A Mediterranean Diet and Walking Intervention to Reduce Cognitive Decline and Dementia Risk in Independently Living Older Australians: The MedWalk Randomized Controlled Trial Experimental Protocol, Including COVID-19 Related Modifications and Baseline Characteristics.

BACKGROUND: Several clinical trials have examined diet and physical activity lifestyle changes as mitigation strategies for risk factors linked to cognitive decline and dementias such as Alzheimer's disease. However, the ability to modify these behaviors longer term, to impact cognitive health has remained elusive. OBJECTIVE: The MedWalk trial's primary aim is to investigate whether longer-term adherence to a Mediterranean-style diet and regular walking, delivered through motivational interviewing and cognitive-behavioral therapy (MI-CBT), can reduce age-associated cognitive decline and other dementia risk factors in older, independently living individuals without cognitive impairment. METHODS: MedWalk, a one-year cluster-randomized controlled trial across two Australian states, recruited 60-90-year-old people from independent living retirement villages and the wider community. Participants were assigned to either the MedWalk intervention or a control group (maintaining their usual diet and physical activity). The primary outcome is 12-month change in visual memory and learning assessed from errors on the Paired Associates Learning Task of the Cambridge Neuropsychological Test Automated Battery. Secondary outcomes include cognition, mood, cardiovascular function, biomarkers related to nutrient status and cognitive decline, MI-CBT effectiveness, Mediterranean diet adherence, physical activity, quality of life, cost-effectiveness, and health economic evaluation.Progress and Discussion:Although COVID-19 impacts over two years necessitated a reduced timeline and sample size, MedWalk retains sufficient power to address its aims and hypotheses. Baseline testing has been completed with 157 participants, who will be followed over 12 months. If successful, MedWalk will inform interventions that could substantially reduce dementia incidence and ameliorate cognitive decline in the community. TRIAL REGISTRATION: Registered on the Australia New Zealand Clinical Trials Registry ANZCTR 12620000978965 (https://www.anzctr.org.au).

Liver and inflammatory biomarker relationships to depression symptoms in healthy older adults.

INTRODUCTION: Early identification and management of physical and mental illness is vital to maintain quality of life as we age. Markers of peripheral inflammation and liver function show elevations with aging, and are also associated with depression symptoms, suggesting a similar pattern in both aging and clinical groups. METHODS: The current study examined the relationship between such markers and measures of depression/negative mood in 284 healthy older adults using data from the Australian Research Council Longevity Intervention (ARCLI). Baseline data in adults aged 60-75 included mood symptoms via Profile of Mood States and Beck Depression Inventory II, and peripheral inflammatory (TNF-α, IL-6, hs-CRP) and liver markers (GGT, ALT, AST, AST:ALT ratio) derived from blood samples. RESULTS: The inflammation and liver enzyme relationship significantly predicted mood symptoms scores. Results showed that a significant relationship between C-reactive protein (CRP) and negative mood scores on Total Mood Disturbance and four of the six subscales (all p < .01) was dependent upon higher levels of gamma-glutamyl transferase (GGT). DISCUSSION: Higher levels of normal-range liver metabolic and peripheral inflammatory markers are observed with negative mood in a healthy older sample experiencing the biological impact of aging, but in the absence of clinical depression symptoms, suggesting a possible role of oxidative stress or other biological mechanisms occurring with aging in depression etiology. Lifestyle interventions are discussed.

A Placebo-Controlled Randomized Trial of Vigabatrin in the Management of Acute Alcohol Withdrawal.

OBJECTIVE: To undertake a double blinded randomised placebo-controlled trial to assess the efficacy of vigabatrin, a GABA-transaminase inhibitor, as a benzodiazepine sparing agent in the management of acute alcohol withdrawal syndrome in a residential setting. METHODS: We enrolled 120 patients with alcohol use disorder who were randomly assigned to either treatment with vigabatrin (2g/day for 4 days) or placebo. The primary outcome was defined as the number of participants in each treatment arm needing diazepam for withdrawal management. A secondary outcome prespecified was the total dose of diazepam received by participants in each treatment arm. Participants were recruited on admission to a residential withdrawal unit at St Vincent's Hospital Melbourne from December 2014 to April 2019. RESULTS: No significant difference was observed in the number of participants requiring benzodiazepines during their residential withdrawal stay with 44 participants (78.6%) in placebo arm requiring at least one dose of diazepam compared to 38 (66.7%) in vigabatrin arm (p = .156). An 18.1% difference was observed between the proportion of participants who received a total dose of >100mg of diazepam during their residential withdrawal stay in placebo arm (32.1%), compared to vigabatrin arm (14.0%, p = .022). There were higher rates of reported adverse events in placebo arm with nine (15.0%) participants reporting adverse events compared with two (3.3%) participants in vigabatrin arm (p = .027). CONCLUSION: Vigabatrin significantly reduced the number of participants requiring >100mg diazepam over the course of their alcohol withdrawal and was associated with a reduction in adverse effects when compared to placebo.

Investigating the Effects of a Multinutrient Supplement on Cognition, Mood and Biochemical Markers in Middle-Aged Adults with 'Optimal' and 'Sub-Optimal' Diets: A Randomized Double Blind Placebo Controlled Trial.

Background: Previous randomized controlled trials examining cognitive and mood effects of combination multivitamin supplements in healthy, non-clinical adults have reported mixed results. One purported explanation for this is that the dietary status of participants at the start of supplement interventions may influence the magnitude of the effect of supplementation. Methods: In this study, we evaluated the effect of a multinutrient formula containing B group vitamins, Bacopa monniera and Ginkgo biloba on memory, attention, mood and biochemical markers of nutrient status in middle-aged adults (M = 52.84 years, n = 141) with 'optimal' and 'sub-optimal' diets over 12 weeks. We hypothesised that active supplementation would differentially improve memory and attention in those with a 'sub-optimal' diet. Results: Mixed model, repeated measures analysis revealed that, in comparison to placebo, active treatment was associated with significant increases in B vitamin status (B1, B6, B12). Regarding behavioural outcomes there was no significant benefit to memory (F(1, 113.51) = 0.53, p = 0.470) nor attention (F(1,113.77) = 1.89, p = 0.171) in the whole cohort. Contrary to our hypothesis, there was a significant beneficial effect of supplementation on attentional performance in individuals with an 'optimal' diet prior to supplementation (F(1,57.25) = 4.94, p = 0.030). In the absence of a main effect of supplementation across the entire cohort, there were also a number of significant three-way interactions (treatment by time by diet group) detected in secondary outcomes including lower state anxiety and mental fatigue in those with an 'optimal' diet. Conclusion: These findings suggest that the cognitive benefit of B vitamin and herbal supplementation may be dependent on diet quality, supporting the concepts of 'co-nutrient optimisation' and interdependency of nutrients. This warrants further investigation. This study advocates characterising the diet of participants prior to supplementation as it may influence the effect of a nutraceutical intervention.

Factors associated with patient experiences of the burden of using medicines and health-related quality of life: A cross-sectional study.

OBJECTIVE: Polypharmacy, defined as the concurrent use of multiple medications, is a growing concern globally. This study aimed to identify the significant factors that predict the perceived burden of medication and health-related quality of life. METHODS: Adults, aged 18 years and above who have used at least two regular medicines, were invited to complete the study questionnaires between June and October 2019. Multiple linear regression analysis was conducted to identify significant predictors for perceived burden of medication and health-related quality of life. RESULTS: A total of 119 participants completed this study. The average age of the participants was 63 years (SD±16 years). Factors significantly predicting perceived burden of medication were participants' current health condition (p = 0.001), overall burden of treatment (p<0.001) and being hypertensive (p = 0.037). Similarly, participants' current health condition (p<0.001) and overall burden of treatment (p = 0.086) were significant predictors for perceived health-related quality of life. CONCLUSIONS: This study revealed that hypertensive participants in poor health tended to experience higher perceived burden of medication, which in turn was found to be correlated with lower perceived health-related quality of life.

The effects of alcohol intoxication on cognitive functions critical for driving: A systematic review.

Alcohol is the most frequently detected substance in drivers involved in road traffic collisions. Given that up to 35% of fatal road collisions are alcohol-related, it is important to determine the influence of alcohol intoxication on driving-related skills. This review provides an updated and systematic evaluation of the available research concerning the effect of alcohol intoxication on cognitive functions critical for driving. Databases EBSCOhost, PsycInfo, PubMed, Scopus, Transport Research International Documentation (TRID) and Web of Science were searched for controlled trials examining the effect of alcohol on divided attention, executive functioning, perception, psychomotor skills, reaction time and/or vigilance. Fourteen studies met the inclusion criteria and were included in this review. We found that each of the cognitive domains assessed in this review showed impairment at blood alcohol concentrations equal to or below the legal driving limit in many jurisdictions. Future research could determine the effects of alcohol on cognitive functioning with greater accuracy by employing more consistent, reliable and comparable measures while considering the translation of deficits to real-life driving.

Kava for generalised anxiety disorder: A 16-week double-blind, randomised, placebo-controlled study.

OBJECTIVE: Previous randomised, double-blind, placebo-controlled studies have shown that Kava (a South Pacific medicinal plant) reduced anxiety during short-term administration. The objective of this randomised, double-blind, placebo-controlled study was to perform a larger, longer-term trial assessing the efficacy and safety of Kava in the treatment of generalised anxiety disorder and to determine whether gamma-aminobutyric acid transporter (SLC6A1) single-nucleotide polymorphisms were moderators of response. METHODS: The trial was a phase III, multi-site, two-arm, 16-week, randomised, double-blind, placebo-controlled study investigating an aqueous extract of dried Kava root administered twice per day in tablet form (standardised to 120 mg of kavalactones twice/day) in 171 currently non-medicated anxious participants with diagnosed generalised anxiety disorder. The trial took place in Australia. RESULTS: An analysis of 171 participants revealed a non-significant difference in anxiety reduction between the Kava and placebo groups (a relative reduction favouring placebo of 1.37 points; p = 0.25). At the conclusion of the controlled phase, 17.4% of the Kava group were classified as remitted (Hamilton Anxiety Rating Scale score < 7) compared to 23.8% of the placebo group (p = 0.46). No SLC6A1 polymorphisms were associated with treatment response, while carriers of the rs2601126 T allele preferentially respond to placebo (p = 0.006). Kava was well tolerated aside from poorer memory (Kava = 36 vs placebo = 23; p = 0.044) and tremor/shakiness (Kava = 36 vs placebo = 23; p = 0.024) occurring more frequently in the Kava group. Liver function test abnormalities were significantly more frequent in the Kava group, although no participant met criteria for herb-induced hepatic injury. CONCLUSION: While research has generally supported Kava in non-clinical populations (potentially for more 'situational' anxiety as a short-term anxiolytic), this particular extract was not effective for diagnosed generalised anxiety disorder.

When should the driver with a history of substance misuse be allowed to return to the wheel? A review of the substance misuse section of the Australian national guidelines.

Assessing fitness to drive in applicants with a historical or current substance use disorder presents a specific clinical challenge. The Australian guidelines require evidence of remission and absence of cognitive change when considering applications for re-licensing driver or individuals applying to reengage in safety-sensitive work. This paper reviews some of the clinical and biochemical indicators that determine whether a particular person is in 'remission' and meets the criteria for return to driving or other safety-sensitive occupation. It provides an overview of the challenges in establishing an evidence-based approach to determining fitness for safety critical activities. There is no internationally accepted definition of 'remission'. Review of the literature and examination of assessment protocols from other national jurisdictions are available for alcohol and the more important drugs of interest in road safety. Assessing fitness to drive when there is a history of substance misuse and/or substance use disorders is a complex issue that requires assessment of biomarkers, clinical findings and clinical assessment before the person returns to driving. We propose that hair testing provides a reliable and reproducible way to demonstrate remission and provide cost-effective monitoring. Standardised psychological tests could provide a reproducible assessment of the cognitive effects of drug use and suitability to resume driving. We recommend that AustRoads amend the national guidelines to reflect an evidence-based approach to assessing fitness to drive after conviction for offences related to alcohol and drug use.

Managing attention deficit hyperactivity disorder in adults using illicit psychostimulants: A systematic review.

CONTEXT: Attention deficit hyperactivity disorder and stimulant use disorder commonly co-exist, and appropriate treatments have not been well established. OBJECTIVE: To provide guidance for treatment of co-existing attention deficit hyperactivity disorder and stimulant use disorder. DATA SOURCES: A systematic review of published English articles using MEDLINE, EMBASE, CINAHL, PsycINFO and Cochrane, utilising consistent search terms. STUDY SELECTION: Randomised controlled trials, comparing any treatment arm with a control group, for participants meeting Diagnostic and Statistical Manual of Mental Disorders or equivalent criteria for both attention deficit hyperactivity disorder and stimulant use disorder. RESULTS: Eight trials were identified for inclusion in this review. Four of eight studies showed improvement in attention deficit hyperactivity disorder outcome measures compared with placebo. Two of six studies that reported substance use outcomes showed improvement in treatment arms compared with placebo. Studies to show effect tended to be those with the highest treatment dosage. CONCLUSION: Evidence for the efficacy of treatment of patients with comorbid stimulant use disorder and attention deficit hyperactivity disorder is limited. Promising outcomes need replication in further studies utilising higher treatment dosage.

Development of a Suicidal Ideation Detection Tool for Primary Healthcare Settings: Using Open Access Online Psychosocial Data.

BACKGROUND: Suicidal patients often visit healthcare professionals in their last month before suicide, but medical practitioners are unlikely to raise the issue of suicide with patients because of time constraints and uncertainty regarding an appropriate approach. INTRODUCTION: A brief tool called the e-PASS Suicidal Ideation Detector (eSID) was developed for medical practitioners to help detect the presence of suicidal ideation (SI) in their clients. If SI is detected, the system alerts medical practitioners to address this issue with a client. The eSID tool was developed due to the absence of an easy-to-use, evidence-based SI detection tool for general practice. MATERIAL AND METHODS: The tool was developed using binary logistic regression analyses of data provided by clients accessing an online psychological assessment function. Ten primary healthcare professionals provided advice regarding the use of the tool. RESULTS: The analysis identified eleven factors in addition to the Kessler-6 for inclusion in the model used to predict the probability of recent SI. The model performed well across gender and age groups 18-64 (AUR 0.834, 95% CI 0.828-0.841, N = 16,703). Healthcare professionals were interviewed; they recommended that the tool be incorporated into existing medical software systems and that additional resources be supplied, tailored to the level of risk identified. CONCLUSION: The eSID is expected to trigger risk assessments by healthcare professionals when this is necessary. Initial reactions of healthcare professionals to the tool were favorable, but further testing and in situ development are required.

The effects of cannabis and alcohol on simulated driving: Influences of dose and experience.

BACKGROUND: Cannabis and alcohol are the most popular drugs amongst recreational users, and most prevalent in injured and deceased drivers. Clarification of the interactive effects of these drugs upon driving behaviour is critical for reducing drug-related road deaths. OBJECTIVES: The current study had two objectives, to examine the effects of cannabis and alcohol on driving performance, and identify if any differences between the effects of cannabis and alcohol on driving performance exist between regular cannabis users and non-regular cannabis users. METHODS: The project involved 80 participants (49 male, 31 female) who were abstinent recreational users of alcohol and marijuana. They participated in six experimental sessions that involved the consumption of cannabis cigarettes containing no THC, 1.8% THC or 3% THC together with the consumption of alcohol to obtain either 0% BAC, 0.03% BAC or 0.05% BAC. The six sessions were double-blind, counter-balanced, placebo-controlled and medically supervised. Forty participants were allocated to the cannabis with low alcohol (0.03% BAC) group, and 40 participants were allocated to the cannabis with high alcohol (0.05% BAC) group. Driving simulator performance was assessed at 20min post-drug administration and blood samples were taken before and after driving. RESULTS: Driving simulator performance was more impaired in the THC and alcohol combined conditions. Consistent with past research, the level of THC detected in blood is higher when THC is consumed with alcohol, than when cannabis is consumed alone, and regular cannabis users returned higher levels of THC in plasma than non-regular users. Generally, regular cannabis users displayed more driving errors than non-regular cannabis users.

Detecting impairment associated with cannabis with and without alcohol on the Standardized Field Sobriety Tests.

RATIONALE: Cannabis and alcohol are the most popular drugs amongst recreational users and most prevalent in injured and deceased drivers. The Standardized Field Sobriety Tests (SFST) are commonly used to establish impairment due to drugs and alcohol, but limited empirical evidence exists concerning the combined effects of these drugs on SFST performance. METHODS: The sample comprised 80 individuals (31 females; 49 males). Age ranged between 21 and 35 years (M = 26.5, SD = 5). Forty participants (15 females; 25 males) took part in the low alcohol condition (BAC, <0.05 %), and 40 participants (16 females; 24 males), took part in the high alcohol condition (BAC, >0.05 %). For each part of the study, two levels of ∆9-tetrahydrocannabinol (THC) were administered (1.8 and 3 % THC) or a matching placebo cigarette (0 % THC) in combination with alcohol. Performance on the SFST was assessed 30 min post-dosing. RESULTS: A number of significant differences in SFST performance were identified with 28 % of the sample failing the test (when the head movement and jerks sign was included) when low alcohol and low THC were administered together. When a higher dose of alcohol was administered with a low dose of THC, 38 % of the sample failed the test, and 35 % also failed when the high dose of alcohol was combined with a higher dose of THC. CONCLUSIONS: The current results highlight the limited ability of the SFST to identify drug consumption in the absence of any evidence of driving impairment or physiological indicators.

Examining the effect of dl-3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine on the Standardized Field Sobriety Tests.

dl-3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine are commonly used illicit drugs that are thought to impair driving ability. The Standardized Field Sobriety Tests (SFSTs) are utilized widely to detect impairment associated with drugs other than alcohol in drivers, although limited evidence concerning MDMA and methamphetamine consumption on SFST performance exists. The aim of this study was to evaluate whether the SFSTs were a sensitive measure for identifying the presence of the specific isomer d-methamphetamine and MDMA. In a double-blind, within-subject, counter-balanced and placebo-controlled study, 58 healthy and abstinent recreational drugs users were administered three treatments: 100mg of MDMA, 0.42 mg/kg d-methamphetamine, and placebo. For each condition the SFSTs were administered at 4 and 25 h post treatment. d-methamphetamine was not found to significantly impair SFST performance unlike MDMA, which significantly impaired SFST performance in comparison to placebo with 22% of the sample failing the test at the 4h testing time-point. No differences were observed at the 25 h testing time-point for any of the conditions. It was concluded that the SFSTs are not efficient in identifying the presence of low level d-methamphetamine, and are significantly better at detecting the presence of MDMA at the levels assessed.

The acute effects of 3,4-methylenedioxymethamphetamine and methamphetamine on driving: a simulator study.

OBJECTIVES: Illicit drugs such as MDMA and methamphetamine are commonly abused drugs that have also been observed to be prevalent in drivers injured in road accidents. Their exact effect on driving and driving behavior has yet to be thoroughly investigated. METHODS: Sixty-one abstinent recreational users of illicit drugs comprised the participant sample, with 33 females and 28 males, mean age 25.45 years. The three testing sessions involved oral consumption of 100 mg MDMA, 0.42 mg/kg methamphetamine, or a matching placebo. The drug administration was counter-balanced, double-blind, and medically supervised. At each session driving performance was assessed 3 h and 24 h post drug administration on a computerized driving simulator. RESULTS: At peak concentration overall impairment scores for driving (F(2,118)=9.042, p<0.001) and signaling (F(2,118)=4.060, p=0.020) were significantly different for the daytime simulations. Performance in the MDMA condition was worse than both the methamphetamine (p=0.023) and placebo (p<0.001) conditions and the methamphetamine condition was also observed to be worse in comparison to the placebo (p=0.055). For signaling adherence, poorer signaling adherence occurred in both the methamphetamine (p=0.006) and MDMA (p=0.017) conditions in comparison to placebo in the daytime simulations. CONCLUSIONS: The findings of this study have for the first time illustrated how both MDMA and methamphetamine effect driving performance, and provide support for legislation regarding testing for the presence of illicit drugs in impaired or injured drivers as deterrents for driving under the influence of illicit drugs.

The acute effects of 3,4-methylenedioxymethamphetamine and d-methamphetamine on human cognitive functioning.

RATIONALE: This study investigated the acute (3-h) and 24-h post-dose cognitive effects of oral 3,4-methylenedioxymethamphetamine (MDMA), d-methamphetamine, and placebo in a within-subject double-blind laboratory-based study in order to compare the effect of these two commonly used illicit drugs on a large number of recreational drug users. METHODS: Sixty-one abstinent recreational users of illicit drugs comprised the participant sample, with 33 females and 28 males, mean age 25.45 years. The three testing sessions involved oral consumption of 100 mg MDMA, 0.42 mg/kg d-methamphetamine, or a matching placebo. The drug administration was counter-balanced, double-blind, and medically supervised. Cognitive performance was assessed during drug peak (3 h) and at 24 h post-dosing time-points. Blood samples were also taken to quantify the levels of drug present at the cognitive testing time-points. RESULTS: Blood concentrations of both methamphetamine and MDMA at drug peak samples were consistent with levels observed in previous studies. The major findings concern poorer performance in the MDMA condition at peak concentration for the trail-making measures and an index of working memory (trend level), and more accurate performance on a choice reaction task within the methamphetamine condition. Most of the differences in performance between the MDMA, methamphetamine, and placebo treatments diminished by the 24-h testing time-point, although some performance improvements subsisted for choice reaction time for the methamphetamine condition. CONCLUSIONS: Further research into the acute effects of amphetamine preparations is necessary to further quantify the acute disruption of aspects of human functioning crucial to complex activities such as attention, selective memory, and psychomotor performance.