Language-Independent Acoustic Biomarkers for Quantifying Speech Impairment in Huntington's Disease.

PURPOSE: Changes in voice and speech are characteristic symptoms of Huntington's disease (HD). Objective methods for quantifying speech impairment that can be used across languages could facilitate assessment of disease progression and intervention strategies. The aim of this study was to analyze acoustic features to identify language-independent features that could be used to quantify speech dysfunction in English-, Spanish-, and Polish-speaking participants with HD. METHOD: Ninety participants with HD and 83 control participants performed sustained vowel, syllable repetition, and reading passage tasks recorded with previously validated methods using mobile devices. Language-independent features that differed between HD and controls were identified. Principal component analysis (PCA) and unsupervised clustering were applied to the language-independent features of the HD data set to identify subgroups within the HD data. RESULTS: Forty-six language-independent acoustic features that were significantly different between control participants and participants with HD were identified. Following dimensionality reduction using PCA, four speech clusters were identified in the HD data set. Unified Huntington's Disease Rating Scale (UHDRS) total motor score, total functional capacity, and composite UHDRS were significantly different for pairwise comparisons of subgroups. The percentage of HD participants with higher dysarthria score and disease stage also increased across clusters. CONCLUSION: The results support the application of acoustic features to objectively quantify speech impairment and disease severity in HD in multilanguage studies. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.25447171.

Australian daily cannabis users' use of police avoidance strategies and compensatory behaviours to manage the risks of drug driving.

INTRODUCTION: Daily use of cannabis is increasing in Australia, yet there is limited understanding of the driving behaviours within this cohort, including how they perceive and manage the risks of being apprehended for drug driving and involved in a crash after consumption. METHODS: An online survey was completed by 487 Australians who reported daily cannabis use (30% medically prescribed patients, 58% male). RESULTS: Current drug driving (i.e., driving within 4 h of consuming cannabis each week) was reported by 86% of participants. Future drug driving was anticipated by 92% of the sample. While most participants (93%) disagreed that their risk of crash increased following cannabis use, participants reported that they would drive more carefully (89%), leave greater headway (79%) and/or drive slower (51%) following cannabis consumption. Half of the sample (53%) perceived the risk of apprehension for drug driving to be likely to some extent. Strategies to reduce the likelihood of being detected were used by 25% of participants, and included using Facebook police location sites (16%), driving on back roads (6%) and/or consuming substances to mask the presence of drugs (13%). The regression analysis revealed that individuals who reported more occasions of cannabis use per day, and who perceived that cannabis does not reduce driving ability, reported a greater extent of current drug driving. DISCUSSION AND CONCLUSIONS: Interventions and education which aim to challenge this perception that 'cannabis does not reduce driving ability' may prove important for reducing drug driving among the most frequent consumers of cannabis.

The drink and drug driving behaviours of young Queensland drivers and attitudes toward apprehension.

OBJECTIVE: This study aimed to explore the self-reported drink and drug driving behaviors of a sample of young drivers from Queensland (Australia) holding a learner license (N = 162, 27%), provisional 1 (P1) license (N = 251, 41.8%), or provisional 2 (P2) license (N = 188, 31.3%), as well as motorists' corresponding perceptions about the likelihood of apprehension and their future intentions to offend. METHODS: The study involved 601 drivers aged between 16 and 24 years (302 males, 50.2% and 296 females, 49.3%) who all completed an online survey. RESULTS: Almost half the sample acknowledged engaging in drink and/or drug driving behaviors in the previous 12 months (N = 264, 44%), with a total of 773 drink driving and 8842 drug driving events reported. Offending was more common among P2 drivers (62% reported at least once), and least common among learner drivers (25% reported at least once). When predicting future drink driving and drug driving intentions, lower certainty of apprehension and greater past offending both emerged as significant predictors. CONCLUSIONS: Young drivers may benefit from reminders throughout the GDL process regarding the laws and risks associated with impaired driving. Greater policing resources for drug and alcohol testing may be needed for young drivers, to establish a high certainty of apprehension, as early as possible in their driving experience.

Facebook and drug driving: Does online sharing work against road safety countermeasures?

INTRODUCTION: Enhancements to technology have transformed several aspects of road safety, communication, and connectivity. At the intersection of these, scholars have begun to speculate whether certain aspects of technology may provide motorists ways to engage in illegal and dangerous driving behaviors without consequences. Police traffic operations such as Roadside Drug Testing are intended to occur "anywhere, anytime" to communicate to motorists that they should not risk offending. A potential challenge for road safety is the emergence of Facebook police location pages and groups, where users can share the locations of police operations. METHOD: In this study, the authors examined two Facebook police location groups and three pages from Queensland (Australia) and conducted a content analysis of posts related to Roadside Drug Testing operations and a thematic analysis of comments on these posts. A total of 282 posts related to Roadside Drug Testing were identified between February and April 2021, with 1,823 comments made. RESULTS: The findings suggest that some users: (a) had lived experiences of avoiding punishment for drug driving; (b) remain unaware of how long to wait between drug consumption and driving; (c) perceived Roadside Drug Testing operations to be for the purpose of revenue raising; and (d) changed their driving behavior upon seeing an operation. CONCLUSIONS: These findings suggest consideration is needed regarding the responsibility of both Facebook, and the government, in allowing groups and pages to exist that undermine law enforcement. PRACTICAL APPLICATIONS: Regarding practice, the comments suggest that greater education is needed regarding "safe" times to drive after drug taking.

Does past offending behaviors catch up with you? A study examining the relationship between traffic offending history and fatal crash involvement.

OBJECTIVE: The aim of the current study was to compare the traffic histories of drivers fatally injured in a road traffic crash, to alive drivers of the same age and gender in order to determine if key markers of increased fatality-risk could be identified. METHODS: The case sample comprised 1,139 (82% male) deceased drivers, while the control sample consisted of 1,139 registered Queensland drivers (who were individually matched to the case sample on age and gender). RESULTS: Using a logistic regression model, and adjusting for age and gender, it was found that a greater number of offenses predicted greater odds of fatal crash involvement, with each increase in offense frequency category increasing ones' odds by 1.98 (95% CI: 1.8, 2.18). When each offense type was considered individually, dangerous driving offenses were most influential, predicting a 3.44 (95% CI: 2, 5.93) increased odds of being in the case group, followed by the following offense types: learner/provisional (2.88, 95% CI: 1.75, 4.74), drink and drug driving (2.82, 95% CI: 1.97, 4.04), not wearing a seatbelt/helmet (2.63, 95% CI: 1.53, 4.51), licensing offenses (1.87, 95% CI: 1.41, 2.49), and speeding (1.48, 95% CI: 1.33, 1.66). In contrast, mobile phone and road rules offenses were not identified as significant predictors. CONCLUSION: The findings indicate that engagement in a range of aberrant driving behaviors may result in an increased odds of future fatal crash involvement, which has multiple implications for the sanctioning and management of apprehended offenders.

Sensory integration therapy for children with autism and sensory processing difficulties: the SenITA RCT.

BACKGROUND: Carers report unmet need for occupational therapy services addressing sensory difficulties in autism, yet insufficient evidence exists to recommend a therapeutic approach. OBJECTIVES: Our aim was to determine the clinical effectiveness and cost-effectiveness of sensory integration therapy for children with autism and sensory difficulties across behavioural, functional and quality-of-life outcomes. DESIGN: We carried out a parallel-group randomised controlled trial, incorporating an internal pilot and a process evaluation. Randomisation utilised random permuted blocks. SETTING AND PARTICIPANTS: Children were recruited via services and self-referral in Wales and England. Inclusion criteria were having an autism diagnosis, being in mainstream primary education and having definite/probable sensory processing difficulties. Exclusion criteria were having current/previous sensory integration therapy and current applied behaviour analysis therapy. INTERVENTION: The intervention was manualised sensory integration therapy delivered over 26 weeks and the comparator was usual care. OUTCOMES: The primary outcome was problem behaviours (determined using the Aberrant Behavior Checklist), including irritability/agitation, at 6 months. Secondary outcomes were adaptive behaviour, functioning and socialisation (using the Vineland Adaptive Behavior Scales); carer stress (measured using the Autism Parenting Stress Index); quality of life (measured using the EuroQol-5 Dimensions and Carer Quality of Life); functional change (according to the Canadian Occupational Performance Measure); sensory processing (determined using the Sensory Processing Measure™ at screening and at 6 months to examine mediation effects); and cost-effectiveness (assessed using the Client Service Receipt Inventory). Every effort was made to ensure that outcome assessors were blind to allocation. RESULTS: A total of 138 participants were randomised (n = 69 per group). Usual care was significantly different from the intervention, which was delivered with good fidelity and adherence and minimal contamination, and was associated with no adverse effects. Trial procedures and outcome measures were acceptable. Carers and therapists reported improvement in daily functioning. The primary analysis included 106 participants. There were no significant main effects of the intervention at 6 or 12 months. The adjusted mean difference between groups on the Aberrant Behavior Checklist - irritability at 6 months post randomisation was 0.40 (95% confidence interval -2.33 to 3.14; p = 0.77). Subgroup differences in irritability/agitation at 6 months were observed for sex of child (intervention × female = 6.42, 95% confidence interval 0.00 to 12.85; p = 0.050) and attention deficit hyperactivity disorder (intervention × attention deficit hyperactivity disorder = -6.77, 95% confidence interval -13.55 to -0.01; p = 0.050). There was an effect on carer stress at 6 months by region (intervention × South England = 7.01, 95% confidence interval 0.45 to 13.56; p = 0.04) and other neurodevelopmental/genetic conditions (intervention × neurodevelopmental/genetic condition = -9.53, 95% confidence interval -18.08 to -0.98; p = 0.030). Carer-rated goal performance and satisfaction increased across sessions (p < 0.001), with a mean change of 2.75 (95% confidence interval 2.14 to 3.37) for performance and a mean change of 3.34 (95% confidence interval 2.63 to 4.40) for satisfaction. Health economic evaluation suggests that sensory integration therapy is not cost-effective compared with usual care alone. LIMITATIONS: Limitations included variability of the intervention setting (i.e. NHS vs. private), delay for some receiving therapy, an error in administration of Vineland Adaptive Behavior Scales and no measurement of comparator arm goal performance. CONCLUSIONS: The intervention did not demonstrate clinical benefit above standard care. Subgroup effects are hypothesis-generating only. The intervention is likely to be effective for individualised performance goals, although it is unclear whether effects were in addition to standard care or were maintained. FUTURE WORK: Further investigation of subgroup effects is needed. TRIAL REGISTRATION: This trial is registered as ISRCTN14716440. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 29. See the NIHR Journals Library website for further project information.

Children with autism often experience problems with processing sensory information (e.g. noise, touch, movement, taste and sight), and this can lead to problems in daily life. This study was designed to see if sensory integration therapy can help children with these difficulties. Sensory integration therapy is a type of face-to-face play-based treatment that is delivered by occupational therapists. We compared sensory integration therapy with the type of treatment normally offered to children with autism (i.e. 'usual care'). We recruited children and their carers from Wales and England. Children could take part in the study if they had an autism diagnosis, had sensory processing difficulties and were in mainstream primary education. The children taking part in the study were randomly split into two groups. Sixty-nine children were given sensory integration therapy and 69 children carried on with their usual care. The sensory integration therapy involved 24 face-to-face sessions in an occupational therapy clinic, followed by two telephone calls with the carer. The sensory integration therapy lasted for 26 weeks. We collected information on the type of care being given to children in the usual-care group. Carers of each child were asked questions about their child's behaviour 6 and 12 months after starting the study. Some carers also completed an interview to talk about what it was like taking part in the study. Therapists delivered the sensory integration therapy well. Carers and therapists said that they saw some improvements. However, sensory integration therapy was not significantly better than the usual care and is a more expensive option. We cannot say that sensory integration therapy is helpful for all children with autism and different sensory processing difficulties; however, it might be helpful for some children to focus on specific problems. Future work could focus on which children and problems it would help the most.

Monitoring and Managing Lifestyle Behaviors Using Wearable Activity Trackers: Mixed Methods Study of Views From the Huntington Disease Community.

BACKGROUND: There are early indications that lifestyle behaviors, specifically physical activity and sleep, may be associated with the onset and progression of Huntington disease (HD). Wearable activity trackers offer an exciting opportunity to collect long-term activity data to further investigate the role of lifestyle, physical activity, and sleep in disease modification. Given how wearable devices rely on user acceptance and long-term adoption, it is important to understand users' perspectives on how acceptable any device might be and how users might engage over the longer term. OBJECTIVE: This study aimed to explore the perceptions, motivators, and potential barriers relating to the adoption of wearable activity trackers by people with HD for monitoring and managing their lifestyle and sleep. This information intended to guide the selection of wearable activity trackers for use in a longitudinal observational clinical study. METHODS: We conducted a mixed methods study; this allowed us to draw on the potential strengths of both quantitative and qualitative methods. Opportunistic participant recruitment occurred at 4 Huntington's Disease Association meetings, including 1 international meeting and 3 United Kingdom-based regional meetings. Individuals with HD, their family members, and carers were invited to complete a user acceptance questionnaire and participate in a focus group discussion. The questionnaire consisted of 35 items across 8 domains using a 0 to 4 Likert scale, along with some additional demographic questions. Average questionnaire responses were recorded as positive (score>2.5), negative (score<1.5), or neutral (score between 1.5 and 2.5) opinions for each domain. Differences owing to demographics were explored using the Kruskal-Wallis and Wilcoxon rank sum tests. Focus group discussions (conducted in English) were driven by a topic guide, a vignette scenario, and an item ranking exercise. The discussions were audio recorded and then analyzed using thematic analysis. RESULTS: A total of 105 completed questionnaires were analyzed (47 people with HD and 58 family members or carers). All sections of the questionnaire produced median scores >2.5, indicating a tendency toward positive opinions on wearable activity trackers, such as the devices being advantageous, easy and enjoyable to use, and compatible with lifestyle and users being able to understand the information from trackers and willing to wear them. People with HD reported a more positive attitude toward wearable activity trackers than their family members or caregivers (P=.02). A total of 15 participants participated in 3 focus groups. Device compatibility and accuracy, data security, impact on relationships, and the ability to monitor and self-manage lifestyle behaviors have emerged as important considerations in device use and user preferences. CONCLUSIONS: Although wearable activity trackers were broadly recognized as acceptable for both monitoring and management, various aspects of device design and functionality must be considered to promote acceptance in this clinical cohort.

A study into the nature and extent of drug driving recidivism in Queensland (Australia).

INTRODUCTION: While research has reported on overall prevalence rates of drug driving, the extent of recidivist offending has yet to be explored. The objective of this research was to examine recidivistic behaviors detected through Roadside Drug Testing (RDT) in Queensland (between December 2007 and June 2020), with a focus on: Delta-9-tetrahydrocannabinol (THC), 3,4-Methylenedioxymethylamphetamine (MDMA), and methamphetamine (MA). METHOD: Data were provided by the Queensland Police Service, and contained information on positive drug detections that were confirmed via laboratory analysis. RESULTS: The analyses revealed 50,442 unique offenders with a total of 67,727 offenses, as 25% (N = 12,490) of all offenders had been apprehended more than once (ranging from 2 to 11 offences). MA use was more common among recidivist offenders, whereas THC was more common for those with one offense. On average, the days between offenses decreased with increases in offense number. CONCLUSIONS: The findings provide evidence for the extent of drug driving recidivism on Queensland roads. PRACTICAL APPLICATIONS: To deter recidivists and the greater motorist population from drug driving, there is need for greater resources dedicated to RDT to increase both the perceived and real likelihood of detection.

Versatile, but not focused, traffic offenders are more likely to be at fault for a fatal crash.

INTRODUCTION: The aim of this study was to determine whether drivers who had received more traffic infringements were more likely to be at fault for the crash in which they were killed. METHOD: The current dataset was derived from the crash and traffic history records provided by the Queensland Department of Transport and Main Roads and Coroner's Court for every driver, with available records, who was killed in a crash in Queensland, Australia, between 2011 and 2019 (N = 1,136). The most common traffic offenses in the current sample were speeding, disobeying road rules, driving under the influence of drugs and alcohol, and unlicensed driving. Logistic regression models were used to compute odds ratios for the number of overall offenses, the number of specific offense types, and for specific offending profiles that were derived from the literature. Age, gender, and crash type were each controlled for by entering them into the initial blocks of the regression models. RESULTS: After accounting for the variance associated with age, gender, and crash type, only the overall number of offenses and the number of unlicensed driving offenses predicted a significant change in a drivers' likelihood of being at fault for the crash that killed them. Furthermore, drivers who were identified as having versatile (i.e., multiple offenses from different categories) or criminal-type offense profiles (i.e., offenses that were considered to approximate criminal offenses) were each significantly more likely to be at fault for a fatal crash. PRACTICAL APPLICATIONS: This study provided an important contribution by demonstrating how a more nuanced approach to understanding how a driver's traffic history might be used to identify drivers who are more at risk of being involved in a crash (i.e., for which they were at fault). The implications of these findings are discussed with recommendations and consideration for future research.

It's not a hard and fast rule: A qualitative investigation into factors influencing speeding among young drivers.

INTRODUCTION: Research demonstrates that young drivers exceed the posted speed limit more frequently than older drivers, and this demographic is also subsequently overrepresented in road crash statistics. This behavior remains a worldwide problem despite legal enforcement efforts that have proven to have limited efficiency and/or produce counterintuitive results. METHOD: Consequently, this study undertook a qualitative analysis in order to understand the factors that are perceived to both prevent and promote speeding behavior among young drivers, guided by self-determination theory (SDT). Focus groups were conducted with a total of 60 young drivers aged 17-25 years. An inductive thematic analysis approach was taken to analyze the data. RESULTS: Findings revealed the following factors influence the prevention of speeding: (1) legal consequences were perceived to deter low-level speeding, (2) fear of injury was believed to prevent high-level speeding, and (3) speed awareness monitors were considered to be an effective countermeasure. Meanwhile, factors perceived to contribute to violating speed restrictions included: (1) perceiving it is safe to do so, (2) a perceived norm to speed, (3) emotions, and (4) unintentional speeding. According to SDT, the factors that were perceived to prevent speeding promote externalized self-regulatory processes and are therefore limited by short-term behavior change. PRACTICAL APPLICATIONS: The findings have important implications for designing countermeasures aimed at young drivers, not least illuminating the need to have education and media campaigns that target and build drivers' perceived competence, autonomy, and relatedness in relation to speeding in order to promote longer term compliance.

Translating cell therapies for neurodegenerative diseases: Huntington's disease as a model disorder.

There has been substantial progress in the development of regenerative medicine strategies for CNS disorders over the last decade, with progression to early clinical studies for some conditions. However, there are multiple challenges along the translational pipeline, many of which are common across diseases and pertinent to multiple donor cell types. These include defining the point at which the preclinical data are sufficiently compelling to permit progression to the first clinical studies; scaling-up, characterization, quality control and validation of the cell product; design, validation and approval of the surgical device; and operative procedures for safe and effective delivery of cell product to the brain. Furthermore, clinical trials that incorporate principles of efficient design and disease-specific outcomes are urgently needed (particularly for those undertaken in rare diseases, where relatively small cohorts are an additional limiting factor), and all processes must be adaptable in a dynamic regulatory environment. Here we set out the challenges associated with the clinical translation of cell therapy, using Huntington's disease as a specific example, and suggest potential strategies to address these challenges. Huntington's disease presents a clear unmet need, but, importantly, it is an autosomal dominant condition with a readily available gene test, full genetic penetrance and a wide range of associated animal models, which together mean that it is a powerful condition in which to develop principles and test experimental therapeutics. We propose that solving these challenges in Huntington's disease would provide a road map for many other neurological conditions. This white paper represents a consensus opinion emerging from a series of meetings of the international translational platforms Stem Cells for Huntington's Disease and the European Huntington's Disease Network Advanced Therapies Working Group, established to identify the challenges of cell therapy, share experience, develop guidance and highlight future directions, with the aim to expedite progress towards therapies for clinical benefit in Huntington's disease.

Do they need to be tested to be deterred? Exploring the impact of exposure to roadside drug testing on drug driving.

INTRODUCTION: Maximizing the deterrent effects of Roadside Drug Testing (RDT) operations remains critical for improving road safety. While preliminary research has explored the impact of being tested at RDT sites, there is yet to be an investigation of different types of exposure (e.g., seeing an operation, being tested) and the subsequent relationship(s) with perceptions of certainty of apprehension and future intentions to offend. The overall objective of this research was to explore these relationships with a sample of drug takers. METHOD: A total of 803 Queensland motorists aged between 16 and 75 (M = 27.12, SD = 13.09) completed an online-based survey, and all reported consuming marijuana, MDMA, and/or methamphetamine at least once in the previous 12 months. A convenience sampling method was utilized (via Facebook). RESULTS: The drug driving proportion of the sample (58%) reported a total of 30,858 instances of drug driving, or 66 instances on average. Seeing RDT in the previous 12 months (26% of sample) was more common than being tested at RDT (7%). The results indicated that seeing RDT two or more times was related to increased certainty of apprehension (compared to those who had seen it only once or never), although the increase was relatively small. Correlational analyses suggest there were some positive (albeit weak relationships) between exposure to RDT (seen and tested) and past and future offending. However, only three significant predictors of future offending emerged: older age, lower perceptions of apprehension certainty, and greater use of marijuana. Practical Applications: The results illuminate the extent of the drug driving problem and the need for greater resourcing to increase the real threat of detection. While the effect of exposure to enforcement was small, it was positive, incremental and supportive of increased roadside police enforcement as well as further research to quantify such deterrent processes.

Deep learning fusion of satellite and social information to estimate human migratory flows.

Human migratory decisions are driven by a wide range of factors, including economic and environmental conditions, conflict, and evolving social dynamics. These factors are reflected in disparate data sources, including household surveys, satellite imagery, and even news and social media. Here, we present a deep learning-based data fusion technique integrating satellite and census data to estimate migratory flows from Mexico to the United States. We leverage a three-stage approach, in which we (1) construct a matrix-based representation of socioeconomic information for each municipality in Mexico, (2) implement a convolutional neural network with both satellite imagery and the constructed socioeconomic matrix, and (3) use the output vectors of information to estimate migratory flows. We find that this approach outperforms alternatives by approximately 10% (r 2), suggesting multi-modal data fusion provides a valuable pathway forward for modeling migratory processes.

Comparative judgements of crash risk and driving ability for speeding behaviours.

INTRODUCTION: Preliminary research has indicated that numerous drivers perceive their risk of traffic crash to be less than other drivers, while perceiving their driving ability to be better. This phenomenon is referred to as 'comparative optimism' (CO) and may prove to inhibit the safe adoption of driving behaviors and/or dilute perceptions of negative outcomes. The objective of this study was to investigate comparative judgments regarding crash risk and driving ability, and how these judgments relate to self-reported speeding. METHOD: There were 760 Queensland motorists comprised of 51.6% males and 48.2% females, aged 16-85 (M = 39.60). Participants completed either a paper or online version of a survey. Judgments of crash risk and driving ability were compared to two referents: the average same-age, same-sex driver, and the average same-age, same-sex V8 supercar champion. RESULTS: Drivers displayed greater optimism when comparing their crash risk and driving ability to the average same-age, same- sex driver (respectively, 72%, 72.4%), than when comparing to a V8 supercar champion (respectively, 60%, 32.9%). When comparing judgements of crash risk and driving ability to a similar driver, it appears that participants in the present study are just about as optimistic about their risk of crash (i.e. 72%) as they are optimistic about their driving ability (i.e. 74.2%).

A unified deterrence-based model of legal and non-legal factors that influence young driver speeding behaviour.

Young driver speeding behaviour remains a large contributor to road trauma worldwide. In order to provide a more-in depth understanding of how to deter young drivers from this behaviour, this study developed and tested a model of the legal and non-legal factors that influence young driver's intentional speeding behaviour (exceeding the speed limit by more than 10 km/hr). A prospective survey design was conducted to measure the impact of perceptions of legal factors (including classical deterrence and reconceptualised deterrence variables) and non-legal factors (including the variables of fear of physical loss, material loss and perceived social sanctions, as well as the perception that it is safe to engage in the behaviour without being involved in a crash) at time 1, on engagement in speeding behaviour at time 2, which occurred 3 months later. A total of 200 participants aged 17-25 years completed both surveys (Mean age = 20.44 years). Using structural equation modelling, a unique model combining classical and extended deterrence theory, as well as prominent non-legal factors was created, and the variables were able to explain 41% of the variance in speeding behaviour. A high perceived severity of the punishment, experiencing direct punishment avoidance and perceiving that it is safe to speed were significant direct predictors. Meanwhile, there were also numerous significant partially mediated relationships found for both legal and non-legal variables. These findings provide important implications for both the application of deterrence-based theories in road safety and for improving countermeasures to deter young drivers more effectively from engagement in speeding.

The who, what and when of drug driving in Queensland: Analysing the results of roadside drug testing, 2015-2020.

Roadside Drug Testing (RDT) is the primary strategy utilised in Australia to detect and deter drug driving. RDT operations have been expanding and evolving in Queensland since their introduction in 2007, with the number of tests increasing by 5.63 times between 2009 and 2019. The objective of this paper was to explore trends and characteristics of the 60,551 positive results detected in Queensland's RDT program (from January 2015 to June 2020), which focuses on the detection of Delta-9-tetrahydrocannabinol (THC), Methylenedioxymethylamphetamine (MDMA) and methamphetamine (MA). The analysis indicated that (over the entire testing period) MA was the most common drug detected in isolation (39.4%), followed by THC (34%) and the combination of MA and THC (21.9%). When considering detections with two or more drugs, MA was present in 64% of detections, THC in 59% and MDMA in 1.8%. THC was most commonly detected among younger drivers (e.g., aged 16 to 24), while MA was most commonly detected with drivers aged 25 and 59 years. Analysis of sociodemographic and contextual factors revealed that positive roadside tests were most commonly associated with males who had consumed methamphetamines, aged between 30 and 39 who were driving a car on a Friday or Saturday between 2:00 pm and 6:00 pm. The findings provide some indication as to the extent of drug driving within Queensland (and growing use of MA) and have clear implications for enforcement activities, not least, directing sufficient resources to address the burgeoning problem.

Protocol for an open label: phase I trial within a cohort of foetal cell transplants in people with Huntington's disease.

Huntington's disease is a progressive neurodegenerative disorder characterized by motor, cognitive and psychiatric symptoms. Currently, no disease-modifying therapies are available to slow or halt disease progression. Huntington's disease is characterized by relatively focal and specific loss of striatal medium spiny neurons, which makes it suitable for cell-replacement therapy, a process involving the transplantation of donor cells to replace those lost due to disease. TRIal DEsigns for delivery of Novel Therapies in neurodegeneration is a phase I Trial Within a Cohort designed to assess safety and feasibility of transplanting human foetal striatal cells into the striatum of people with Huntington's disease. A minimum of 18 participants will be enrolled in the study cohort, and up to five eligible participants will be randomly selected to undergo transplantation of 12-22 million foetal cells in a dose escalation paradigm. Independent reviewers will assess safety outcomes (lack of significant infection, bleeding or new neurological deficit) 4 weeks after surgery, and ongoing safety will be established before conducting each subsequent surgery. All participants will undergo detailed clinical and functional assessment at baseline (6 and 12 months). Surgery will be performed 1 month after baseline, and transplant participants will undergo regular clinical follow-up for at least 12 months. Evaluation of trial processes will also be undertaken. Transplant participants and their carers will be interviewed ∼1 month before and after surgery. Interviews will also be conducted with non-transplanted participants and healthcare staff delivering the intervention and involved in the clinical care of participants. Evaluation of clinical and functional efficacy outcomes and intervention costs will be carried out to explore plausible trial designs for subsequent randomized controlled trials aimed at evaluating efficacy and cost-effectiveness of cell-replacement therapy. TRIal DEsigns for delivery of Novel Therapies in neurodegeneration will enable the assessment of the safety, feasibility, acceptability and cost of foetal cell transplants in people with Huntington's disease. The data collected will inform trial designs for complex intra-cranial interventions in a range of neurodegenerative conditions and facilitate the development of stable surgical pipelines for delivery of future stem cell trials. Trial Registration: ISRCTN52651778.

Drug-free Holidays: Compliance, Tolerability, and Acceptability of a 3-Day Atovaquone/Proguanil Schedule for Pretravel Malaria Chemoprophylaxis in Australian Travelers.

BACKGROUND: Poor compliance with chemoprophylaxis is a major contributing factor to the risk of malaria in travelers. Pre-travel chemoprophylaxis may improve compliance by enabling "drug-free holidays." The standard treatment dose of atovaquone/proguanil (250 mg/100 mg, 4 tablets/day for 3 days) provides protection against malaria for at least 4 weeks, and could therefore potentially be used for pre-travel chemoprophylaxis. In this study, we assessed the compliance, tolerability, and acceptability of the 3-day atovaquone/proguanil schedule for malarial chemoprophylaxis. METHODS: Two hundred thirty-three participants were recruited from 4 specialized travel medicine clinics in Australia. Adults traveling to malaria-endemic areas with low/medium risk for ≤4 weeks were enrolled and prescribed the 3-day schedule of atovaquone/proguanil, completed at least 1 day before departure. Questionnaires were used to collect data on demographics, travel destination, medication compliance, side effects, and reasons for choosing the 3-day schedule. RESULTS: Overall, 97.7% of participants complied with the 3-day schedule. Although side effects were reported in 43.3% of the participants, these were well tolerated, and mainly occurred during the first and second days. None of the participants developed malaria. The main reasons for choosing the 3-day schedule over standard chemoprophylaxis options were that it was easier to remember (72.1%), required taking fewer tablets (54.0%), and to help scientific research (54.0%). CONCLUSIONS: The 3-day atovaquone/proguanil schedule had an impressively high compliance rate, and was well tolerated and accepted by travelers. Further studies are required to assess the effectiveness of this schedule for chemoprophylaxis in travelers. CLINICAL TRIALS REGISTRATION: ACTRN12616000640404.

Lack of Cell Proliferative and Tumorigenic Effects of 4-Hydroxyestradiol in the Anterior Pituitary of Rats: Role of Ultrarapid O-Methylation Catalyzed by Pituitary Membrane-Bound Catechol-O-Methyltransferase.

In animal models, estrogens are complete carcinogens in certain target sites. 4-Hydroxyestradiol (4-OH-E2), an endogenous metabolite of 17ß-estradiol (E2), is known to have prominent estrogenic activity plus potential genotoxicity and mutagenicity. We report here our finding that 4-OH-E2 does not induce pituitary tumors in ACI female rats, whereas E2 produces 100% pituitary tumor incidence. To probe the mechanism, we conducted a short-term animal experiment to compare the proliferative effect of 4-OH-E2 in several organs. We found that, whereas 4-OH-E2 had little ability to stimulate pituitary cell proliferation in ovariectomized female rats, it strongly stimulates cell proliferation in certain brain regions of these animals. Further, when we used in vitro cultured rat pituitary tumor cells as models, we found that 4-OH-E2 has similar efficacy as E2 in stimulating cell proliferation, but its potency is approximately 3 orders of magnitude lower than that of E2. Moreover, we found that the pituitary tumor cells have the ability to selectively metabolize 4-OH-E2 (but not E2) with ultrahigh efficiency. Additional analysis revealed that the rat pituitary expresses a membrane-bound catechol-O-methyltransferase that has an ultralow Km value (in nM range) for catechol estrogens. On the basis of these observations, it is concluded that rapid metabolic disposition of 4-OH-E2 through enzymatic O-methylation in rat anterior pituitary cells largely contributes to its apparent lack of cell proliferative and tumorigenic effects in this target site.

Naturally-occurring estradiol-17beta-fatty acid esters, but not estradiol-17beta, preferentially induce mammary tumorigenesis in female rats: implications for an important role in human breast cancer.

Because mammary glands are surrounded by adipose tissues, we hypothesize that the ultra-lipophilic endogenous estrogen-17beta-fatty acid esters may have preferential hormonal and carcinogenic effects in mammary tissues compared to other target organs (such as the uterus and pituitary). This hypothesis is tested in the present study. We found that all 46 rats implanted with an estradiol-17beta pellet developed large pituitary tumors (average weight=251+/-103 mg) and had to be terminated early, but only 48% of them developed mammary tumors. In addition, approximately one-fourth of them developed a huge uterus. In the 26 animals implanted with a mixture containing estradiol-17beta-stearate and estradiol-17beta-palmitate (two representative estradiol-17beta-fatty acid esters) or in the 29 animals implanted with estradiol-17beta-stearate alone (in the same molar dose as estradiol-17beta), 73% and 79%, respectively, of them developed mammary tumors, whereas only 3 or 2 animals, respectively, had to be terminated early due to the presence of a large pituitary tumor. Both tumorous and normal mammary tissues contained much higher levels of estrogen esterase than other tissues, which catalyzes the releases of bioactive estrogens from their fatty acid esters. In conclusion, while estradiol-17beta is much stronger in inducing pituitary tumor (100% incidence) than mammary tumor, estradiol-17beta-fatty acid esters have a higher efficacy than estradiol-17beta in inducing mammary tumor and yet it only has little ability to induce uterine out-growth and pituitary tumorigenesis. This study establishes the endogenous estrogen-17beta-fatty acid esters as preferential inducers of mammary tumorigenesis.