Valence, instrumentality, expectancy, and ability as determinants of faking, and the effects of faking on criterion-related validity

We investigated individual differences in faking in simulated high-stakes personality assessments through the lens of expectancy (VIE) theory, using a novel experimental paradigm. Three hundred ninety-eight participants (MTurk) completed a “low-stakes” HEXACO personality assessment for research purposes. Three months later, we invited all 398 participants to compete for an opportunity to complete a genuine, well-paid, one-off MTurk job, and 201 accepted. After viewing the selection criteria, which described high levels of perfectionism as critical for selection, these participants completed the HEXACO personality assessment as part of their applications (“high-stakes”). All 201 participants were then informed their applications were successful and were invited to complete the performance task, with 189 accepting the offer. The task, which involved checking text data for inconsistencies, captured two objective performance criteria. We observed faking on measures of diligence and perfectionism. We found that perceived job desirability (valence) was the strongest (positive) determinant of individual differences in faking, along with perceived instrumentality and expectancy. Honesty-humility was also associated with faking however, unexpectedly, the association was positive. When all predictors were combined, only perceived job desirability remained a significant motivational determinant of faking, with cognitive ability also being a positive predictor. We found no evidence that cognitive ability moderated the relations of motivation and faking. To investigate the role of faking on predictive validity, we split the sample into those who had faked to a statistically large extent, and those who had not. We found that the validity of high-stakes assessments was higher amongst the group that had faked

Selective Effects of D- and L-Govadine in Preclinical Tests of Positive, Negative, and Cognitive Symptoms of Schizophrenia

There is a critical need to develop novel pharmacotherapeutics capable of addressing the positive, negative, and cognitive symptoms of schizophrenia. Building on recent studies with a racemic mixture of the synthetic tetrahydroprotoberberine, D,L-Govadine, we isolated the D- and L-stereoisomers and employed a battery of behavioral, neurochemical, and electrophysiological procedures to assess their individual therapeutic potential. Rodent models predictive of antipsychotic efficacy and those that model positive symptoms were employed and we found that L-Govadine, but not D-Govadine, improved these measures. Pretreatment with either stereoisomer during CS pre-exposure prevented the disruption of latent inhibition by amphetamine. Moreover, pretreatment with either stereoisomer also improved deficits in social interaction in the neonatal ventral hippocampal lesioned rat. Improved cognitive performance in two different prefrontal cortex-dependent tasks was observed with D-, but not L-Govadine, which strongly suggests that the D-steroisomer may be an effective cognitive enhancer. Alterations in dopamine efflux were also assessed and L-Govadine increased dopamine efflux in both the prefrontal cortex and nucleus accumbens. However, D-Govadine only increased dopamine efflux in the prefrontal cortex and not in the nucleus accumbens. Electrophysiological studies confirmed that L-Govadine is a DA-D2 antagonist, whereas D-Govadine shows no appreciable physiological effects at this receptor. Collectively these data show that L-Govadine performs well on measures predictive of antipsychotic efficacy and rodent models of positive symptoms through antagonism of DA-D2 receptors, whereas D-Govadine improves impairments in compromised memory function in delayed response tasks possibly through selective increases in DA efflux in the frontal cortex

Literacia histórica e história transformativa

Resumo A Educação Histórica, como a própria história, é uma conquista precária; é vulnerável a agendas políticas e educacionais que procuram mesclá-la com outras partes do currículo ou reduzi-la a um veículo para a cidadania ou valores comuns patrióticos. Se tivermos a expectativa de nos engajarmos em uma discussão séria na Educação Histórica em face destes desafios, devemos evitar lemas polares como "tradicional versus progressista", "centrado na criança versus centrado na matéria" e "habilidades versus conteúdo", que têm produzido muita confusão na literatura. Em particular, deve-se evitar falar de competências, com a sua infeliz concessão de licenças a convenientes e tolos currículos genéricos. A história é uma forma pública de conhecimento e o desenvolvimento de uma tradição metacognitiva, com as suas próprias normas e critérios. Há evidências que sugerem que a história é contraintuitiva e que entendê-la envolve a alteração ou até mesmo o abandono de ideias cotidianas que tornam o conhecimento do passado impossível. Consequentemente o ensino de história envolve o desenvolvimento de um aparato conceitual de segunda ordem que permite que a história siga em frente, em vez de imobilizá-la e, ao fazê-lo, abre a perspectiva de mudança de uma visão cotidiana da natureza e do estado do conhecimento do passado para uma de conhecimento histórico. Isto nos permite dar conta do que significa saber um pouco de história - um provisório conceito de literacia histórica - como um aprendizado de uma compreensão disciplinar da história, como a aquisição das disposições que derivam e impulsionam essa compreensão histórica e como o desenvolvimento de uma imagem do passado, que permite que os alunos se orientem no tempo. Existem pesquisas para informar o debate sobre o primeiro componente, mas há pouco disponível para o segundo. Há um interesse atual considerável no terceiro componente, mas o debate centrou-se sobre a questão perene da "ignorância" das crianças, em vez de reconhecer que o problema é encontrar maneiras de permitir que os alunos adquiram passados ​históricos utilizáveis que não são histórias fixas. A obtenção de literacia histórica potencialmente transforma a visão de mundo de crianças (e de adultos) e permite ações até então - literalmente - inconcebíveis para eles. Entender a importância disto para o ensino da história significa abandonar hábitos de pensar com base em um presente instantâneo, em que uma forma de apartheid temporal separa o passado do presente e do futuro. Significa, também, desencaixotar as formas em que a história pode transformar como vemos o mundo. Tais transformações podem ser dramáticas em longas extensões ou mais localizadas e específicas. Elas podem mudar a forma como vemos oportunidades e constrangimentos políticos ou sociais, a nossa própria identidade ou dos outros, a nossa percepção das feridas e fardos que herdamos e a adequação das explicações das principais características do nosso mundo. Elas podem sugerir revisões constrangedoras do nosso entendimento e expectativas de como o mundo humano funciona. E elas podem nos ajudar a conhecer melhor o que não dizer. Literacia histórica envolve tratar o passado como uma ecologia temporal interconectada capaz de suportar uma gama indefinida de histórias, não apenas algo que usamos para contar a história que melhor se adapte aos nossos objetivos e desejos imediatos. Como outras formas públicas de conhecimento, a história é uma tradição metacognitiva que as pessoas têm lutado longa e duramente para desenvolver e ser capaz de praticar. É uma conquista frágil, a ser tratada com respeito e cuidado nas escolas

Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis

Background: Cystic fibrosis (CF) is a chronic, life-limiting disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene leading to abnormal airway surface ion transport, chronic lung infections, inflammation and eventual respiratory failure. With the exception of the small-molecule potentiator, ivacaftor (Kalydeco®, Vertex Pharmaceuticals, Boston, MA, USA), which is suitable for a small proportion of patients, there are no licensed therapies targeting the basic defect. The UK Cystic Fibrosis Gene Therapy Consortium has taken a cationic lipid-mediated CFTR gene therapy formulation through preclinical and clinical development. Objective: To determine clinical efficacy of the formulation delivered to the airways over a period of 1 year in patients with CF. Design: This was a randomised, double-blind, placebo-controlled Phase IIb trial of the CFTR gene–liposome complex pGM169/GL67A. Randomisation was performed via InForm™ version 4.6 (Phase Forward Incorporated, Oracle, CA, USA) and was 1 : 1, except for patients in the mechanistic subgroups (2 : 1). Allocation was blinded by masking nebuliser chambers. Settings: Data were collected in the clinical and scientific sites and entered onto a trial-specific InForm, version 4.6 database. Participants: Patients with CF aged ≥ 12 years with forced expiratory volume in the first second (FEV1) between 50% and 90% predicted and any combination of CFTR mutations. The per-protocol group (≥ 9 doses) consisted of 54 patients receiving placebo (62 randomised) and 62 patients receiving gene therapy (78 randomised). Interventions: Subjects received 5 ml of nebulised pGM169/G67A (active) or 0.9% saline (placebo) at 28 (±5)-day intervals over 1 year. Main outcome measures: The primary end point was the relative change in percentage predicted FEV1 over the 12-month period. A number of secondary clinical outcomes were assessed alongside safety measures: other spirometric values; lung clearance index (LCI) assessed by multibreath washout; structural disease on computed tomography (CT) scan; the Cystic Fibrosis Questionnaire – Revised (CFQ-R), a validated quality-of-life questionnaire; exercise capacity and monitoring; systemic and sputum inflammatory markers; and adverse events (AEs). A mechanistic study was performed in a subgroup in whom transgene deoxyribonucleic acid (DNA) and messenger ribonucleic acid (mRNA) was measured alongside nasal and lower airway potential difference. Results: There was a significant (p = 0.046) treatment effect (TE) of 3.7% [95% confidence interval (CI) 0.1% to 7.3%] in the primary end point at 12 months and in secondary end points, including forced vital capacity (FVC) (p = 0.031) and CT gas trapping (p = 0.048). Other outcomes, although not reaching statistical significance, favoured active treatment. Effects were noted by 1 month and were irrespective of sex, age or CFTR mutation class. Subjects with a more severe baseline FEV1 had a FEV1 TE of 6.4% (95% CI 0.8% to 12.1%) and greater changes in many other secondary outcomes. However, the more mildly affected group also demonstrated benefits, particularly in small airway disease markers such as LCI. The active group showed a significantly (p = 0.032) greater bronchial chloride secretory response. No difference in treatment-attributable AEs was seen between the placebo and active groups. Conclusions: Monthly application of the pGM169/GL67A gene therapy formulation was associated with an improvement in lung function, other clinically relevant parameters and bronchial CFTR function, compared with placebo. Limitations: Although encouraging, the improvement in FEV1 was modest and was not accompanied by detectable improvement in patients’ quality of life. Future work: Future work will focus on attempts to increase efficacy by increasing dose or frequency, the coadministration of a CFTR potentiator, or the use of modified viral vectors capable of repeated administration. Trial registration: ClinicalTrials.gov NCT01621867. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership

Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis:a randomised, double-blind, placebo-controlled, phase 2b trial

Background: Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis. Methods: We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50–90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene–liposome complex or 0·9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (<70 vs ≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01621867. Findings: Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3·7%, 95% CI 0·1–7·3; p=0·046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups. Interpretation: Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in efficacy and consistency of response to the current formulation are needed before gene therapy is suitable for clinical care; however, our findings should also encourage the rapid introduction of more potent gene transfer vectors into early phase trials

Functional and quality of life outcomes of localised prostate cancer treatments (prostate testing for cancer and treatment [ProtecT] study)

Objective To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. Patients and Methods Men aged 50–69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. Results Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. Conclusion Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes

The role of hippocampal long-term depression in novel spatial exploration

The exploration and encoding of a novel environment is a fundamental learning process that occurs on a short time scale, and is a useful model for studying how the hippocampus encodes and represents complex and arbitrary associations, as is required for episodic memory. Novelty exploration has been demonstrated to promote long-term depression (LTD) induction in area CA1 of the hippocampus, but it is unclear what role this LTD plays as the novel space becomes familiarized and encoded in the hippocampus. In order to determine whether de novo LTD occurs during novelty exploration, we utilized multi-array electrophysiological recording in freely moving rats and demonstrated an AMPA receptor endocytosis-dependent LTD in CA1 in the absence of a paired LTD induction protocol. To determine what role this LTD played in forming spatial representations, we recorded the spiking activity of multiple single units in hippocampal CA1 using multi-tetrode electrophysiological recordings to observe the development of place field firing in a novel environment, and the effect of LTD blockade using an inhibitor of AMPAR endocytosis. Place fields formed in the presence of LTD blockade, however the maintenance of place field firing location between the novel environmental exposure and re-exposure one day later was impaired by inhibition of LTD. To investigate the dynamics of place field formation over the first several minutes of exposure, hippocampal neurons were recorded during exposure to a novel linear environment. While fields developed and stabilized over several minutes in control rats, we found that LTD blockade produced a rapid establishment of stable place fields after a single lap, suggesting the dynamics of field formation are altered with LTD blockade. To test the role of this LTD in novel spatial learning, the effect of LTD blockade on contextual fear was assessed using a modification of inhibitory avoidance training that separated the acquisition of contextual information from the pairing with an aversive stimulus. This demonstrated that LTD is required on the first exposure to a novel context. These results place the activity dependent weakening of synapses as a central process in the rapid acquisition of novel spatial information in the hippocampus.Medicine, Faculty ofGraduat

Disruption of Long-Term Depression Potentiates Latent Inhibition: Key Role for Central Nucleus of the Amygdala

Background: Latent inhibition (LI) reflects an adaptive form of learning impaired in certain forms of mental illness. Glutamate receptor activity is linked to LI, but the potential role of synaptic plasticity remains unspecified. Methods: Accordingly, the present study examined the possible role of long-term depression (LTD) in LI induced by prior exposure of rats to an auditory stimulus used subsequently as a conditional stimulus to signal a pending footshock. We employed 2 mechanistically distinct LTD inhibitors, the Tat-GluA23Y peptide that blocks endocytosis of the GluA2-containing glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, or the selective glutamate n-methyl-d-aspartate receptor 2B antagonist, Ro25-6981, administered prior to the acquisition of 2-way conditioned avoidance with or without tone pre-exposure. Results: Systemic LTD blockade with the Tat-GluA23Y peptide strengthened the LI effect by further impairing acquisition of conditioned avoidance in conditional stimulus-preexposed rats compared with normal conditioning in non-preexposed controls. Systemic Ro25-6981 had no significant effects. Brain region-specific microinjections of the Tat-GluA23Y peptide into the nucleus accumbens, medial prefrontal cortex, or central or basolateral amygdala demonstrated that disruption of glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor endocytosis in the central amygdala also potentiated the LI effect. Conclusions: These data revealed a previously unknown role for central amygdala LTD in LI as a key mediator of cognitive flexibility required to respond to previously irrelevant stimuli that acquire significance through reinforcement. The findings may have relevance both for our mechanistic understanding of LI and its alteration in disease states such as schizophrenia, while further elucidating the role of LTD in learning and memory

Valence, instrumentality, expectancy, and ability as determinants of faking, and the effects of faking on criterion related validity

We investigated individual differences in faking in simulated high-stakes personality assessments through the lens of expectancy (VIE) theory, using a novel experimental paradigm. 398 participants (MTurk) completed a ‘low-stakes’ HEXACO personality assessment for research purposes. Three months later, we invited all 398 participants to compete for an opportunity to complete a genuine, well-paid, one-off MTurk job, and 201 accepted. After viewing the selection criteria, which described high levels of perfectionism as critical for selection, these participants completed the HEXACO personality assessment as part of their applications (‘high-stakes’). All 201 participants were then informed their applications were successful, and were invited to complete the performance task, with 189 accepting the offer. The task, which involved checking text data for inconsistencies, captured two objective performance criteria. We observed faking on measures of diligence and perfectionism. We found that perceived job desirability (valence) was the strongest (positive) determinant of individual differences in faking, along with perceived instrumentality and expectancy. Honesty-humility was also associated with faking however, unexpectedly, the association was positive. When all predictors were combined, only perceived job desirability remained a significant motivational determinant of faking, with cognitive ability also being a positive predictor. We found no evidence that cognitive ability moderated the relations of motivation and faking. To investigate the role of faking on predictive validity, we split the sample into those who had faked to a statistically large extent, and those who had not. We found that the validity of high-stakes assessments was higher amongst the group that had faked