Comparing objective wakefulness and vigilance tests to on-the-road driving performance in narcolepsy and idiopathic hypersomnia.

Patients with narcolepsy or idiopathic hypersomnia (IH) are at increased risk of driving accidents. Both excessive daytime sleepiness, i.e. unwanted sleep episodes during the day, and disturbed vigilance are core features of these disorders. We tested on-the-road driving performance of patients with narcolepsy or IH coming in for a routine driving fitness evaluation and examined: (1) correlations between driving performance and the Maintenance of Wakefulness Test (MWT), Sustained Attention to Response Task (SART) and Psychomotor Vigilance Test (PVT) as objective tests; (2) the predictive power of the MWT and SART for increased risk of impaired driving; (3) the best set of objective predictors for increased risk of impaired driving. Participants were 44 patients (aged 18-75 years) with narcolepsy type 1 (NT1), type 2 (NT2) or IH. They completed the MWT, SART, PVT, a subjective sleepiness questionnaire, and a standardised on-the-road driving test. The standard deviation of the lateral position (SDLP) was used as outcome measure of driving performance. The MWT had low correlation with the SDLP (ρ = -0.41 to -0.49, p < 0.01). The SART and PVT had low correlations with SDLP (ρ = 0.30 and ρ = 0.39, respectively, both p < 0.05). The predictive power of MWT for an increased risk of impaired driving was significant, but low (area under the curve = 0.273, p = 0.012), and non-significant for SART. We conclude that in our present group, none of the tests had adequate ability to predict impaired driving, questioning their use for clinical driving fitness evaluation in narcolepsy and IH. Real-time monitoring of sleepiness while driving seems more promising in these patients.

Associations between psychoactive substance use and sensation seeking behavior among drivers in Norway.

BACKGROUND/AIM: Drug use and risky driving is associated with sensation seeking. The aim of this study was to investigate the association between use of psychoactive substances and levels of the sensation seeking personality trait as measured with the Brief Sensation Seeking Scale 4 among drivers in Norway. METHOD: A cross-sectional design was applied to estimate the association between psychoactive substance use and sensation seeking behavior. Drivers in normal traffic were included in two roadside surveys: one in the north (September 2014 - October 2015) and the other in the south-east of Norway (April 2016 - April 2017). Oral fluid was analyzed for alcohol and psychoactive drugs, and data on sex, age and time of participation were recorded. Participants filled in the Brief Sensation Seeking Scale 4 questionnaire. RESULTS: A total of 8053 drivers were included, of which 32% were women and 62% were under 40 years. The prevalence of alcohol was 0.3%, stimulants 0.6%, tetrahydrocannabinol 1.4%, benzodiazepines and/or z-hypnotics 2.0% and polydrug use 0.6%. Associations were found between the use of tetrahydrocannabinol or benzodiazepines and/or z-hypnotics and a low score on the "thrill and adventure seeking" domain of the Brief Sensation Seeking Scale 4 (OR = 1.723, 95% C.I. = 1.001-2.966). Associations were also found between the use of stimulants and the highest scores on the "experience seeking" (OR = 2.085, 95% C.I. = 1.084-4.009) and "disinhibition" (OR = 4.791, 95% C.I. =1.748-13.135) domains of the Brief Sensation Seeking Scale 4. No associations were found between sensation seeking behavior and alcohol or polydrug use. CONCLUSION: A high degree of sensation seeking was found among drivers who had used stimulating drugs, in contrast to drives who had used tetrahydrocannabinol and benzodiazepines and/or z-hypnotics who showed a low degree of sensation seeking. The combination of sensation seeking behavior and the use of stimulants might lead to increased risky behavior and thus traffic crashes.

Artificial intelligence supported patient self-care in chronic heart failure: a paradigm shift from reactive to predictive, preventive and personalised care.

Heart failure (HF) is one of the most complex chronic disorders with high prevalence, mainly due to the ageing population and better treatment of underlying diseases. Prevalence will continue to rise and is estimated to reach 3% of the population in Western countries by 2025. It is the most important cause of hospitalisation in subjects aged 65 years or more, resulting in high costs and major social impact. The current "one-size-fits-all" approach in the treatment of HF does not result in best outcome for all patients. These facts are an imminent threat to good quality management of patients with HF. An unorthodox approach from a new vision on care is required. We propose a novel predictive, preventive and personalised medicine approach where patients are truly leading their management, supported by an easily accessible online application that takes advantage of artificial intelligence. This strategy paper describes the needs in HF care, the needed paradigm shift and the elements that are required to achieve this shift. Through the inspiring collaboration of clinical and high-tech partners from North-West Europe combining state of the art HF care, artificial intelligence, serious gaming and patient coaching, a virtual doctor is being created. The results are expected to advance and personalise self-care, where standard care tasks are performed by the patients themselves, in principle without involvement of healthcare professionals, the latter being able to focus on complex conditions. This new vision on care will significantly reduce costs per patient while improving outcomes to enable long-term sustainability of top-level HF care.

Mephedrone and Alcohol Interactions in Humans.

Mephedrone (4-MMC, mephedrone) is a synthetic cathinone derivative included in the class of new psychoactive substances. It is commonly used simultaneously with alcohol (ethanol). The aim of the present study was to evaluate the interactions on subjective, cardiovascular and hormone effects and pharmacokinetics between mephedrone and alcohol in humans. Eleven male volunteers participated as outpatients in four experimental sessions in a double-blind, randomized, cross-over, and placebo-controlled clinical trial. Participants received a single oral dose of 200 mg of mephedrone plus 0.8 g/kg of alcohol (combination condition); 200 mg of mephedrone plus placebo alcohol (mephedrone condition); placebo mephedrone plus 0.8 g/kg of ethanol (alcohol condition); and placebo mephedrone plus placebo alcohol (placebo condition). Outcome variables included physiological (blood pressure, heart rate, temperature, and pupil diameter), psychomotor (Maddox wing), subjective (visual analogue scales, Addiction Research Center Inventory 49 item short form, and Valoración de los Efectos Subjetivos de Sustancias con Potencial de Abuso questionnaire), and pharmacokinetic parameters (mephedrone and ethanol concentrations). The study was registered in ClinicalTrials.gov, number NCT02294266. The mephedrone and alcohol combination produced an increase in the cardiovascular effects of mephedrone and induced a more intense feeling of euphoria and well-being in comparison to the two drugs alone. Mephedrone reduced the sedative effects produced by alcohol. These results are similar to those obtained when other psychostimulants such as amphetamines and 3,4-methylenedioxymethamphetamine are combined simultaneously with alcohol. The abuse liability of mephedrone combined with alcohol is greater than that induced by mephedrone alone.

Challenges in personalised management of chronic diseases-heart failure as prominent example to advance the care process.

Chronic diseases are the leading causes of morbidity and mortality in Europe, accounting for more than 2/3 of all death causes and 75 % of the healthcare costs. Heart failure is one of the most prominent, prevalent and complex chronic conditions and is accompanied with multiple other chronic diseases. The current approach to care has important shortcomings with respect to diagnosis, treatment and care processes. A critical aspect of this situation is that interaction between stakeholders is limited and chronic diseases are usually addressed in isolation. Health care in Western countries requires an innovative approach to address chronic diseases to provide sustainability of care and to limit the excessive costs that may threaten the current systems. The increasing prevalence of chronic diseases combined with their enormous economic impact and the increasing shortage of healthcare providers are among the most critical threats. Attempts to solve these problems have failed, and future limitations in financial resources will result in much lower quality of care. Thus, changing the approach to care for chronic diseases is of utmost social importance.

Alcohol calibration of tests measuring skills related to car driving.

RATIONALE: Medication and illicit drugs can have detrimental side effects which impair driving performance. A drug's impairing potential should be determined by well-validated, reliable, and sensitive tests and ideally be calibrated by benchmark drugs and doses. To date, no consensus has been reached on the issue of which psychometric tests are best suited for initial screening of a drug's driving impairment potential. OBJECTIVE: The aim of this alcohol calibration study is to determine which performance tests are useful to measure drug-induced impairment. The effects of alcohol are used to compare the psychometric quality between tests and as benchmark to quantify performance changes in each test associated with potentially impairing drug effects. METHODS: Twenty-four healthy volunteers participated in a double-blind, four-way crossover study. Treatments were placebo and three different doses of alcohol leading to blood alcohol concentrations (BACs) of 0.2, 0.5, and 0.8 g/L. RESULTS: Main effects of alcohol were found in most tests. Compared with placebo, performance in the Divided Attention Test (DAT) was significantly impaired after all alcohol doses and performance in the Psychomotor Vigilance Test (PVT) and the Balance Test was impaired with a BAC of 0.5 and 0.8 g/L. The largest effect sizes were found on postural balance with eyes open and mean reaction time in the divided attention and the psychomotor vigilance test. CONCLUSIONS: The preferable tests for initial screening are the DAT and the PVT, as these tests were most sensitive to the impairing effects of alcohol and being considerably valid in assessing potential driving impairment.

Effects of dexamphetamine with and without alcohol on simulated driving.

RATIONALE: In party circuits dexamphetamine is frequently used in combination with alcohol. It is hypothesized that co-administration of dexamphetamine to alcohol might reduce the sedative effects of alcohol, but may potentiate risk-taking behaviour. OBJECTIVES: The study was aimed at assessing the effects of alcohol, dexamphetamine and the combination of both on simulated driving and cognitive performance. METHOD: Eighteen subjects participated in a randomized, crossover, placebo-controlled study employing four conditions: 10 mg dexamphetamine, 0.8 g/kg alcohol, 10 mg dexamphetamine + 0.8 g/kg alcohol, and placebo. Fundamental driving skills and risk-taking behaviour were assessed in a driving simulator. Subjects also completed vigilance and divided attention tasks, and subjective ratings. RESULTS: Mean BAC levels during simulated driving were between 0.91‰ and 0.64‰. Subjects using alcohol showed a significantly larger mean standard deviation of lateral position and shorter accepted gap time and distance. Use of alcohol or dexamphetamine + alcohol was associated with a higher frequency of red light running and collisions than the dexamphetamine or placebo conditions. Performance of vigilance and divided attention tasks was significantly impaired in the alcohol condition and, to a lesser degree, in the dexamphetamine + alcohol condition. CONCLUSION: Single doses of 0.8 g/kg alcohol increased risk-taking behaviours and impaired tracking, attention and reaction time during a 3-h period after drinking when BACs declined from 0.9 to 0.2 mg/ml. The stimulatory effects of co-administration of dexamphetamine 10 mg were not sufficient to overcome the impairing effects of alcohol on skills related to driving.

Thermotropic ruthenium(II)-containing metallomesogens based on substituted 1,10-phenanthroline ligands.

Imidazo[4,5-f]-1,10-phenanthroline and pyrazino[2,3-f]-1,10-phenanthroline substituted with long alkyl chains are versatile ligands for the design of metallomesogens because of the ease of ligand substitution. Whereas the ligands and the corresponding rhenium(I) complexes were not liquid-crystalline, mesomorphism was observed for the corresponding ionic ruthenium(II) complexes with chloride, hexafluorophosphate, and bistriflimide counterions. The mesophases were identified as smectic A phases by high-temperature small-angle X-ray scattering (SAXS) using synchrotron radiation. The transition temperatures depend on the anion, the highest temperatures being observed for the chloride salts and the lowest for the bistriflimide salts. The ruthenium(II) complexes are examples of luminescent ionic liquid crystals.

A propeller-like uranyl metallomesogen.

Uranyl triflate forms with three imidazo[4,5-f]-1,10-phenanthroline ligands a propeller-like complex that exhibits a hexagonal columnar phase. The ligand is not liquid-crystalline, but a mesophase is induced upon complex formation with the uranyl salt. The thermal behavior has been investigated by polarizing optical microscopy and by high-temperature X-ray diffraction. A model of the stacking of the molecules in the mesophase is proposed.

Transient memory impairment after acute dose of 75mg 3.4-Methylene-dioxymethamphetamine.

A range of studies has indicated that users of 3.4-Methylene-dioxymethamphetamine (MDMA, 'Ecstasy') display cognitive deficits, particularly memory impairment, as compared to non-drug using controls. Yet it is difficult to determine whether these deficits are caused by MDMA or some other confounding factor, such as polydrug use. The present study was designed to establish the direct relation between MDMA and memory impairment under placebo-controlled conditions. Eighteen recreational MDMA users participated in a double blind, placebo controlled, 3-way crossover design. They were treated with placebo, MDMA 75mg and methylphenidate 20mg. Memory tests were conducted between 1.5-2h (intoxication phase) and between 25.5-26h (withdrawal phase) post dosing. Results showed that a single dose of MDMA caused impairment of immediate and delayed recall on a verbal learning task during the intoxication phase. However, there was no residual memory impairment during the withdrawal phase. Subjects reported more fatigue and less vigour, but no symptoms of depression during the withdrawal phase of MDMA treatment. Methylphenidate did not affect memory or mood at any time of testing. A single dose of MDMA produces transient memory impairment.

Validation of an ELISA-based screening assay for the detection of amphetamine, MDMA and MDA in blood and oral fluid.

The use of amphetamine and 'ecstasy' (MDMA) has increased exponentially in many European countries since the late nineties, leading to a rapid growth in the number of clinical and forensic analyses. Therefore, a rapid screening procedure for these substances in biological specimens has become an important part of routine toxicological analysis in forensic laboratories. The objective of this study was to evaluate the Cozart amphetamine enzyme-linked immunosorbent assay (ELISA) for the screening of plasma samples and oral fluid samples (collected with the Intercept device). Authentic plasma samples from drivers (n=360) were screened, using an 1:5-fold dilution. True positive, true negative, false positive and false negative results were determined relative to the in-house routine GC-MS analysis. Samples consisted of 144 amphetamine-only positives, 141MDMA/MDA-only positives, and 74 negatives when using the limit of quantitation as the cut-off level for confirmation (10 ng/mL). Using these results, receiver operating characteristic (ROC) curves were generated and optimal cut-off values for the screening assay were calculated. Analysis showed that the ELISA is able to predict the presence of either amphetamine or *MDMA/MDA (*MDMA as its metabolite MDA) in plasma samples with 98.3% sensitivity and 100% specificity at a cut-off value of 66.5 ng/mL d-amphetamine equivalents. A similar analysis was conducted on 216 oral fluid specimens collected from a controlled double blind study. Subjects received placebo or a high (100 mg) or low (75 mg) dose of MDMA. Oral fluid samples were collected at 1.5 and 5.5h after administration. Combined results of the analysis of the high and low dose oral fluid samples indicated a screening cut-off of 51 ng/mL d-amphetamine equivalents with both a sensitivity and specificity of 98.6% (using a LC-MS/MS confirmation cut-off of 10 ng/mL). In conclusion, these data indicate that the Cozart AMP EIA plates constitute a fast and accurate screening technique for the identification of amphetamine and MDMA/MDA positive plasma samples and oral fluid specimens (collected with Intercept. It should be emphasized that method validation should be performed for each type of biological matrix.

Quantitative analysis of multiple illicit drugs in preserved oral fluid by solid-phase extraction and liquid chromatography-tandem mass spectrometry.

We present a validated method for the simultaneous analysis of basic drugs which comprises a sample clean-up step, using mixed-mode solid-phase extraction (SPE), followed by LC-MS/MS analysis. Deuterated analogues for all of the analytes of interest were used for quantitation. The applied HPLC gradient ensured the elution of all the drugs examined within 14 min and produced chromatographic peaks of acceptable symmetry. Selectivity of the method was achieved by a combination of retention time, and two precursor-product ion transitions for the non-deuterated analogues. Oral fluid was collected with the Intercept, a FDA approved sampling device that is used on a large scale in the US for workplace drug testing. However, this collection system contains some ingredients (stabilizers and preservatives) that can cause substantial interferences, e.g. ion suppression or enhancement during LC-MS/MS analysis, in the absence of suitable sample pre-treatment. The use of the SPE was demonstrated to be highly effective and led to significant decreases in the interferences. Extraction was found to be both reproducible and efficient with recoveries >76% for all of the analytes. Furthermore, the processed samples were demonstrated to be stable for 48 h, except for cocaine and benzoylecgonine, where a slight negative trend was observed, but did not compromise the quantitation. In all cases the method was linear over the range investigated (2-200 microg/L) with an excellent intra-assay and inter-assay precision (coefficients of variation <10% in most cases) for QC samples spiked at a concentration of 4, 12 and 100 microg/L. Limits of quantitation were estimated to be at 2 microg/L with limits of detection ranging from 0.2 to 0.5 microg/L, which meets the requirements of SAMHSA for oral fluid testing in the workplace. The method was subsequently applied to the analysis of Intercept samples collected at the roadside by the police, and to determine MDMA and MDA levels in oral fluid samples from a controlled study.