life. Sexual satisfaction and psychological well-being did not differ between those who reported masturbating before and those who did not. Among those with masturbation experience, higher frequency of masturbation was associated with less sexual satisfaction and more symptoms of anxiety and stress. Masturbation frequency was not associated with life satisfaction or reports of depressive symptoms. Gender, frequency of partnered sex, availability of a sexual partner, and religiosity did not moderate the relationships between masturbation frequency with sexual satisfaction and psychological well-being. Although the limitations of the current study impede generalizability, masturbation was found to be a common behavior among the current sample. Causal inferences cannot be drawn from the significant associations found in the current study, as the findings indicate such relationships may be bidirectional. Supplementary Information: The online version contains supplementary material available at 10.1007/s12119-023-10101-2.

Extracellular vesicles, the cornerstone of next-generation cancer diagnosis?

Cancer has risen up to be a major cause of mortality worldwide over the past decades. Despite advancements in cancer screening and diagnostics, a significant number of cancers are still diagnosed at a late stage with poor prognosis. Hence, the discovery of reliable and accurate methods to diagnose cancer early would be of great help in reducing cancer mortality. Extracellular vesicles (EVs) are phospholipid vesicles found in many biofluids and are released by almost all types of cells. In recent years, using EVs as cancer biomarkers has garnered attention as a novel technique of cancer diagnosis. Compared with traditional tissue biopsy, there are many advantages that this novel diagnostic tool presents - it is less invasive, detects early-stage asymptomatic cancers, and allows for monitoring of tumour progression. As such, EV biomarkers have great potential in improving the diagnostic accuracy of cancers and guiding subsequent therapeutic decisions. Efficient isolation and accurate characterization of EVs are essential for reliable outcomes of clinical application. However, these are complicated by the size and biomolecular diversity of EVs. In this review, we present an analysis and evaluation of the current techniques of EV isolation and characterization, as well as discuss the potential EV biomarkers for specific types of cancer. Taken together, EV biomarkers have a lot of potential as a novel method in cancer diagnostics and diagnosis. However, more work is still needed to streamline the purification, characterization and biomarker identification process to ensure optimal outcomes for patients.

Montreal cognitive assessment as a screening instrument for cognitive impairment in systemic lupus erythematosus patients without overt neuropsychiatric manifestations.

OBJECTIVES: The Montreal Cognitive Assessment (MoCA) is an increasingly used screening tool for cognitive impairment. The aim of this study was to examine how MoCA performed in identifying cognitive impairment (CI) domains in SLE patients compared with formal standardized neuropsychological testing (NPT). Factors related to SLE disease, immunologic and psychological state associated with CI were also explored. METHODS: This cross-sectional study recruited 50 SLE patients without overt neuropsychiatric manifestations from April 2017 to May 2018. The patients were evaluated with MoCA, formal NPT and the Depression, Anxiety, and Stress Scales (DASS) 42-item self-report questionnaire. Values of sensitivity and specificity were computed for different cut-offs of MoCA within each cognitive domain of NPT and descriptive analysis was used to identify the factors affecting cognitive function. RESULTS: The median score for MoCA was 27.5 (range 22-30). Using a MoCA cutoff of <26, 18 (36%) were identified to have CI using NPT compared to 8 (16%) using MoCA. The most frequently affected cognitive domain was executive functioning with 15 affected patients. Sensitivities and specificities of the MoCA range from 50% to 100% and 5.7% to 16.7%, respectively, across cognitive domains. A lower MoCA cutoff of <25 improve sensitivity of identifying impairment in executive functioning from 60% to 80%. In univariate analysis, DASS scores, disease activity, presence of antiphospholipid antibodies, presence of concurrent autoimmune disease, current, and cumulative corticosteroid therapy did not predict cognitive performance. CONCLUSION: MoCA may be a useful screening tool to identify the most frequently affected cognitive domain which is executive functioning using a lower cutoff of <25 in SLE patients without overt neuropsychiatric manifestations.

Task Errors Drive Memories That Improve Sensorimotor Adaptation.

Traditional views of sensorimotor adaptation (i.e., adaptation of movements to perturbed sensory feedback) emphasize the role of automatic, implicit correction of sensory prediction errors. However, latent memories formed during sensorimotor adaptation, manifest as improved relearning (e.g., savings), have recently been attributed to strategic corrections of task errors (failures to achieve task goals). To dissociate contributions of task errors and sensory prediction errors to latent sensorimotor memories, we perturbed target locations to remove or enforce task errors during learning and/or test, with male/female human participants. Adaptation improved after learning in all conditions where participants were permitted to correct task errors, and did not improve whenever we prevented correction of task errors. Thus, previous correction of task errors was both necessary and sufficient to improve adaptation. In contrast, a history of sensory prediction errors was neither sufficient nor obligatory for improved adaptation. Limiting movement preparation time showed that the latent memories driven by learning to correct task errors take at least two forms: a time-consuming but flexible component, and a rapidly expressible, inflexible component. The results provide strong support for the idea that movement corrections driven by a failure to successfully achieve movement goals underpin motor memories that manifest as savings. Such persistent memories are not exclusively mediated by time-consuming strategic processes but also comprise a rapidly expressible but inflexible component. The distinct characteristics of these putative processes suggest dissociable underlying mechanisms, and imply that identification of the neural basis for adaptation and savings will require methods that allow such dissociations.SIGNIFICANCE STATEMENT Latent motor memories formed during sensorimotor adaptation manifest as improved adaptation when sensorimotor perturbations are reencountered. Conflicting theories suggest that this "savings" is underpinned by different mechanisms, including a memory of successful actions, a memory of errors, or an aiming strategy to correct task errors. Here we show that learning to correct task errors is sufficient to show improved subsequent adaptation with respect to naive performance, even when tested in the absence of task errors. In contrast, a history of sensory prediction errors is neither sufficient nor obligatory for improved adaptation. Finally, we show that latent sensorimotor memories driven by task errors comprise at least two distinct components: a time-consuming, flexible component, and a rapidly expressible, inflexible component.

Acoustic stimulation increases implicit adaptation in sensorimotor adaptation.

Sensorimotor adaptation is an important part of our ability to perform novel motor tasks (i.e., learning of motor skills). Efforts to improve adaptation in healthy and clinical patients using non-invasive brain stimulation methods have been hindered by inter-individual and intra-individual variability in brain susceptibility to stimulation. Here, we explore unpredictable loud acoustic stimulation as an alternative method of modulating brain excitability to improve sensorimotor adaptation. In two experiments, participants moved a cursor towards targets, and adapted to a 30º rotation of cursor feedback, either with or without unpredictable acoustic stimulation. Acoustic stimulation improved initial adaptation to sensory prediction errors in Study 1, and improved overnight retention of adaptation in Study 2. Unpredictable loud acoustic stimulation might thus be a potent method of modulating sensorimotor adaptation in healthy adults.

Facilitators and barriers to medication adherence with adjuvant endocrine therapy in women with breast cancer: a structural equation modelling approach.

PURPOSE: To identify a structure to explain the relationship between socio-clinico factors, necessity-concerns beliefs, and perceived barriers to adherence with adjuvant endocrine therapy (AET) amongst women with breast cancer. METHODS: Participants were 244 patients with early-stage breast cancer recruited from two tertiary hospitals from May 2015 to December 2018 who completed questionnaires on medication adherence (Simplified Medication Adherence Questionnaire), necessity-concerns beliefs (Beliefs about Medicine Questionnaire), and barriers to adherence (Adherence Starts with Knowledge Questionnaire). Socio-clinico variables were collected via interview and medical records review. Structural equation modelling was applied to examine the relationships between these variables and possible mediating effects of necessity-concerns beliefs on adherence to AET. RESULTS: The median age of the study participants was 61 (range 32-80) years and the median duration on AET was 1.6 (IQR 1.2-2.6) years. Adherence was positively associated with age (ß = 0.145, 95% CI: 0.011 to 0.279, p = 0.034) and negatively associated with barriers (ß = - 0.381, 95% CI: - 0.511 to - 0.251, p < 0.001). There was no effect of Necessity (ß = 0.006, 95% CI: - 0.145 to 0.158, p = 0.933) or Concerns (ß = 0.041, 95% CI: - 0.117 to 0.199, p = 0.614) on adherence. Necessity-concerns beliefs were also not significant mediators in the relationship between socio-clinico factors and medication adherence. CONCLUSIONS: Older age and lower barriers to adherence were associated with higher adherence scores. Necessity-concerns beliefs did not have a significant effect on adherence as majority of the patients identified forgetfulness as a reason for non-adherence.

How groove in music affects gait.

Rhythmic auditory stimulation (RAS) is a gait intervention in which gait-disordered patients synchronise footsteps to music or metronome cues. Musical 'groove', the tendency of music to induce movement, has previously been shown to be associated with faster gait, however, why groove affects gait remains unclear. One mechanism by which groove may affect gait is that of beat salience: music that is higher in groove has more salient musical beats, and higher beat salience might reduce the cognitive demands of perceiving the beat and synchronizing footsteps to it. If groove's effects on gait are driven primarily by the impact of beat salience on cognitive demands, then groove's effects might only be present in contexts in which it is relevant to reduce cognitive demands. Such contexts could include task parameters that increase cognitive demands (such as the requirement to synchronise to the beat), or individual differences that may make synchronisation more cognitively demanding. Here, we examined whether high beat salience can account for the effects of high-groove music on gait. First, we increased the beat salience of low-groove music to be similar to that of high-groove music by embedding metronome beats in low and high-groove music. We examined whether low-groove music with high beat salience elicited similar effects on gait as high-groove music. Second, we examined the effect of removing the requirement to synchronise footsteps to the beat (i.e., allowing participants to walk freely with the music), which is thought to remove the cognitive demand of synchronizing movements to the beat. We tested two populations thought to be sensitive to the cognitive demands of synchronisation, weak beat-perceivers and older adults. We found that increasing the beat salience of low-groove music increased stride velocity, but strides were still slower than with high-groove music. Similarly, removing the requirement to synchronise elicited faster, less variable gait, and reduced bias for stability, but high-groove music still elicited faster strides than low-groove music. These findings suggest that beat salience contributes to groove's effect on gait, but it does not fully account for it. Despite reducing task difficulty by equalizing beat salience and removing the requirement to synchronise, high-groove music still elicited faster, less variable gait. Therefore, other properties of groove also appear to play a role in groove's effect on gait.

Primary care implementation study to scale up early identification and brief intervention and reduce alcohol-related negative outcomes at the community level (PINO): study protocol for a quasi-experimental 3-arm study.

BACKGROUND: Primary healthcare-based Early Identification and Brief Intervention (EIBI) for hazardous and harmful alcohol use is both a clinically relevant and cost-effective strategy to reduce heavy drinking. Unfortunately, it remains poorly implemented in daily practice. Multiple studies have shown that training and support (T&S) programs can increase the use of EIBI. Nonetheless, gains have only been modest and short-term at best. Suggestions have been made to rely more on multicomponent programs that simultaneously address several barriers to the implementation of EIBI. The PINO-project aims to evaluate the added value of such a multicomponent program to improve EIBI delivery in daily practice. METHODS/DESIGN: A quasi-experimental three-arm implementation study in Flanders (Belgium) will assess the effects of tailored T&S to General Practitioners (GPs) with or without community mobilisation on EIBI delivery in general practice. The study lasts 18 months and will take place in three comparable municipalities. In municipality 1 and 2, GPs receive a tailored T&S program. The T&S is theoretically founded and tailored to the GPs' views, needs and practice characteristics. Furthermore, community actions will be embedded within municipality 1 providing additional, contextual, support. In municipality 3, GPs are offered a minimal intervention to facilitate data collection. The primary outcome is the proportion of adult patients screened for hazardous and harmful alcohol use at the end of an 18-month implementation period. The secondary outcome is the scaling up activity at municipal level in screening rates, as assessed every 3 months, and the proportion of patients who received an additional brief intervention when necessary. Furthermore, the correlation between the opinions and needs of the GP's, their practice organisation and their EIBI performance will be explored. DISCUSSION: The PINO-project addresses the gap between what is theoretically possible and the current practice. This is an innovative study combining T&S at GP level with community actions. At the same time, it implements and evaluates practice T&S based on the theoretical domains framework. TRIAL REGISTRATION: This trial was approved by the Ethics Committee for Research of UZ/KU Leuven (reference number s63342 and G-2020-2177-R2(MAR)) and is registered on clinicaltrials.gov ( NCT04398576 ) in May 2020.

A unique CDK4/6 inhibitor: Current and future therapeutic strategies of abemaciclib.

Cell cycle dysregulation, characterised by aberrant activation of cyclin dependent kinases (CDKs), is a hallmark of cancer. After years of research on the first and second generations of less selective CDK inhibitors with unfavourable clinical activity and toxicity profiles, CDK4/6 inhibitors become the first and only class of highly specific CDK inhibitors being approved for cancer treatment to date. CDK4/6 inhibitors have transformed the treatment paradigm of estrogen receptor-positive (ER+) breast cancer, dramatically improving the survival outcomes of these patients when incorporated with conventional endocrine therapies in both the first and later-line settings. Currently, the efficacies of CDK4/6 inhibitors in other breast cancer subtypes and cancers are being actively explored. All three CDK4/6 inhibitors have demonstrated very similar clinical efficacies. However, being the least similar structurally, abemaciclib is the only CDK4/6 inhibitor with single agent activity in refractory metastatic ER + breast cancer, the ability to cross the blood brain barrier efficiently, and a distinct toxicity profile of lower myelosuppression such that it can be dosed continuously. Here, we further discuss the distinguishing features of abemaciclib as compared to the other two CDK4/6 inhibitors, palbociclib and ribociclib. Besides being the most potent inhibitor of CDK4/6, abemaciclib exhibits a wider selectivity towards other CDKs and kinases, and functions through additional mechanisms of action besides inducing G1 cell cycle arrest, in a dose dependent manner. Hence, abemaciclib has the potential to act independently of the CDK4/6-cyclin D-RB pathway, resulting in crucial implications on the possibly expanded clinical indications and predictive biomarkers of abemaciclib, in contrast to the other CDK4/6 inhibitors. The current status of preclinical evidence and clinical studies of abemaciclib as a single agent and in combination treatment in breast and other cancers, together with its potential predictive biomarkers, is also summarised in this review.

Biopharmacological considerations for accelerating drug development of deguelin, a rotenoid with potent chemotherapeutic and chemopreventive potential.

Deguelin is a rotenoid compound that exists in abundant quantities in the bark, roots, and leaves of the Leguminosae family of plants. An analysis of evidence from both in vitro and in vivo studies suggests that deguelin displays potent anticancer activity against multiple cancer types and exhibits chemopreventive potential in Akt-inducible transgenic mouse models. Deguelin appears to impede carcinogenesis by enhancing cell apoptosis and hindering malignant transformation and tumor cell propagation. Crucial oncogenic pathways likely targeted by deguelin include the epithelial-to-mesenchymal transition; angiogenesis-related pathways; and the phosphoinositide 3-kinase/Akt, Wnt, epidermal growth factor receptor, c-Met, and hedgehog signal transduction cascades. This review article provides a comprehensive summary of current preclinical research featuring deguelin as a leading chemotherapeutic and chemopreventive compound, and it highlights the importance of identifying companion molecular biomarkers and performing systemic pharmacokinetic studies for accelerating the process of developing deguelin as a clinical anticancer agent.

Task errors contribute to implicit aftereffects in sensorimotor adaptation.

Perturbations of sensory feedback evoke sensory prediction errors (discrepancies between predicted and actual sensory outcomes of movements), and reward prediction errors (discrepancies between predicted rewards and actual rewards). When our task is to hit a target, we expect to succeed in hitting the target, and so we experience a reward prediction error if the perturbation causes us to miss it. These discrepancies between intended task outcomes and actual task outcomes, termed "task errors," are thought to drive the use of strategic processes to restore success, although their role is incompletely understood. Here, as participants adapted to a 30° rotation of cursor feedback representing hand position, we investigated the role of task errors in sensorimotor adaptation: during target-reaching, we either removed task errors by moving the target mid-movement to align with cursor feedback of hand position, or enforced task error by moving the target away from the cursor feedback of hand position, by 20-30° randomly (clockwise in half the trials, counterclockwise in half the trials). Removing task errors not only reduced the extent of adaptation during exposure to the perturbation, but also reduced the amount of post-adaptation aftereffects that persisted despite explicit knowledge of the perturbation removal. Hence, task errors contribute to implicit adaptation resulting from sensory prediction errors. This suggests that the system which predicts the sensory consequences of actions via exposure to sensory prediction errors is also sensitive to reward prediction errors.

Genotype-guided versus traditional clinical dosing of warfarin in patients of Asian ancestry: a randomized controlled trial.

BACKGROUND: Genotype-guided warfarin dosing has been shown in some randomized trials to improve anticoagulation outcomes in individuals of European ancestry, yet its utility in Asian patients remains unresolved. METHODS: An open-label, non-inferiority, 1:1 randomized trial was conducted at three academic hospitals in South East Asia, involving 322 ethnically diverse patients newly indicated for warfarin (NCT00700895). Clinical follow-up was 90 days. The primary efficacy measure was the number of dose titrations within the first 2 weeks of therapy, with a mean non-inferiority margin of 0.5 over the first 14 days of therapy. RESULTS: Among 322 randomized patients, 269 were evaluable for the primary endpoint. Compared with traditional dosing, the genotype-guided group required fewer dose titrations during the first 2 weeks (1.77 vs. 2.93, difference -1.16, 90% CI -1.48 to -0.84, P < 0.001 for both non-inferiority and superiority). The percentage of time within the therapeutic range over 3 months and median time to stable international normalized ratio (INR) did not differ between the genotype-guided and traditional dosing groups. The frequency of dose titrations (incidence rate ratio 0.76, 95% CI 0.67 to 0.86, P = 0.001), but not frequency of INR measurements, was lower at 1, 2, and 3 months in the genotype-guided group. The proportions of patients who experienced minor or major bleeding, recurrent venous thromboembolism, or out-of-range INR did not differ between both arms. For predicting maintenance doses, the pharmacogenetic algorithm achieved an R2 = 42.4% (P < 0.001) and mean percentage error of -7.4%. CONCLUSIONS: Among Asian adults commencing warfarin therapy, a pharmacogenetic algorithm meets criteria for both non-inferiority and superiority in reducing dose titrations compared with a traditional dosing approach, and performs well in prediction of actual maintenance doses. These findings imply that clinicians may consider applying a pharmacogenetic algorithm to personalize initial warfarin dosages in Asian patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00700895 . Registered on June 19, 2008.

Improving medication adherence with adjuvant aromatase inhibitor in women with breast cancer: study protocol of a randomised controlled trial to evaluate the effect of short message service (SMS) reminder.

BACKGROUND: Medication adherence refers to whether a patient takes medication according to the frequency prescribed, or continues to take a prescribed medication. Inadequate adherence to medication may cause alterations in risk-benefit ratios, resulting in reduced benefits, increased risks or both, and is significantly associated with adverse clinical outcomes and higher healthcare costs. We aim to examine the effect of a computer generated short message service (SMS) reminder in improving medication adherence, and inhibiting the aromatisation process amongst breast cancer women receiving oral aromatase inhibitor therapy. METHODS/DESIGN: In this randomised controlled trial, eligible patients will be equally allocated to receive either SMS reminder or standard care. The former receives weekly SMS reminder to take medication while the latter does not receive any. The primary endpoint of medication adherence at 1-year is assessed using the Simplified Medication Adherence Questionnaire, and compared using the χ2 test. Adjustment for baseline covariate and potential confounders will be made using the logistic regression. Secondary outcomes involving estrone and androstenedione levels will be compared using the analysis of covariance, whereas the estradiol levels (< 18.4 pmol/L versus ≥18.4 pmol/L) will be compared using the χ2 test, and the logistic regression. Further, the assessment of knowledge, attitude, behaviour, and barriers and facilitating factors of medication adherence will be made via logistic regression. DISCUSSION: This will be the first study to evaluate short-term clinical outcomes from SMS reminder for breast cancer patients on aromatase inhibitor therapy. Random allocation to SMS reminder or control arm ensures that patients in both arms will be comparable with respect to demographic and clinical characteristics, and any difference in outcomes can be attributed to the intervention. Participants are not blinded to the assignment of intervention, thus there may be potential for bias in outcome assessments. TRIAL REGISTRATION: NCT02524548 . Retrospectively registered on 17 August 2015.

The role of attention and intention in synchronization to music: effects on gait.

Anecdotal accounts suggest that individuals spontaneously synchronize their movements to the 'beat' of background music, often without intending to, and perhaps even without attending to the music at all. However, the question of whether intention and attention are necessary to synchronize to the beat remains unclear. Here, we compared whether footsteps during overground walking were synchronized to the beat when young healthy adults were explicitly instructed to synchronize (intention to synchronize), and were not instructed to synchronize (no intention) (Experiment 1: intention). We also examined whether reducing participants' attention to the music affected synchronization, again when participants were explicitly instructed to synchronize, and when they were not (Experiment 2: attention/intention). Synchronization was much less frequent when no instructions to synchronize were given. Without explicit instructions to synchronize, there was no evidence of synchronization in 60% of the trials in Experiment 1, and 43% of the trials in Experiment 2. When instructed to synchronize, only 26% of trials in Experiment 1, and 14% of trials in Experiment 2 showed no evidence of synchronization. Because walking to music alters gait, we also examined how gait kinematics changed with or without instructions to synchronize, and attention to the music was required for synchronization to occur. Instructions to synchronize elicited slower, shorter, and more variable strides than walking in silence. Reducing attention to the music did not significantly affect synchronization of footsteps to the beat, but did elicit slower gait. Thus, during walking, intention, but not attention, appears to be necessary to synchronize footsteps to the beat, and synchronization elicits slower, shorter, and more variable strides, at least in young healthy adults.

Estimating the implicit component of visuomotor rotation learning by constraining movement preparation time.

When sensory feedback is perturbed, accurate movement is restored by a combination of implicit processes and deliberate reaiming to strategically compensate for errors. Here, we directly compare two methods used previously to dissociate implicit from explicit learning on a trial-by-trial basis: 1) asking participants to report the direction that they aim their movements, and contrasting this with the directions of the target and the movement that they actually produce, and 2) manipulating movement preparation time. By instructing participants to reaim without a sensory perturbation, we show that reaiming is possible even with the shortest possible preparation times, particularly when targets are narrowly distributed. Nonetheless, reaiming is effortful and comes at the cost of increased variability, so we tested whether constraining preparation time is sufficient to suppress strategic reaiming during adaptation to visuomotor rotation with a broad target distribution. The rate and extent of error reduction under preparation time constraints were similar to estimates of implicit learning obtained from self-report without time pressure, suggesting that participants chose not to apply a reaiming strategy to correct visual errors under time pressure. Surprisingly, participants who reported aiming directions showed less implicit learning according to an alternative measure, obtained during trials performed without visual feedback. This suggests that the process of reporting can affect the extent or persistence of implicit learning. The data extend existing evidence that restricting preparation time can suppress explicit reaiming and provide an estimate of implicit visuomotor rotation learning that does not require participants to report their aiming directions.NEW & NOTEWORTHY During sensorimotor adaptation, implicit error-driven learning can be isolated from explicit strategy-driven reaiming by subtracting self-reported aiming directions from movement directions, or by restricting movement preparation time. Here, we compared the two methods. Restricting preparation times did not eliminate reaiming but was sufficient to suppress reaiming during adaptation with widely distributed targets. The self-report method produced a discrepancy in implicit learning estimated by subtracting aiming directions and implicit learning measured in no-feedback trials.