Education and Training in Addiction Medicine and Psychology across Europe: A EUFAS Survey.

INTRODUCTION: Training in addiction medicine and addiction psychology is essential to ensure the quality of treatment for patients with substance use disorders. Some earlier research has shown varying training between countries, but no comprehensive study of addiction training across Europe has been performed. The present study by the European Federation for Addiction Societies (EUFAS) aimed to fill this gap. METHODS: A Delphi process was used to develop a questionnaire on specialist training in addiction treatment in 24 European countries. The final questionnaire consisted of 14 questions on either addiction medicine or addiction psychology, covering the nature and content of the training and institutional approval, the number of academic professorial positions, and the estimated number of specialists in each country. RESULTS: Information was not received from all countries, but six (Belgium, Denmark, Ireland, Italy, Poland, and Romania) reported no specialized addiction medicine training, while 17 countries did. Seven countries (Belgium, France, Ireland, Italy, Russia, Switzerland, and the Netherlands) reported no specialized addiction psychology training, while 14 countries did. Training content and evaluation methods varied. Approval was given either by governments, universities, or professional societies. Eighteen countries reported having professorships in addiction medicine and 12 in addiction psychology. The number of specialists in addiction medicine or psychology varied considerably across the countries. DISCUSSION: The survey revealed a large heterogeneity in training in addiction medicine and addiction psychology across Europe. Several countries lacked formal training, and where formal training was present, there was a large variation in the length of the training. Harmonization of training, as is currently the case for other medical and psychology specializations, is warranted to ensure optimal treatment for this under-served patient group.

Phosphatidylethanol (PEth) for Monitoring Sobriety in Liver Transplant Candidates: Preliminary Results of Differences Between Alcohol-Related and Non-Alcohol-Related Cirrhosis Candidates.

BACKGROUND Monitoring sobriety is mandatory for liver transplant (LT) candidates with alcohol-related cirrhosis in Germany. Prior to listing, abstinence of 6 months is required. However, little is known about biomarker performance in alcohol-related cirrhosis. Routine testing of ethyl glucuronide in urine (uEtG) or hair (hEtG) is prone to manipulation or is unfeasible in anuria. Phosphatidylethanol (PEth) in dried-blood spots is a promising alternative. We compared PEth with routine parameters and self-reports in alcohol-related and non-alcohol-related cirrhosis at our transplant center. MATERIAL AND METHODS All patients received self-report questionnaires (AUDIT & TLFB). Blood, urine and hair samples, as well as PEth dried-blood spots were drawn at baseline. In addition, survival analyses were conducted. RESULTS Out of 66 patients, 53 were listed for LT and 13 were candidates not listed so far. An alcohol-use disorder was found in 25 patients. Positive results for uEtG, hEtG, and PEth were found in 5/65, 9/65, and 34/66 cases, respectively. PEth positivity was found in 52% of patients with alcohol-related cirrhosis, while 53% of patients with other liver diseases were positive. While uEtG, hEtG, and TLFB correlated with higher PEth values, active waiting list status was significantly correlated with negative PEth values. During the mean follow-up of 41.15 months, 23 patients were transplanted (34.9%). None of the biomarkers significantly predicted survival. CONCLUSIONS PEth can importantly assist abstinence monitoring in LT candidates due to its high validity and objectivity. The high percentage of patients with alcohol consumption in the non-alcoholic liver disease cohort underscores the importance of testing all transplant candidates.

Phosphatidylethanol Reliably and Objectively Quantifies Alcohol Consumption in Adolescents and Young Adults.

BACKGROUND: Alcohol contributes to numerous annual deaths and various societal problems not just in adult, but also in adolescent, populations. Therefore, it is vital to find methods for reliably detecting alcohol use for early preventative measures. Research has shown phosphatidylethanol (PEth) to be superior to self-report instruments and indirect biomarkers for alcohol consumption in adult populations. However, the transferability onto an adolescent population has not yet been investigated. METHODS: N = 106 adolescents and young adults aged between 13 and 21 years were included. PEth analysis using high-pressure liquid chromatography-tandem mass spectrometry was performed on dried blood spot samples. Self-report questionnaires for alcohol consumption (Alcohol Use Disorders Identification Test-Consumption, AUDIT-C, and Timeline Followback, TLFB) and drug and alcohol consumption (Detection of Alcohol and Drug Problems in Adolescents, DEP-ADO) were completed by each participant. RESULTS: AUDIT-C scores showed large correlations with PEth 16:0/18:1 (rs  = 0.732) and PEth 16:0/18:2 (rs  = 0.661) concentrations. AUDIT-C with a cutoff value ≥3 was largely correlated with PEth 16:0/18:1 (η = 0.411) and showed a medium-sized correlation with PEth 16:0/18:2 (η = 0.397) concentrations. Using an AUDIT-C cutoff value ≥5 showed large correlations with both PEth 16:0/18:1 (η = 0.510) and PEth 16:0/18:2 (η = 0.497) concentrations, respectively. ROC curves indicated higher PEth concentrations are a good model for detecting positive AUDIT-C cutoff values (AUROC range: 0.800 to 0.849). PEth concentrations showed medium to large correlations with DEP-ADO and TLFB subscales (range rs  = 0.469 to 0.746). CONCLUSION: The results suggest that PEth is a reliable and objective marker for quantifying alcohol consumption in adolescents and young adults. This could be of importance for early preventative measures against hazardous alcohol consumption, which is increasingly common at younger ages.

A Survey on the Medical Use of Cannabis in Europe: A Position Paper.

AIM: This study was aimed at investigating the availability and prescription of different medicinal variants of cannabis and their status in European countries. METHODS: A -web-based survey was sent to all member societies of the -European Federation of Addiction Societies (EUFAS) in 2 waves during the summer of 2017. All 34 member societies in 19 different European countries were invited to participate. RESULTS: We received 28 responses from 17 European countries. The cannabis extract nabiximol (Sativex®) is the most prevalent cannabis-based medicinal product marketed in Europe. Synthetic cannabinoids and standardized cannabis are less prevalent, and no country allows the growing of cannabis for personal medical use. The bringing of medical cannabis products from across borders to countries where the drug is not marketed is quite limited. The use of medical cannabis is restricted to some central medical conditions, but off-label use is prevalent in some countries. CONCLUSION: The use of medical cannabis in Europe seems to be restricted mostly to the use of the cannabis extract, nabiximol. There is only limited use of the cannabis plant as such for medical purposes, possibly indicating a different scenario in Europe as compared to the USA. Position Statement: EUFAS as an umbrella association of European addiction societies stresses the need for further studies on the efficacy of medical cannabis and warrants for possible dangers associated with the increasing popularity of medical cannabis. We need regulations at European level concerning registration and medical indications, development of uniform compounds and strength of products, and rules concerning sales and marketing.

Type of gambling as an independent risk factor for suicidal events in pathological gamblers.

Individuals with pathological gambling have an increased risk for suicidal events. Additionally, the prevalence of comorbid psychiatric disorders is high among pathological gamblers. This study analyzes whether the type of gambling is associated with suicidal events in pathological gamblers independently from comorbidity. Participants were recruited in 4 different ways: via random telephone sample from the general population, via individual invitation for study participation in gambling locations, through various media and the distribution of a leaflet in various settings, and via inpatient treatment facilities for pathological gambling. The final sample included 442 participants with a lifetime diagnosis of pathological gambling. A standardized clinical interview was conducted. High financial losses were associated with suicidal events (odds ratio [OR] = 1.94, 95% 95% confidence interval [CI], [1.11, 3.37]), as were mood disorders (OR = 7.70, 95% CI, [4.44, 13.37]) and female gender (OR = 2.52, 95% CI, [1.20, 5.28]). Gambling on electronic gambling machines in gambling halls or bars was associated with increased odds of suicidal events (OR = 2.94, 95% CI, [1.38, 6.24]). Other types of gambling, such as casino games or betting on sports, or the number of DSM-IV criteria for pathological gambling were not associated independently with suicidal events. Our findings suggest that gambling on electronic gambling machines in gambling halls or bars is associated with suicidal events in pathological gamblers independently of comorbidity. This result shows that the type of gambling needs to be considered as a relevant factor in gambling research.

Suicidal events among pathological gamblers: the role of comorbidity of axis I and axis II disorders.

The risk for suicidal ideation and suicide attempts among pathological gamblers is high compared to the general population. Little is known about the interplay of Axis I and Axis II disorders, severity of gambling disorder, and suicidal ideation and suicide attempts. The study aims to address this linkage. The sampling design of the study "Pathological Gambling and Epidemiology" (PAGE) included four recruitment channels: general population, gambling locations, project telephone hotline, and in-patient treatment for pathological gambling. A total of 442 study participants with lifetime pathological gambling received a clinical interview. The multivariate analysis showed mood disorders (Relative Risk Ratio, RRR=5.14, 95%-Confidence Interval, CI=2.91-9.07), substance use disorders (RRR=1.73, CI=1.02-2.94), and early onset of gambling disorder (RRR=0.96, CI=0.93-0.99) to be associated with suicidal ideation. Suicidal attempts were associated with female sex (RRR=3.58, CI=1.56-8.19), mood disorders (RRR=11.92, CI=4.70-30.26), and Cluster B personality disorders (RRR=2.40, CI=1.13-5.10). Among study participants with suicide attempts, more had a Cluster B personality disorder than among participants with ideation solely (RRR=3.08, CI=1.48-6.40). Among this large mixed sample of pathological gamblers, high proportions of individuals with suicidal events, multi-morbidity on Axis I, and a strong linkage to Cluster B personality disorders were found.

Progress in monitoring alcohol consumption and alcohol abuse by phosphatidylethanol.

For early diagnosis and therapy of alcohol-related disorders, alcohol biomarkers are highly valuable. Concerning specificity, indirect markers can be influenced by nonethanol-related factors, whereas direct markers are only formed after ethanol consumption. Sensitivity of the direct markers depends on cut-offs of analytical methods, material for analysis and plays an important role for their utilization in different fields of application. Until recently, the biomarker phosphatidylethanol has been used to differentiate between social drinking and alcohol abuse. After method optimization, the detection limit could be lowered and phosphatidylethanol became sensitive enough to even detect the consumption of low amounts of alcohol. This perspective gives a summary of most common alcohol biomarkers and summarizes new developments for monitoring alcohol consumption habits.

[40 years in-patient suicide research of the working group "Suicidality and the psychiatric hospital"]. / 40 Jahre Kliniksuizidverbundstudie der AG "Suizidalität und Psychiatrisches Krankenhaus".

OBJECTIVE: To give an retrospective overview according to the so-called in-patient suicide especially in German psychiatric hospitals. METHOD: Summary of results of the working group "Suicidality and the psychiatric hospital" during the last four decades in Germany. RESULTS: First, it could be shown that there was a real increase of in-patient suicides during the 70(th) and 80(th) years. Two other results are important 1) an impressive decrease of suicide rates in the two last decades and 2) the observation of a change from the new high-risk group "young schizophrenic patients" back to the traditional suicide risk group of depressed patients.

Cannabis use among a sample of 16 to 18 year-old students in Switzerland.

BACKGROUND: The aim of this study was to estimate the prevalence of cannabis use among Swiss students and to assess their attitudes regarding health and safety issues associated with drug use. SUBJECTS AND METHODS: After a workshop, 173 students (23.1% male, 75.7% female; 44.4% age 16, 43.8% age 17 and 11.8% age 18) from a Swiss school were surveyed by questionnaire. RESULTS: 59.3% (n=103) of all participants had tried cannabis, and 30.1% of those who reported cannabis use had consumed more than 100 joints. Of those 103 students with cannabis experience, 6.8% rated the risk of cannabis-related psychic effects as low, and 9.8% were not concerned about driving under the influence of cannabis. In cases of heavy cannabis use, the chance of increased tobacco, alcohol or other drug use is higher than for those with less or no cannabis use at all (odds ratios of 4.33-10.86). CONCLUSIONS: This paper deals primarily with cannabis prevalence data in adolescents from previous studies and sources, and shows that our findings deviate significantly - and surprisingly - from past research. Our data from a school survey indicates higher cannabis use than data from official drug policy studies. Additionally, our data shows that the students' self-reported attitudes towards health and safety issues were mostly realistic. The examination of methodological issues that might impact prevalence estimates should be added to the cannabis literature.

[What ethanol metabolites as biological markers tell us about alcohol use]. / Was Ethanolmetabolite als Biomarker über Alkoholkonsum aussagen.

Alcohol and tobacco related disorders are the two leading and most expensive causes of illness in central Europe. In addition to self reports and questionnaires, biomarkers are of relevance in diagnosis and therapy of alcohol use disorders. Traditional biomarkers such as gamma glutamyl transpeptidase or mean corpuscular volume are indirect biomarkers and are subject to influence of age, gender and non alcohol related diseases, among others.Direct ethanol metabolites such as ethyl glucuronide (EtG), ethyl sulphate (EtS) and phosphatidylethanol (PEth) are direct metabolites of ethanol, that are positive after intake of ethyl alcohol. They represent useful diagnostic tools for identifying alcohol use even more accurately than traditional biomarkers. Each of these drinking indicators remains positive in serum and urine for a characteristic time spectrum after the cessation of ethanol intake--EtG and EtS in urine up to 7 days, EtG in hair for months after ethanol has left the body. Applications include clinical routine use, emergency room settings, proof of abstinence in alcohol rehabilitation programs, driving under influence offenders, workplace testing, assessment of alcohol intake in the context of liver transplantation and fetal alcohol syndrome.

How therapists react to patient's suicide: findings and consequences for health care professionals' wellbeing.

OBJECTIVES: To test the robustness of the findings of previous studies in a large aggregated sample regarding (a) the impact of a patient's suicide on therapist's distress; (b) identify a potential subgroup of therapists needing special postvention; (c) and assess potential differences in overall distress between professional groups and at different levels of care. METHODS: A questionnaire, characterizing the therapists, their reactions and the patients, had been sent out to 201 psychiatric hospitals in Germany providing different levels of care. Aggregated data from previous studies have been used. RESULTS: In 39.6% of all cases, therapists suffer from severe distress after a patients' suicide. The global item "overall distress" can be used as an indicator to identify a subgroup of therapists that might need individualized postvention. No significant difference in overall distress experienced was observed between professional groups and at different levels of care. CONCLUSION: Our data suggest that identifying the severely distressed subgroup could be done using a visual analogue scale for overall distress. As a consequence, more specific, individualized and intensified help could be provided to these professionals, helping them to overcome distress and thereby ensuring delivery of high quality care to the patient.

The therapist's reaction to a patient's suicide: results of a survey and implicationsfor health care professionals'well-being.

BACKGROUND: A substantial proportion of therapists experience the loss of a patient to suicide at some point during their professional life. AIMS: To assess (1) the impact of a patient's suicide on therapists distress and well-being over time, (2) which factors contribute to the reaction, and (3) which subgroup might need special interventions in the aftermath of suicide. METHODS: A 63-item questionnaire was sent to all 185 Psychiatric Clinics at General Hospitals in Germany. The emotional reaction of therapists to patient's suicide was measured immediately, after 2 weeks, and after 6 months. RESULTS: Three out of ten therapists suffer from severe distress after a patients' suicide. The item "overall distress" immediately after the suicide predicts emotional reactions and changes in behavior. The emotional responses immediately after the suicide explained 43.5% of the variance of total distress in a regression analysis. LIMITATIONS: The retrospective nature of the study is its primary limitation. CONCLUSIONS: Our data suggest that identifying the severely distressed subgroup could be done using a visual analog scale for overall distress. As a consequence, more specific and intensified help could be provided to these professionals.

Patient suicide: a survey of therapists' reactions.

A substantial proportion of therapists will at some point in their professional life experience the loss of a patient to suicide. Our aims were to assess how therapists react to patient's suicide over time and which factors contribute to the reaction. One third of the therapists, mostly women, suffer from severe distress. The impact is not different for therapists in institutional settings and therapists in private practice. The item "overall distress" immediately after the suicide predicts emotional reactions and changes in behavior. Our data suggest that identifying the severely distressed subgroup could be done using a visual analogue scale for overall distress. As a consequence, more specific and intensified help could be provided to these individuals.

Urine tested positive for ethyl glucuronide and ethyl sulfate after the consumption of yeast and sugar.

BACKGROUND: To an increasing degree, EtG and EtS are routinely used for the proof of abstinence for purposes of traffic, occupational, addiction and social medicine. This routine use demands further investigations on the sensitivity and specificity of these analytes and the examination of possible genesis of positive EtG and EtS concentrations even without the consumption of ethanol. In vivo fermentation with consecutive formation of EtG and EtS was addressed by experiments with yeast products. METHODS: Two experiments with baker's yeast and brewer's yeast tablets were performed. The ethanol concentrations in urine of the 2 and 4 volunteers, respectively, were detected by HS-GC-FID, EtG and EtS analysis was performed by LC-ESI-MS/MS, and the creatinine concentration was determined using a method based on the Jaffé reaction. RESULTS AND CONCLUSIONS: After the consumption of baker's yeast the maximum concentrations of EtG and EtS normalised to creatinine were found to be 0.67 and 1.41mg/L, respectively, and therefore clearly above the commonly applied cut-off value for the proof of abstinence of 0.1mg/L. In contrast, in this study the, uptake of yeast tablets did not result in a detection of EtG and EtS in urine.

Phosphatidylethanol: normalization during detoxification, gender aspects and correlation with other biomarkers and self-reports.

Phosphatidylethanol (PEth) is a direct ethanol metabolite, and has recently attracted attention as biomarker of ethanol intake. The aims of the current study are: (1) to characterize the normalization time of PEth in larger samples than previously conducted; (2) to elucidate potential gender differences; and (3) to report the correlation of PEth with other biomarkers and self-reported alcohol consumption. Fifty-seven alcohol-dependent patients (ICD 10 F 10.25; 9 females, 48 males) entering medical detoxification at three study sites were enrolled. The study sample was comprised of 48 males and 9 females, with mean age 43.5. Mean gamma glutamyl transpeptidase (GGT) was 209.61 U/l, average mean corpuscular volume (MCV) was 97.35 fl, mean carbohydrate deficient transferrin (%CDT) was 8.68, and mean total ethanol intake in the last 7 days was 1653 g. PEth was measured in heparinized whole blood with a high-pressure liquid chromatography method, while GGT, MCV and %CDT were measured using routine methods. PEth levels at day 1 of detoxification ranged between 0.63 and 26.95 micromol/l (6.22 mean, 4.70 median, SD 4.97). There were no false negatives at day 1. Sensitivities for the other biomarkers were 40.4% for MCV, 73.1% for GGT and 69.2% for %CDT, respectively. No gender differences were found for PEth levels at any time point. Our data suggest that PEth is (1) a suitable intermediate term marker of ethanol intake in both sexes; and (2) sensitivity is extraordinary high in alcohol dependent patients. The results add further evidence to the data that suggest that PEth has potential as a candidate for a sensitive and specific biomarker, which reflects longer-lasting intake of higher amounts of alcohol and seemingly has the above mentioned certain advantages over traditional biomarkers.

Assessment of alcohol use among methadone maintenance patients by direct ethanol metabolites and self-reports.

BACKGROUND: Heavy alcohol consumption may accelerate the progression of hepatitis C (HCV)-related liver disease and/or limit efforts at antiviral treatment. As most of the patients in methadone maintenance treatment (MMT) suffer from hepatitis C infection, this study was conducted to identify the alcohol intake among these patients at a Swiss Psychiatric University Clinic by self-reports and direct ethanol metabolites as biomarkers of ethanol consumption. PATIENTS AND METHODS: A convenience sample of 40 MMT patients (15 women, 25 men; median age 39 years) of the total 124 patients was asked and consented to participate in this study. This sample was not different in age, gender distribution, and rate of hepatitis C infection from the total sample. The Alcohol Use Disorders Identification Test (AUDIT) and self-reported ethanol intake during the previous 7 days were assessed. In addition, ethyl glucuronide (EtG) in urine, and fatty acid ethyl esters (FAEEs) and EtG in hair were determined using LC-MS/MS and gas chromatograph/mass spectrometer. The limit of quantitation for UEtG, HEtG, and FAEEs were 0.1 mg/l, 2.3 pg/mg, and 0.1 ng/mg, respectively. RESULTS: Fourteen participants reported abstinence from alcohol for the previous 7 days. AUDIT scores were > or =8 in 15 male and >5 in 5 female participants. Direct ethanol metabolites were as follows (median, min, max, standard deviation): UEtG (19 positives; 9.91, 1.38 to 251, 62.39 mg/l); the values of HEtG were 17.65, 0 to 513, 105.62 pg/mg [in 2 cases no material, 8 abstinent (up to 7 pg/mg), 15 social drinkers (up to 50 g per day), and 15 excessive users (>50/60 g/d)]. For the 13 cases, where enough material for additional determination of HFAEEs was available, the values were 0.32, 0 to 1.32, 0.44 ng/mg. Among the 30 HEtG-positive participants, 20 had not reported the corresponding ethanol intake using question 1 (frequency) and 2 (quantity) of the AUDIT. Of the 14 participants reporting no alcohol intake during the previous 7 days, 4 were UEtG-positive. HEtG and AUDIT correlated significantly (r = 0.622, p < 0.0001), but this was not the case for UEtG and self-reported ethanol intake during the previous 7 days. CONCLUSION: (1) HEtG identified 20 cases of daily ethanol intake of more than 20 g, that would have been missed by the sole use of question 1 (frequency) and 2 (quantity) of the AUDIT. (2) Using the total score of the AUDIT, HEtG confirmed 10 more cases positive for alcohol intake. (3) Episodic heavy drinking is with 22.5% more frequent than in general population, and (4) of the 14 participants who reported no alcohol intake during the previous 7 days, 4 were UEtG positive. Improved detection of alcohol consumption, which is hazardous or harmful in the context of HCV and opiate dependence, would allow for earlier intervention in this population which is at particular risk of liver disease and fatal respiratory-depressed overdose. The combined use of self-reports and direct ethanol metabolites seems promising.

The usefulness of direct ethanol metabolites in assessing alcohol intake in nonintoxicated male patients in an emergency room setting.

BACKGROUND: A major part of medical pathology in internal medicine is associated with chronic alcoholism. The aim of the current study was to investigate whether screening for Alcohol Use Disorders (AUD) can be improved through determination of direct ethanol metabolites compared to traditional biological state markers, the Alcohol Use Disorders Identification Test (AUDIT) and additional self-reports beyond the detection time period of a positive blood alcohol concentration (BAC). METHODS: A total of 74 blood alcohol negative male patients who presented at the emergency room with either thoracic or gastrointestinal complaints were included. Phosphatidylethanol (PEth) was determined in whole blood, and ethyl glucuronide (EtG) in serum and urine samples. Traditional biological state markers [carbohydrate deficient transferrin (%CDT), gamma glutamyl transpeptidase (GGT), mean corpuscular volume (MCV)] were determined. The AUDIT was obtained and furthermore, all patients completed an additional self-report of alcohol consumption. Patients were divided into two (2) groups: AUDIT scores < 8 and AUDIT scores >or= 8. RESULTS: After assessment of the AUDIT, patients were allocated to one of the following groups: patients with AUDIT scores < 8 (n = 52) and with AUDIT scores >or= 8 (n = 22). Twenty-five percent of the patients with AUDIT scores below the cut-off (n = 13/52) were tested positive for both PEth and UEtG. Of the patients who declared to be sober during the past 12 months, 38.5% were tested positive for PEth and UEtG. PEth discriminated similarly as %CDT for AUDIT scores >or= 8 (AUC: 0.672; 95%CI 0.524 to 0.821). Self-reports of alcohol consumption were unreliable. CONCLUSION: Determination of direct ethanol metabolites such as PEth and UEtG provides additional evidence in screening for AUD in an ER setting. Determination of PEth might be considered complementary with or alternatively to %CDT.

Measurement of direct ethanol metabolites suggests higher rate of alcohol use among pregnant women than found with the AUDIT--a pilot study in a population-based sample of Swedish women.

OBJECTIVES: The objective of the study was to investigate whether biomarkers of alcohol consumption would provide additional information to the use of a validated alcohol questionnaire in pregnant women. STUDY DESIGN: One hundred three pregnant women were included in the study. The women completed the Alcohol Use Disorders Identification Test (AUDIT) questionnaire, and a urine and hair sample was collected. The urine samples were used for determination of ethyl glucuronide (EtG) and ethyl sulfate and the hair samples for EtG and fatty acid ethyl esters (FAEE). RESULTS: Twenty-six women (25.2%) were identified as possible alcohol consumers by the combined use of AUDIT and direct ethanol metabolites. Seven subjects had EtG or FAEE levels in hair highly suspicious of heavy drinking, but only 1 of these were positive according to the AUDIT questionnaire CONCLUSION: The combined use of the AUDIT questionnaire and direct ethanol metabolites appear to identify more potential alcohol consumers among pregnant women than does the sole use of the AUDIT questionnaire.