Cost-effectiveness of LiveLighter® - a mass media public education campaign for obesity prevention.

BACKGROUND: The Western Australian LiveLighter® program has implemented a series of mass media advertising campaigns that aim to encourage adults to achieve and maintain a healthy weight through healthy behaviours. This study aimed to assess the cost-effectiveness of the LiveLighter® campaign in preventing obesity-related ill health in the Western Australian population from the health sector perspective. METHODS: Campaign effectiveness (delivered over 12 months) was estimated from a meta-analysis of two cohort studies that surveyed a representative sample of the Western Australian population aged 25-49 years on discretionary food consumption one month pre- and one month post-campaign. Campaign costs were derived from campaign invoices and interviews with campaign staff. Long-term health (measured in health-adjusted life years (HALYs)) and healthcare cost-savings resulting from reduced obesity-related diseases were modelled over the lifetime of the population using a validated multi-state lifetable Markov model (ACE-Obesity Policy model). All cost and health outcomes were discounted at 7% and presented in 2017 values. Uncertainty analyses were undertaken using Monte-Carlo simulations. RESULTS: The 12-month intervention was estimated to cost approximately A$2.46 million (M) (95% uncertainty interval (UI): 2.26M; 2.67M). The meta-analysis indicated post-campaign weekly reduction in sugary drinks consumption of 0.78 serves (95% UI: 0.57; 1.0) and sweet food of 0.28 serves (95% UI: 0.07; 0.48), which was modelled to result in average weight reduction of 0.58 kilograms (95%UI: 0.31; 0.92), 204 HALYs gained (95%UI: 103; 334), and healthcare cost-savings of A$3.17M (95%UI: A$1.66M; A$5.03M). The mean incremental cost-effectiveness ratio showed that LiveLighter® was dominant (cost-saving and health promoting; 95%UI: dominant; A$7 703 per HALY gained). The intervention remained cost-effective in all sensitivity analyses conducted. CONCLUSION: The LiveLighter® campaign is likely to represent very good value-for-money as an obesity prevention intervention in Western Australia and should be included as part of an evidence-based obesity prevention strategy.

Teaching Programming Online: Design, Facilitation and Assessment Strategies and Recommendations for High School Teachers.

Current research surrounding online computer science education emphasizes the need for high-quality professional development opportunities. However, there is a gap in research in the inclusion of online computer science educators to identify needs and strategies that make the online computer science courses effective. Through a Research-to-Practice Partnership (RPP), this paper examines the instructional strategies and recommendations from online Computer Science teachers. This study seeks to better understand (1) What design, facilitation, and assessment strategies do teachers use to teach programming online? and (2) What recommendations do teachers have for those interested in teaching programming online? The feedback teachers provided during the study assisted in identifying the current needs in online AP Computer Science. The participants suggested additional ways the RPP could support teachers in strengthening their practice, which has assisted in the production of high-quality professional development to support novice teachers entering the field of Computer Science.

Investigation of SARS-CoV-2 infection and associated lesions in exotic and companion animals.

Documented natural infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in exotic and companion animals following human exposures are uncommon. Those documented in animals are typically mild and self-limiting, and infected animals have only infrequently died or been euthanized. Through a coordinated One Health initiative, necropsies were conducted on 5 animals from different premises that were exposed to humans with laboratory-confirmed SARS-CoV-2 infection. The combination of epidemiologic evidence of exposure and confirmatory real-time reverse transcriptase-polymerase chain reaction testing confirmed infection in 3 cats and a tiger. A dog was a suspect case based on epidemiologic evidence of exposure but tested negative for SARS-CoV-2. Four animals had respiratory clinical signs that developed 2 to 12 days after exposure. The dog had bronchointerstitial pneumonia and the tiger had bronchopneumonia; both had syncytial-like cells with no detection of SARS-CoV-2. Individual findings in the 3 cats included metastatic mammary carcinoma, congenital renal disease, and myocardial disease. Based on the necropsy findings and a standardized algorithm, SARS-CoV-2 infection was not considered the cause of death in any of the cases. Continued surveillance and necropsy examination of animals with fatal outcomes will further our understanding of natural SARS-CoV-2 infection in animals and the potential role of the virus in development of lesions.

A cross-sectional study in healthy elderly subjects aimed at development of an algorithm to increase identification of Alzheimer pathology for the purpose of clinical trial participation.

BACKGROUND: In the current study, we aimed to develop an algorithm based on biomarkers obtained through non- or minimally invasive procedures to identify healthy elderly subjects who have an increased risk of abnormal cerebrospinal fluid (CSF) amyloid beta42 (Aß) levels consistent with the presence of Alzheimer's disease (AD) pathology. The use of the algorithm may help to identify subjects with preclinical AD who are eligible for potential participation in trials with disease modifying compounds being developed for AD. Due to this pre-selection, fewer lumbar punctures will be needed, decreasing overall burden for study subjects and costs. METHODS: Healthy elderly subjects (n = 200; age 65-70 (N = 100) and age > 70 (N = 100)) with an MMSE > 24 were recruited. An automated central nervous system test battery was used for cognitive profiling. CSF Aß1-42 concentrations, plasma Aß1-40, Aß1-42, neurofilament light, and total Tau concentrations were measured. Aß1-42/1-40 ratio was calculated for plasma. The neuroinflammation biomarker YKL-40 and APOE ε4 status were determined in plasma. Different mathematical models were evaluated on their sensitivity, specificity, and positive predictive value. A logistic regression algorithm described the data best. Data were analyzed using a 5-fold cross validation logistic regression classifier. RESULTS: Two hundred healthy elderly subjects were enrolled in this study. Data of 154 subjects were used for the per protocol analysis. The average age of the 154 subjects was 72.1 (65-86) years. Twenty-four (27.3%) were Aß positive for AD (age 65-83). The results of the logistic regression classifier showed that predictive features for Aß positivity/negativity in CSF consist of sex, 7 CNS tests, and 1 plasma-based assay. The model achieved a sensitivity of 70.82% (± 4.35) and a specificity of 89.25% (± 4.35) with respect to identifying abnormal CSF in healthy elderly subjects. The receiver operating characteristic curve showed an AUC of 65% (± 0.10). CONCLUSION: This algorithm would allow for a 70% reduction of lumbar punctures needed to identify subjects with abnormal CSF Aß levels consistent with AD. The use of this algorithm can be expected to lower overall subject burden and costs of identifying subjects with preclinical AD and therefore of total study costs. TRIAL REGISTRATION: ISRCTN.org identifier: ISRCTN79036545 (retrospectively registered).

Safety, pharmacokinetics and exploratory pro-cognitive effects of HTL0018318, a selective M1 receptor agonist, in healthy younger adult and elderly subjects: a multiple ascending dose study.

BACKGROUND: The cholinergic system and M1 receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M1 receptor partial agonist HTL0018318 is under development for the symptomatic treatment of Dementia's including Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). We investigated the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of multiple doses of HTL0018318 in healthy younger adults and elderly subjects. METHODS: This randomised, double blind, placebo-controlled study was performed, investigating oral doses of 15-35 mg/day HTL0018318 or placebo in 7 cohorts of healthy younger adult (n = 36; 3 cohorts) and elderly (n = 50; 4 cohorts) subjects. Safety, tolerability and pharmacokinetic measurements were performed. Pharmacodynamics were assessed using a battery of neurocognitive tasks and electrophysiological biomarkers of synaptic and cognitive functions. RESULTS: HTL0018318 was generally well-tolerated in multiple doses up to 35 mg/day and were associated with mild or moderate cholinergic adverse events. There were modest increases in blood pressure and pulse rate when compared to placebo-treated subjects, with tendency for the blood pressure increase to attenuate with repeated dosing. There were no clinically significant observations or changes in blood and urine laboratory measures of safety or abnormalities in the ECGs and 24-h Holter assessments. HTL0018318 plasma exposure was dose-proportional over the range 15-35 mg. Maximum plasma concentrations were achieved after 1-2 h. The apparent terminal half-life of HTL0018318 was 16.1 h (± 4.61) in younger adult subjects and 14.3 h (± 2.78) in elderly subjects at steady state. HTL0018318 over the 10 days of treatment had significant effects on tests of short-term (working) memory (n-back) and learning (Milner maze) with moderate to large effect sizes. CONCLUSION: Multiple doses of HTL0018138 showed well-characterised pharmacokinetics and were safe and generally well-tolerated in the dose range studied. Pro-cognitive effects on short-term memory and learning were demonstrated across the dose range. These data provide encouraging data in support of the development of HTL0018138 for cognitive dysfunction in AD and DLB. TRIAL REGISTRATION: Netherlands Trial Register identifier NTR5781 . Registered on 22 March 2016.

Safety, pharmacokinetics and pharmacodynamics of HTL0009936, a selective muscarinic M1 -acetylcholine receptor agonist: A randomized cross-over trial.

AIMS: HTL0009936 is a selective M1 muscarinic receptor agonist in development for cognitive dysfunction in Alzheimer's disease. Safety, tolerability and pharmacokinetics and exploratory pharmacodynamic effects of HTL0009936 administered by continuous IV infusion at steady state were investigated in elderly subjects with below average cognitive functioning (BACF). METHODS: Part A was a four-treatment open label sequential study in healthy elderly investigating 10-83 mg HTL0009936 (IV) and a 24 mg HTL0009936 single oral dose. Part B was a five-treatment randomized, double-blind, placebo and physostigmine controlled cross-over study with IV HTL0009936 in elderly subjects with BACF. Pharmacodynamic assessments were performed using neurocognitive and electrophysiological tests. RESULTS: Pharmacokinetics of HTL0009936 showed dose-proportional increases in exposure with a mean half-life of 2.4 hours. HTL0009936 was well-tolerated with transient dose-related adverse events (AEs). Small increases in mean systolic blood pressure of 7.12 mmHg (95% CI [3.99-10.24]) and in diastolic of 5.32 mmHg (95% CI [3.18-7.47]) were noted at the highest dose in part B. Overall, there was suggestive, but no definitive, positive or negative pharmacodynamic effects. Statistically significant effects were observed on P300 with HTL0009936 and adaptive tracking with physostigmine. CONCLUSIONS: HTL0009936 showed well-characterized pharmacokinetics and single doses were safe and generally well-tolerated in healthy elderly subjects. Due to physostigmine tolerability issues and subject burden, the study design was changed and some pharmacodynamic assessments (neurocognitive) were performed at suboptimal drug exposures. Therefore no clear conclusions can be made on pharmacodynamic effects of HTL0009936, although an effect on P300 is suggestive of central target engagement.

Factors associated with ordering food via online meal ordering services.

OBJECTIVE: Online meal ordering services are increasing in popularity in Australia and globally. Meals ordered online for home delivery are typically less healthy than home-made meals, potentially contributing to weight gain. The aim of the present study was to identify the types of consumers who are most likely to engage in online meal ordering. DESIGN: A cross-sectional survey including items relating to demographic and lifestyle factors was disseminated via a web panel provider. SETTING: Australia. PARTICIPANTS: A total of 2010 Australian adults aged 18+ years. RESULTS: More than a quarter of respondents (28 %) engaged in online meal ordering at least once in the previous month. Younger respondents, those with a higher BMI, and those with higher education and income levels were more likely to have done so. Consuming higher levels of sugary drinks and fast-food restaurant patronage were significantly associated with ordering meals online for home delivery. CONCLUSIONS: The outcomes of this study suggest that the use of online meal ordering services is becoming a common practice in Australia, and it is therefore important to implement evidence-based strategies and policies to encourage individuals to make healthy food choices when using these services.

Attachment, rumination, and disordered eating among adolescent girls: The moderating role of stress.

PURPOSE: Disordered eating behaviors are prevalent and problematic in adolescent girls. Given that disordered eating has been linked to attachment insecurity and emotion dysregulation, the current study used an emotion regulation model of attachment theory to investigate pathways to disordered eating among adolescent girls. While past research has examined attachment and eating, an emotion regulation perspective is rarely used. Additionally, limited studies have investigated specific types of eating or mediators or moderators. To address these research gaps, this study examined whether rumination mediates the relationship between attachment anxiety and avoidance and three types of disordered eating and whether stress moderates this mediation. METHODS: 100 adolescent girls (Mage = 14.35 years, SD = 2.29) completed online surveys including the Relationship Structures Questionnaire, Dutch Eating Behaviour Questionnaire, Rumination Questionnaire, and Perceived Stress Scale. RESULTS: The interaction between stress and attachment anxiety on rumination was significant (b = .09, SE = .04, p < .05), and stress and attachment anxiety predicted emotional eating through rumination (b = .50, SE = .15, p < .05). Rumination also predicted external eating (b = .32, SE = .11, p < .05). The mediation was not significant for restrained eating. Attachment avoidance did not significantly predict eating behaviors. CONCLUSION: The emotion regulation model of attachment theory provides a suitable framework for studying disordered eating in adolescent girls. Future research may continue the use of this framework to examine related topics. Clinicians treating girls experiencing disordered eating may use interventions to promote healthy emotion regulation strategies. LEVEL OF EVIDENCE: Level V: cross-sectional descriptive study.

Anti-fat attitudes and dietary restraint within mother-daughter dyads: an Actor-Partner Interdependence Model (APIM) analysis.

PURPOSE: This study examined the association between anti-fat attitudes (fear of fat, dislike of fat, willpower) and dietary restraint within the mother-daughter relationship. METHODS: Mother-adolescent daughter dyads (Npairs = 100) were recruited from a Midwestern community to participate in a study together. They completed self-report measures of anti-fat attitudes and eating behavior. Data were analyzed with an Actor-Partner Interdependence Model (APIM). RESULTS: Significant actor effects for mothers include fear of fat (b = 0.270, B = 0.319, p < 0.05) and willpower (b = 0.228, B = 0.280, p < 0.05) predicting her own dietary restraint. For daughters, fear of fat (b = 0.554, B = 0.612, p < 0.05) and dislike (b = 0.202, B = 0.214, p < 0.05) predict her own dietary restraint. Regarding partner effects, mothers' fear of fat was related to daughters' dietary restraint (b = 0.126, B = 0.138, p < 0.05), and daughters' dislike was related to mothers' restraint (b = 0.257, B = 0.294, p < 0.05). Regarding dyad-level interaction effects, mother and daughter fear of fat interacted to predict daughter dietary restraint (b = 0.184, B = 0.201, p < 0.05), such that when both mother and daughter fear of fat is high, daughters appear to engage in more dietary restraint. CONCLUSIONS: Given the role of mothers' fear of fat in daughter eating behavior, parent-focused or parent-involved interventions may improve family culture around weight and eating, contributing to better adolescent outcomes. LEVEL OF EVIDENCE: V, cross-sectional descriptive study.

First-in-man study to investigate safety, pharmacokinetics and exploratory pharmacodynamics of HTL0018318, a novel M1 -receptor partial agonist for the treatment of dementias.

AIMS: HTL0018318 is a selective M1 receptor partial agonist currently under development for the symptomatic treatment of cognitive and behavioural symptoms in Alzheimer's disease and other dementias. We investigated safety, tolerability, pharmacokinetics and exploratory pharmacodynamics (PD) of HTL0018318 following single ascending doses. METHODS: This randomized, double-blind, placebo-controlled study in 40 healthy younger adult and 57 healthy elderly subjects, investigated oral doses of 1-35 mg HTL0018318. Pharmacodynamic assessments were performed using a battery of neurocognitive tasks and electrophysiological measurements. Cerebrospinal fluid concentrations of HTL0018318 and food effects on pharmacokinetics of HTL0018318 were investigated in an open label and partial cross-over design in 14 healthy subjects. RESULTS: Pharmacokinetics of HTL0018318 were well-characterized showing dose proportional increases in exposure from 1-35 mg. Single doses of HTL0018318 were associated with mild dose-related adverse events of low incidence in both younger adult and elderly subjects. The most frequently reported cholinergic AEs included hyperhidrosis and increases in blood pressure up to 10.3 mmHg in younger adults (95% CI [4.2-16.3], 35-mg dose) and up to 11.9 mmHg in elderly subjects (95% CI [4.9-18.9], 15-mg dose). There were no statistically significant effects on cognitive function but the study was not powered to detect small to moderate effect sizes of clinical relevance. CONCLUSION: HTL0018318 showed well-characterized pharmacokinetics and following single doses were generally well tolerated in the dose range studied. These provide encouraging data in support of the development for HTL0018318 for Alzheimer's disease and other dementias.

Safety, pharmacokinetics and pharmacodynamics of SBT-020 in patients with early stage Huntington's disease, a 2-part study.

AIMS: Huntington's disease (HD) is a neurodegenerative disease with cognitive, motor and psychiatric symptoms. Toxic accumulation of misfolded mutant huntingtin protein induces mitochondrial dysfunction, leading to a bioenergetic insufficiency in neuronal and muscle cells. We evaluated the safety, pharmacokinetics and pharmacodynamics of SBT-020, a novel compound to improve mitochondrial function, in a 2-part study in early stage HD patients. METHODS: Part 1 consisted of 7-day multiple ascending dose study to select the highest tolerable dose for Part 2, a 28-day multiple dose study. Mitochondrial function was measured in the visual cortex and calf muscle, using phosphorous magnetic resonance spectroscopy, and in circulating peripheral blood mononuclear cells. RESULTS: Treatment-emergent adverse events were mild and more present in the SBT-020 group. Injection site reactions occurred in 91% in Part 1 and 97% in Part 2. Mitochondrial function in calf muscle, peripheral blood mononuclear cells or visual cortex was not changed overall due to treatment with SBT-020. In a posthoc analysis, patients with a higher degree of mitochondrial dysfunction (below the median [∆Ψm < 3412 and τPCr > 42.5 s]) showed more improvement than patients with a relatively lower level of mitochondrial dysfunction. CONCLUSION: SBT-020 was safe at all doses, but no significant differences in any of the pharmacodynamic measurements between the treatment groups and placebo group could be demonstrated. The data suggest that the better than expected mitochondrial function in our patient population at baseline might explain the lack of effect of SBT-020.

Brain Bio-Energetic State Does Not Correlate to Muscle Mitochondrial Function in Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disease with cognitive, motor and psychiatric symptoms. A toxic accumulation of misfolded mutant huntingtin protein (Htt) induces mitochondrial dysfunction, leading to a bioenergetic insufficiency in neuronal and muscle cells. Improving mitochondrial function has been proposed as an opportunity to treat HD, but it is not known how mitochondrial function in different tissues relates. OBJECTIVE: We explored associations between central and peripheral mitochondrial function in a group of mild to moderate staged HD patients. METHODS: We used phosphorous magnetic resonance spectroscopy (31P-MRS) to measure mitochondrial function in vivo in the calf muscle (peripheral) and the bio-energetic state in the visual cortex (central). Mitochondrial function was also assessed ex vivo in circulating peripheral blood mononuclear cells (PBMCs). Clinical function was determined by the Unified Huntington's Disease Rating Scale (UHDRS) total motor score. Pearson correlation coefficients were computed to assess the correlation between the different variables. RESULTS: We included 23 manifest HD patients for analysis. There was no significant correlation between central bio-energetics and peripheral mitochondrial function. Central mitochondrial function at rest correlated significantly to the UHDRS total motor score (R = -0.45 and -0.48), which increased in a subgroup with the largest number of CAG repeats. DISCUSSION: We did not observe a correlation between peripheral and central mitochondrial function. Central, but not peripheral, mitochondrial function correlated to clinical function. Muscle mitochondrial function is a promising biomarker to evaluate disease-modifying compounds that improve mitochondrial function, but Huntington researchers should use central mitochondrial function to demonstrate proof-of-pharmacology of disease-modifying compounds.

Safety, pharmacokinetics, and pharmacodynamics of Gln-1062, a prodrug of galantamine.

INTRODUCTION: Gln-1062 (MEMOGAIN) is an intranasally administered lipophilic prodrug of galantamine. Based on high brain-to-blood concentrations observed in pre-clinical studies, Gln-1062 is expected to have superior cognitive efficacy compared to oral galantamine. METHODS: Forty-eight healthy elderly subjects were randomized 12:4 to Gln-1062 (5.5, 11, or 22 mg, b.i.d., for 7 days) or placebo. Safety, tolerability, pharmacokinetics, and pharmacodynamics were assessed repeatedly. Pharmacokinetics were compared with 16 mg oral galantamine. RESULTS: Gln-1062 up to 22 mg, b.i.d., was well tolerated. Gln-1062 plasma concentrations increased immediately following dosing (median Tmax of 0.5 hour [range 0.5-1.0]). Cmax and AUC0-last increased in a dose-linear manner over all three dose levels. Gln-1062 was rapidly cleaved into galantamine. Gln-1062 significantly improved adaptive tracking (sustained attention) with 1.95% (95% confidence interval [CI] 0.630-3.279, P = 0.0055) compared to placebo after correction for individual baseline performance. DISCUSSION: Gln-1062 was considered to be safe and caused fewer gastrointestinal side effects than oral galantamine. Gln-1062 behaved pharmacokinetically as expected and improved performance on cognitive tests.

Quantification of tremor using consumer product accelerometry is feasible in patients with essential tremor and Parkinson's disease: a comparative study.

BACKGROUND: To quantify pharmacological effects on tremor in patients with essential tremor (ET) or Parkinson's Disease (PD), laboratory-grade accelerometers have previously been used. Over the last years, consumer products such as smartphones and smartwatches have been increasingly applied to measure tremor in an easy way. However, it is unknown how the technical performance of these consumer product accelerometers (CPAs) compares to laboratory-grade accelerometers (LGA). This study was performed to compare the technical performance of CPAs with LGA to measure tremor in patients with Parkinson's Disease (PD) and essential tremor (ET). METHODS: In ten patients with PD and ten with ET, tremor peak frequency and corresponding amplitude were measured with 7 different CPAs (Apple iPhone 7, Apple iPod Touch 5, Apple watch 2, Huawei Nexus 6P, Huawei watch, mbientlabMetaWear (MW) watch, mbientlab MW clip) and compared to a LGA (Biometrics ACL300) in resting and extended arm position. RESULTS: Both in PD and ET patients, the peak frequency of CPAs did not significantly differ from the LGA in terms of limits of agreement. For the amplitude at peak frequency, only the iPhone and MW watch performed comparable to the LGA in ET patients, while in PD patients all methods performed comparable except for the iPod Touch and Huawei Nexus. Amplitude was higher when measured with distally-located CPAs (Clip, iPhone, iPod) compared with proximally-located CPAs (all watches). The variability between subjects was higher than within subjects for frequency (25.1% vs. 13.4%) and amplitude measurement (331% vs. 53.6%). Resting arm position resulted in lower intra-individual variability for frequency and amplitude (13.4 and 53.5%) compared to extended arm position (17.8 and 58.1%). CONCLUSIONS: Peak frequencies of tremor could be measured with all tested CPAs, with similar performance as LGA. The amplitude measurements appeared to be driven by anatomical location of the device and can therefore not be compared. Our results show that the tested consumer products can be used for tremography, allowing at-home measurements, in particular in studies with a cross-over or intra-individual comparison design using the resting arm position. TRIAL REGISTRATION: This trial was registered in the Dutch Competent Authority (CCMO) database with number NL60672.058.17 on May 30th 2017.

"I just don't want to be fat!": body talk, body dissatisfaction, and eating disorder symptoms in mother-adolescent girl dyads.

PURPOSE: Mothers serve as a primary socializing figure among adolescent girls at a time when they are at high risk of body image concerns and disordered eating behavior, and this influence may vary by weight status. Body talk may be one mechanisms of influence in this relationship. The current study utilized an observational measure of body talk to investigate the relationship between adolescent girls' body talk with mothers, eating disorder symptoms, and body dissatisfaction. METHODS: Participants included 100 mother-daughter dyads who completed self-report measures of body dissatisfaction and eating behavior and engaged in a 10-min discussion about the daughter's body image. RESULTS: Results indicated that the relationship between both positive and negative body talk and body dissatisfaction varied by weight status. For healthy/underweight adolescents, negative body talk is related to higher body dissatisfaction (b = 0.04, SE 0.01, p < 0.01) and positive talk is related to lower body dissatisfaction (b = - 0.06, SE 0.02, p < 0.001). No relationship was found for individuals of overweight/obese status. Body talk was unrelated to eating disorder symptoms for all adolescents. CONCLUSIONS: Given the current findings, mothers should continue to limit their engagement in body talk (particularly negative talk) within the home. LEVEL OF EVIDENCE: V, cross-sectional descriptive study.

A Computerized Test Battery to Study Pharmacodynamic Effects on the Central Nervous System of Cholinergic Drugs in Early Phase Drug Development.

Investigating potential pharmacodynamic effects in an early phase of central nervous system (CNS) drug research can provide valuable information for further development of new compounds. A computerized and thoroughly validated battery of neuropsychological and neurophysiological tests has been shown to be sensitive to detect drug-induced effects of multiple new and existing compounds. The test battery covers the main CNS domains, which have been shown to respond to drug effects and can be repeatedly administered following drug administration to characterize the concentration-effect profile of a drug. The standard tests in the battery are saccadic eye movement, smooth pursuit eye movement, the Bowdle visual analog scale (VAS), the Bond and Lader VAS, body sway, adaptive tracking, visual verbal learning, and quantitative electroencephalography (qEEG). However, the test battery is adaptive in nature, meaning that it can be composed and adjusted with tests fit to investigate specific drug classes, or even specific receptors. Showing effects of new cholinergic drugs designed to have a pro-cognitive outcome has been difficult. The pharmacological challenge model is a tool for early proof-of-pharmacology. Here, a marketed drug is used to induce temporary and reversible disease-like symptoms in healthy subjects, via a pharmacological mechanism related to the disease that is targeted as indication for the new compound. The test battery was implemented to investigate the potential of the nicotinic receptor antagonist mecamylamine to be used as a challenge model for cholinergic dysfunction, as seen in neurodegenerative disorders. A worsening of scores in a dose dependent manner on the visual verbal learning test (VVLT; a test for learning and memory abilities) and the adaptive tracking test (a measure of visuomotor control and arousal), in particular, showed that the test battery is sensitive to showing acute pharmacodynamic effect after administration of anti-cholinergic drugs.

Predictors of simulated driving performance in Huntington's disease.

BACKGROUND: As the disease progresses, patients with Huntington's disease (HD), an inherited neurodegenerative disorder, become less independent in their daily life activities and have to consider if they can still drive a car. For most patients, the decision to quit driving is difficult and affects their independence and social activities. OBJECTIVE: To investigate if cognitive, motor, or psychiatric symptoms can predict driving performance in HD gene carriers using a simulator situation. METHODS: Twenty-nine controls, 28 premanifest HD, and 30 manifest HD participated in this observational, cross-sectional study and underwent neuropsychological, motor, and psychiatric evaluations. All participants drove a motorway scenario in a driving simulator to evaluate driving performance. Group differences were analyzed using Analysis of Covariance and stepwise forward linear regression analysis was used to investigate which clinical assessments were predictors of driving simulator outcomes. RESULTS: Manifest HD drove slower and had less vehicle control in the driving simulator compared to controls and premanifest HD. They also performed worse on all clinical assessments compared to controls. Postural sway and slower speed of information processing were predictors of the driving simulator outcome measures. Psychiatric symptoms were unrelated to simulated driving. There were no significant differences between premanifest HD and controls. CONCLUSIONS: Increased postural sway and slower speed of processing are predictive of driving simulator performance in manifest HD. Worse performance on these clinical tasks might be useful as a first screening and could assist clinicians in their referral for an official on-road driving test.

Interactive role of weight status and fat talk on body dissatisfaction: an observation of women friends.

PURPOSE: The current study examined the interactive role of weight status and fat talk on body dissatisfaction among women friends. METHOD: Sixty pairs of women friends completed a measure of body dissatisfaction and engaged in an observed fat talk interaction with their friend. RESULTS: Women's weight status was related to their own, but not their friend's, body dissatisfaction. Observed fat talk was significantly related to individuals' own and their friend's body dissatisfaction. A significant interaction effect showed that the association between fat talk and body dissatisfaction was minimal for women with higher weight status. In contrast, fat talk was associated with more body dissatisfaction for women with lower weight status. CONCLUSION: These findings suggest the importance of examining the conjoint effect of personal (e.g., weight status) and contextual (e.g., fat talk) factors on body image issues. LEVEL OF EVIDENCE: V, cross-sectional descriptive study.

Altered driving performance of symptomatic Huntington's disease gene carriers in simulated road conditions.

OBJECTIVE: In clinical practice, patients with Huntington's disease (HD) often decide to solely drive in their own familiar neighborhoods and not on a motorway or in an unknown area. The aim of the study was to identify differences in driving performance between HD gene carriers and healthy individuals in simulated urban and motorway environments. METHODS: This cross-sectional study included 87 participants (28 premanifest HD, 30 manifest HD, 29 controls). All participants were active drivers and were assessed using a driving simulator, a driving history questionnaire, and the Unified Huntington's Disease Rating Scale. The driving simulator session included urban and motorway scenarios. Analysis of variance and Kruskal-Wallis tests were used to compare urban and motorway driving across all 3 groups. RESULTS: Manifest HD drove slower compared to controls and premanifest HD when speed limits increased (80 and 100 km/h) and they had a less steady speed compared to premanifest HD on the motorway and in a 30 km/h zone. Manifest HD also had a larger standard deviation of the lateral position (i.e., more weaving of the car/less vehicle control) compared to controls and premanifest HD on the motorway. CONCLUSIONS: Manifest HD drive more cautious in a driving simulator when speed limits increase compared to premanifest HD and controls and they have less vehicle control on the motorway. The driving simulator parameters are able to discriminate between manifest HD and healthy individuals, so a driving simulator seems a feasible tool to use when investigating changes in driving in manifest HD.

An EEG nicotinic acetylcholine index to assess the efficacy of pro-cognitive compounds.

OBJECTIVES: Cognitive impairment models are used in clinical studies aimed at proving pharmacology of drugs being developed for Alzheimer's disease and other cognitive disorders. Due to rising interest in nicotinic agonists, we aimed to establish a method to monitor neurophysiological effects of modulating the nicotinic cholinergic system. METHODS: In a four-way cross-over study, eyes-closed rest EEG was recorded in 28 healthy subjects receiving mecamylamine-a nicotinic acetylcholine receptor (nAChR) antagonist, which induces temporary cognitive dysfunction in healthy subjects-with co-administration of placebo, nicotine or galantamine. RESULTS: Using machine learning to optimally contrast the effects of 30 mg of mecamylamine and placebo on the brain, we developed a nAChR index that consists of 10 EEG biomarkers and shows high classification accuracy (∼95% non-cross-validated, ∼70% cross-validated). Importantly, using the nAChR index, we demonstrate reversal of mecamylamine-induced neurophysiological effects due to 16 mg of galantamine as well as administering 21 mg of nicotine transdermally. CONCLUSIONS: Our findings indicate that the mecamylamine challenge model jointly with the nAChR index-a measure of the nicotinic EEG profile-could aid future proof-of-pharmacology studies to demonstrate effects of nicotinic cholinergic compounds. SIGNIFICANCE: This novel measure for quantifying nicotinic cholinergic effects on the EEG could serve as a useful tool in drug development of pro-cognitive compounds.