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This review summarizes current evidence on the abuse and misuse of the gabapentinoids pregabalin and gabapentin. Pharmacovigilance studies, register-based studies, surveys, clinical toxicology studies, and forensic toxicology studies were identified and scrutinized with the goal to define the problem, identify risk factors, and discuss possible methods to reduce the potential for abuse and misuse. Studies found that gabapentinoids are abused and misused and that individuals with a history of psychiatric disorders or substance use disorder seem to be at high risk. Moreover, some evidence supports the notion that patients with opioid use disorders may be at an increased risk of abusing gabapentinoids. Available evidence also suggests that abuse and misuse are more frequent in users of pregabalin compared with users of gabapentin. Health professionals and prescribers should be aware of the risk for misuse of pregabalin and gabapentin, which eventually could lead to abuse, substance dependence, and intoxications. Prescribing to patients belonging to risk populations such as those with psychiatric disorders or substance use disorder should be avoided if possible and, if prescribed, signs of misuse and abuse should be monitored. Funding Agencies|Linkoping University

Objective: To compare the assessments of 10-year probability by patients and their physicians of cardiovascular complications of hypertension with actual outcomes. Design: Patients with uncomplicated hypertension treated with at least one antihypertensive drug at inclusion were followed for 10 years through mandatory national health registers. Setting: 55 primary health care centres, 11 hospital outpatient clinics in Sweden Patients: 848 patient, 212 physicians. Main outcome measures: Patients and physicians estimated the probability of hypertension-related complications with treatment (death, heart failure, acute myocardial infarction/AMI, and stroke) for each patient in 848 pairs. Estimates were compared with the clinical outcomes 10 years later using data from the Mortality Register and the National Patient Register. Results: Patients were significantly better (p p Conclusions: Patients were better than their physicians in estimating the average probability of morbidity due to hypertension. Both the patients and their attending physicians had difficulty in estimating the individual patient’s risk of complications. The results support the use of evidence-based tools in consultations for assessing the risk of cardiovascular complications associated with hypertension.Key points • Shared decision making relies on a common understanding of risks and benefits. Tools for risk assessment of hypertension have been introduced in the last two decades. • Without tools for risk assessment, both patients and physicians had difficulties in estimating the individual patient’s risk of cardiovascular morbidity. • Patients were better than physicians in estimating actual average cardiovascular morbidity due to hypertension during a follow-up of 10 years. • The results support the use of evidence-based tools in consultations for assessing the risk of cardiovascular complications associated with hypertension. • Shared decision making relies on a common understanding of risks and benefits. Tools for risk assessment of hypertension have been introduced in the last two decades. • Without tools for risk assessment, both patients and physicians had difficulties in estimating the individual patient’s risk of cardiovascular morbidity. • Patients were better than physicians in estimating actual average cardiovascular morbidity due to hypertension during a follow-up of 10 years. • The results support the use of evidence-based tools in consultations for assessing the risk of cardiovascular complications associated with hypertension.

Context: Amlodipine is the most common calcium channel blocker (CCB) on the Swedish market, and poison center (PC) consultations for amlodipine overdoses are increasing. The clinical picture is dom...

Objective To assess the impact of lymphadenectomy and lymphoedema of the lower limbs (LLL) on health-related quality of life (HRQoL) 1 year after surgery for endometrial cancer (EC). Design Prospective longitudinal cohort multicentre study. Setting Departments of obstetrics and gynaecology at four university hospitals, six central hospitals and four county hospitals in Sweden. Population Two-hundred-and-thirty-five women with early stage EC were included; 116 with high-risk EC underwent surgery including lymphadenectomy (+LA), and 119 with low-risk EC had surgery without lymphadenectomy (-LA). Methods The generic SF-36 and EQ-5D-3L and the lymphoedema-specific LYMQOL questionnaire were used to assess HRQoL. LLL was assessed by systematic circumferential measurements of the legs enabling volume estimation, clinical evaluation and patient-reported perception of leg swelling. All assessments were carried out on four occasions; preoperatively, and 4-6 weeks, 6 months and 1 year postoperatively. Main outcome measure HRQoL scores. Results No significant differences were seen in HRQoL between the +LA and -LA groups 1 year postoperatively. Irrespective of method of determining LLL, women with LLL were significantly more affected in the LYMQOL domains Function, Appearance/body image and Physical symptoms, but not in the domain Emotion/mood, than women without LLL. No such differences were seen in the generic HRQoL or in the LYMQOL global score between the groups with and without LLL. Conclusions Lymphadenectomy did not seem to affect generic HRQoL adversely. Irrespective of the method of measuring, LLL affected the lymphoedema-specific HRQoL negatively, mainly in physical domains, but had no impact on the generic HRQoL. Tweetable abstract Lymphoedema has impact on lymphoedema-specific, but not on generic, HRQoL, 1 year after surgery for EC. Funding Agencies|Swedish Cancer Society (Cancerfonden)Swedish Cancer Society [CAN2013/620]; Medical Research Council of Southeast SwedenUK Research & Innovation (UKRI)Medical Research Council UK (MRC) [FORSS-308611, FORSS-391311, FORSS-662141, FORSS-858611]; Uppsala-Orebro Regional Research Council [LUL-349271]; Scientific Council of the Region Halland; County Council of Ostergotland; Linkoping University

Food frequency questionnaires (FFQ) are commonly used dietary assessment tools. The aim was to assess the relative validity of a 15-item FFQ, designed for the screening of poor dietary patterns with a validated diet history (DH). The study population was derived from the Gothenburg H70 Birth Cohort Studies. The DH registrations were harmonized in accordance with the FFQ frequencies. The agreement was assessed by Cohen’s kappa with corresponding confidence intervals (CI) for the frequency and categorical variables. Bland–Altman plots were used for the numeric variables. The study comprised data from 848 individuals (55.2% women). Overall, there was high agreement between the methods, with the exact and adjacent level of agreement over 80% for eight variables. The proportion attributed to the opposite frequency was fairly low for most of the frequency variables. Most of the kappa values were in fair or moderate agreement. The highest kappa values were calculated for the type of cooking fat (k = 0.68, CI = 0.63–0.72) and sandwich spread (k = 0.55, CI = 0.49–0.53), and the lowest for type of bread (0.13, CI = 0.07–0.20) and sweets (0.22 CI = 0.18–0.27). In conclusion, the FFQ showed overall good agreement compared with the DH. We, therefore, think it, with some improvements, could serve as a simple screening tool for poor dietary patterns., (This article belongs to the Special Issue Health Promotion in a Life Span Perspective)

Introduction/Background* Risk factors for lymphoedema of the lower limbs (LLL) after treatment of endometrial cancer (EC) is disputed. Body mass index (BMI) is strongly associated with LLL. The aim of this study was to determine the impact of BMI on risk factors for LLL, assessed as crude volume increase ≥10% or as BMI-standardised volume increase (BMI-SV) ≥10%, one year after surgery for early-stage EC . Methodology An observational prospective multicentre study was conducted in 14 Swedish hospitals enrolling 234 women with EC; 116 underwent surgery including pelvic and para-aortic lymphadenectomy (LA) and 119 had surgery without LA. LLL was assessed at baseline preoperatively and one year postoperatively by systematic circumferential measurements of the legs, enabling estimation of leg volume. Leg volume was determined as the de facto volume, i.e. crude volume and as the leg volume to a standardised BMI, i.e. BMI-SV. Risk factors were analysed using multiple logistic forward stepwise regression models. Result(s)* Lower BMI and medication with diuretics were independent risk factors for LLL determined by crude leg volume ≥10% (aOR 0.88, 95%CI 0.80-0.97 and aOR 2.67, 95%CI 1.04-6.89, respectively) whereas LA was not a risk factor. The BMI and change in BMI from baseline to one year outweighed the effect of LA as a risk factor. Neither number of lymph nodes removed, location, nor extent of LA were independent risk factors for LLL determined by crude volume increase ≥10%. By using BMI-SV volume increase ≥10% as LLL independent risk factors were adjuvant radiation therapy (aOR 15.02, 95%CI 2.34–96.57), LA (aOR 14.42, 95%CI 3.49–59.62), diabetes mellitus (aOR 5.44, 95%CI 1.67–17.66), and age (aOR 1.07, 95%CI 1.00–1.15). Simultaneously, the number of lymph nodes removed, location and extent of LA were strongly predictive for development of LLL. Conclusion* BMI was a strong risk factor for LLL that outweighed the effect of obvious risk factors and therefore should be adjusted for when assessing LLL. Adjuvant radiation therapy and LA were strong independent risk factors for LLL together with age and diabetes mellitus. There is a need for a `gold standard` for determining LLL when addressing risk factors.

PURPOSE To investigate vision-related quality of life (VRQoL), visual function and predictors of poor vision in a population of 70-year-olds. METHODS Self-reported ocular morbidity and responses to the National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) in a cross-sectional population study (N = 1203) in Gothenburg, Sweden, were compared with results from ophthalmic examination (N = 560). RESULTS The most common self-reported ophthalmic morbidities were cataract (23.4%), age-related macular degeneration (AMD; 4.7%), glaucoma (4.3%) and diabetic retinopathy (1.4%). Cataract was more prevalent in women (p = 0.001). The composite score from NEI VFQ-25 for the entire cohort was 91.4 (standard deviation: 27.5). When comparing composite score for different eye diseases, persons with cataract or AMD exhibited lower scores (p = 0.029 and 0.018, respectively). Best-corrected visual acuity (BCVA) was normal (≥0.5 decimal) in 98.9%; two individuals had low vision (

Background The Internet is increasingly becoming an infrastructure for a number of services, both commercial, public (including health related) and personal. Using the internet have the potential to promote social interaction and social connectedness by upholding social networks and social contacts. However, Internet use is lower in older adults compared to other age groups. This digital divide is considered a risk to the health of older adults since it limits their participation in society, access and use of relevant health related information and services. This study focuses on whether there is an association between Internet use and self-rated health. Method A cross-sectional population-based sample of 70-year-olds from The Gothenburg H70 Birth Cohort Study (n = 1136) was examined in 2014–16. All data was collected using structured interviews and questionnaires. Differences in proportions were tested with chi-square test and ordinary least square regression analysis was used to estimate the relationship between Internet use and self-rated health controlling for health factors, hearing and visual impairment, and social contacts. Results There is a relationship between more frequent Internet use and good self-rated health (unstandardized β 0.101 p β 0.082 p Conclusion Although the direction of the relationship between more frequent interne use and better self-rated health is undetermined in the present study, it can be suggested that using the Internet informs and educates older adults, strengthening their position as active and engaged participants of society. It can also be suggested that those using the Internet report less loneliness and a possibility to establish new computer-mediated relationships within online communities. Further research needs to examine what aspects of Internet use, and in what contexts such positive perceptions arise.

At the Swedish national forensic toxicology laboratory, a measured testosterone/epitestosterone (T/E) ratio ≥ 12 together with testosterone/luteinizing hormone (T/LH) in urine > 400 nmol/IU is considered as a proof of exogenous testosterone administration. However, according to the rules of the World Anti-Doping Agency (WADA), samples with T/E ratio > 4 are considered suspicious and shall be further analysed by gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS) to confirm the origin of testosterone and its metabolites. The aim of this study was to investigate the possibility of false negative results and to estimate the frequency of negative results using the current criteria for detection of abuse of testosterone in forensic investigations. Urine and serum samples were collected by the police at suspected infringement of the doping law in Sweden. Fifty-eight male subjects were included in the study. Urinary testosterone was determined by gas chromatography-mass spectrometry (GC-MS), serum testosterone and LH-by immunoassay. The origin of testosterone and its metabolites was confirmed by means of GC-C-IRMS. Twenty-six of the 57 analysed subjects tested positive for exogenous testosterone using the criteria T/E ≥ 12 combined with T/LH > 400 nmol/IU. The IRMS analyses confirmed 47 positives; thus, 21 were considered false negatives. Negative predictive value was 32% (95% confidence interval [CI]: 16%-50%) and sensitivity 55%. No false positive subjects were found. The number of false negative cases using the current criteria for the detection of testosterone abuse and hence the low sensitivity indicates a need to discuss introduction of new strategies in forensic doping investigations.

Background: The proportion of older adults is increasing rapidly, and the majority are female. In 2050, the number of persons aged 60 years and over is estimated to reach 2.1 billion worldwide, constituting one-third of the total population of Europe. Long-term back pain is a disabling and common condition, primarily affecting older women. Although standardized functional evaluations are essential in the screening of older adults, self-rated activities of daily living capture a different aspect of the person’s ability in the context of his or her environment and social support system. This study aimed to describe how older women with or without long-term back pain self-rate their activities of daily living (ADL) and instrumental activities of daily living (IADL) in relation to their performance-based testing of physical function, including walking test, leg muscle strength, balance, and endurance. Method: This study is part of the Gothenburg H70 Birth Cohort Studies in Sweden (H70 studies) and uses data from the 1944 birth cohort examined in 2015–16 at age 70. In the present study, only female participants were included in the analysis, and all cases of dementia (n = 17) and cases of acute and sub-acute back pain excluded (n = 181), leaving an effective sample of 446 female participants. Results: Women with long-term back pain self-perceived their ADL and IADL as being as good as those without back pain, although they performed poorer in all performance-based tests and perceived themselves as less physically fit. © 2021, The Author(s). Funding: The study was financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (ALF 716681), the Swedish Research Council (2012–5041, 2015–02830, 2019–01096, 2013–8717, 2017–00639), Swedish Research Council for Health, Working Life and Welfare (2013–1202, 2018–00471, AGECAP 2013–2300, 2013–2496), Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, Hjärnfonden, Alzheimerfonden, Eivind och Elsa K:son Sylvans stiftelse, Gun & Bertil Stohnes forskningsstipendium, Fredrik & Ingrid Thurings stiftelse, Wilhelm & Martina Lundgrens foundation, Hjalmar Svensson Foundation, the Söderström-König Foundation and Stiftelsen Ragnhild & Einar Lundströms minne. This study also received support from the Health and Medical Care Committee of the Regional Executive Board, Region Västra Götaland, as well as the Centre for Person-Centred Care (GPCC) at the University of Gothenburg. The GPCC is in turn funded by the Swedish Government’s grant for Strategic Research Areas, Care Sciences (2009–1088). The funding sources had no involvement in the design, methods, data collection, analysis or preparation of this manuscript or the decision to submit it for publication. Open Access funding provided by Halmstad University.

OBJECTIVE: The aim of the study was to determine risk factors for lymphedema of the lower limbs, assessed by four methods, 1 year after surgery for endometrial cancer. METHODS: A prospective longitudinal multicenter study was conducted in 14 Swedish hospitals. 235 women with endometrial cancer were included; 116 underwent surgery including lymphadenectomy, and 119 had surgery without lymphadenectomy. Lymphedema was assessed preoperatively and 1 year postoperatively objectively by systematic circumferential measurements of the legs, enabling volume estimation addressed as (1) crude volume and (2) body mass index-standardized volume, or (3) clinical grading, and (4) subjectively by patient-reported perception of leg swelling. In volume estimation, lymphedema was defined as a volume increase ≥10%. Risk factors were analyzed using forward stepwise logistic regression models and presented as adjusted odds ratio (aOR) and 95% confidence interval (95% CI). RESULTS: Risk factors varied substantially, depending on the method of determining lymphedema. Lymphadenectomy was a risk factor for lymphedema when assessed by body mass index-standardized volume (aOR 14.42, 95% CI 3.49 to 59.62), clinical grading (aOR 2.11, 95% CI 1.04 to 4.29), and patient-perceived swelling (aOR 2.51, 95% CI 1.33 to 4.73), but not when evaluated by crude volume. Adjuvant radiotherapy was only a risk factor for lymphedema when assessed by body mass index-standardized volume (aOR 15.02, 95% CI 2.34 to 96.57). Aging was a risk factor for lymphedema when assessed by body mass index-standardized volume (aOR 1.07, 95% CI 1.00 to 1.15) and patient-perceived swelling (aOR 1.06, 95% CI 1.02 to 1.10), but not when assessed by crude volume or clinical grading. Increase in body mass index was a risk factor for lymphedema when estimated by crude volume (aOR 1.92, 95% CI 1.36 to 2.71) and patient-perceived swelling (aOR 1.36, 95% CI 1.11 to 1.66), but not by body mass index-standardized volume or clinical grading. The extent of lymphadenectomy was strongly predictive for the development of lymphedema when assessed by body mass index-standardized volume and patient-perceived swelling, but not by crude volume or clinical grading. CONCLUSION: Apparent risk factors for lymphedema differed considerably depending on the method used to determine lymphedema. This highlights the need for a 'gold standard' method when addressing lymphedema for determining risk factors. Funding: Swedish Cancer Society (Cancerfonden)Swedish Cancer Society [CAN2013/620]; Medical Research Council of Southeast SwedenUK Research & Innovation (UKRI)Medical Research Council UK (MRC) [FORSS-308611, FORSS-391311, FORSS-662141, FORSS-858611]; Uppsala-Orebro Regional Research Council [LUL-349271]; Scientific Council of the Region Halland; County Council of Ostergotland; Linkoping University

Objective. The study aimed to determine the incidence of lower limb lymphedema (LLL) after surgery for endometrial cancer (EC) by means of three methods, and to determine the incidence of lymphocysts after one year. Methods. A prospective longitudinal multicenter study was conducted in 14 hospitals in Sweden. Two-hundred-and-thirty-five women with EC were included; 116 underwent surgery that included lymphadenectomy (+LA) and 119 were without lymphadenectomy ( -LA). Lymphedema was assessed objectively on four occasions; preoperatively, at 4-6 weeks, six months and one year postoperatively using systematic measurement of leg circumferences, enabling calculation of leg volumes, and a clinical grading of LLL, and subjectively by the patients perception of lymphedema measured by a lymphedema-specific quality-of-life instrument. Lymphocyst was evaluated by vaginal ultrasonography. Results. After one year the incidence of LLL after increase in leg volume adjusted for body mass index was 15.8% in +LA women and 3.4% in -IA women. The corresponding figures for clinical grading were 24.1% and 11.8%, and for patient-reported perceived LLL 10.7% and 5.1%. The agreement between the modalities revealed fair to moderate correlation between patient-reported LLL and clinical grading, but poor agreement between volume increase and patient-reported LLL or clinical grading. Lymphocysts were found in 43% after one year. Conclusions. Although the incidence of ILL and lymphocysts after surgery for EC including LA seemed to be relatively high the study demonstrated significant variations in incidence depending on the measurement modality. This emphasizes the need for a gold standard of measurement of LLL in clinical practice and research. (C) 2020 Elsevier Inc. All rights reserved. Funding Agencies|Swedish Cancer Society [Cancerfonden]Swedish Cancer Society [CAN2013/620]; Medical Research Council of Southeast Sweden [FORSS-308611, FORSS-391311, FORSS-662141, FORSS-858611]; Uppsala-Orebro Regional Research Council [LUL-349271]; Scientific Council of the Region Halland; County Council of Ostergotland; Linkoping University

OBJECTIVES We evaluated birth-cohort differences in depressive symptom burden, prevalence of depression diagnoses, and neuroticism, among Swedish 70-year-olds examined between 1976 and 2016. METHODS We used a repeated cross-sectional design examining four representative population samples of Swedish 70-year-olds (total n = 2279) with identical methods in 1976-77 (n = 392), 1992-93 (n = 226), 2000-02 (n = 487), and 2014-16 (n = 1166). Depressive symptom burden was rated with the Montgomery Asberg Depression Rating Scale. Major depression was diagnosed according to DSM-5, and minor depression according to DSM-IV-TR research criteria. Neuroticism was rated with the Eysenck Personality Inventory. RESULTS For women in 2014-16, MADRS score (4.4 vs. 6.1 vs. 5.8; P

Driving under the influence of alcohol is a major problem for traffic-safety and a popular defence argument is alleged consumption after driving, commonly referred to as the hip-flask defence. Forensic toxicologists are often called as expert witnesses in drinking and driving cases where the suspect has claimed the hip-flask defence, to assess the credibility of the explanation. Several approaches to help the expert have been introduced but the scientific data used to support or challenge this is solely based on data from controlled single doses of ethanol administered during a short time and in abstinent subjects. In reality, we believe that even in drinking after driving cases, the subject many times has alcohol on board at time of the hip-flask drink. This questions the applicability of the data used as basis to investigate the hip-flask defence. To fill this knowledge gap, we aimed to investigate how blood and urine ethanol kinetics vary after an initial drinking session of beer and then a subsequent hip-flask drink of three different doses of whiskey. Fifteen subjects participated in the study and each provided 10 urine samples and 17 blood samples over 7h. The initial drink was 0.51g ethanol/kg and the second was either 0.25, 0.51, or 0.85g/kg. Our data suggested that the difference between the ethanol concentrations in two consecutive urine samples is a more sensitive parameter than the ratio between urine and blood alcohol to detect a recent intake when ethanol from previous intakes are already present in the body. Twelve subjects presented results that fully supported a recent intake using the criteria developed from a single intake of ethanol. Three subjects showed unexpected results that did not fully support a recent intake. We conclude that data from one blood sample and two urine samples provide good evidence for investigating the hip-flask defence even if alcohol was on board at the time of the hip-flask drink.

BACKGROUND The older adult population is increasing worldwide, as is the number of older adults who consume alcohol. Although there is a growing body of research on alcohol consumption among older people, few studies focus on changes in at-risk consumption over time across well-defined birth cohorts of older adults. METHODS This study used a serial cross-sectional design in order to compare alcohol consumption patterns among birth cohorts of Swedish 70-year-olds (total n = 2,268) examined in 1976 to 1977 (n = 393), 1992 to 1993 (n = 248), 2000 to 2002 (n = 458), and 2014 to 2016 (n = 1,169). Participants took part in a multidisciplinary study on health and aging. Face-to-face interviews were conducted by healthcare professionals. Protocols regarding alcohol consumption were similar for all cohorts. The volume of weekly alcohol consumption was estimated during the past month. At-risk consumption was defined as ≥100 g alcohol/wk corresponding roughly to the National Institute on Alcohol Abuse and Alcoholism definition of heavy consumption. RESULTS The proportion of at-risk consumers among men increased from 16.1% in 1976 to 1977 to 29.9% in 2000 to 2002 (p = 0.001) and 45.3% in 2014 to 2016 (p

PurposeWe endeavored to investigate whether previous findings of an association between antemortem exposure to selective serotonin re-uptake inhibitors (SSRI) and method of suicide could be replicated.MethodsUsing the Swedish National Board of Forensic Medicines toxicology database and the Swedish National Board of Health and Welfares national registries of causes of death and prescriptions, 10,002 incidents of suicide were retrieved. Risks of violent suicide conferred by SSRIs, expressed as odds ratios (ORs) with 95% confidence intervals (CIs), were estimated using logistic regression. In accordance with previous work, suicide by violent meanscaseswere defined as death attributable to causes designated by ICD-10 codes X70-X83 and Y20-Y33; and suicide by non-violent meanscontrolsby codes X60-X69 and Y10-Y19.ResultsOur results imply that SSRI exposure confers a risk of violent suicide for shorter treatment durations; and that antemortem exposure to other substances (including illegal drugs) confounds estimates of risk. After adjustment for age, sex, and other substances, SSRIs treatment not exceeding 28days conferred an almost fourfold risk of violent suicide (OR 3.6 [95% CI 1.9-6.8]), a finding partly in line with a recent Swedish study that employed a case-crossover design.ConclusionsAlthough risks associated with shorter treatment duration may reflect latencies to onset of therapeutic effect, it is unclear how latencies would influence the choice of suicide method, unless conditions for which SSRIs are prescribed are themselves associated with violent suicide. Finally, in the total dataset, SSRIs were not associated with an increased risk of violent suicide; however, by adjusting for other substances, we avoided the spurious conclusion that the effect of medications in this regard is protective.

3-methoxyphencyclidine (3-MeO-PCP) appeared on the illicit drug market in 2011 and is an analogue of phencyclidine, which exhibits anesthetic, analgesic and hallucinogenic properties. In this paper, we report data from a non-fatal intoxication and seven deaths involving 3-MeO-PCP in Sweden during the period March 2014 until June 2016.The non-fatal intoxication case, a 19-year-old male with drug problems and a medical history of depression, was found awake but tachycardic, hypertensive, tachypnoeic and catatonic at home. After being hospitalized, his condition worsened as he developed a fever and lactic acidosis concomitant with psychomotor agitation and hallucinations. After 22h of intensive care, the patient had made a complete recovery. During his hospitalization, a total of four blood samples were collected at different time points. The seven autopsy cases, six males and one female, were all in their twenties to thirties with psychiatric problems and/or an ongoing drug abuse.3-MeO-PCP was identified with liquid chromatography (LC)/time-of-flight technology and quantified using LC-tandem mass spectrometry.In the clinical case, the concentration of 3-MeO-PCP was 0.14μg/g at admission, 0.08μg/g 2.5h after admission, 0.06μg/g 5h after admission and 0.04μg/g 17h after admission. The half-life of 3-MeO-PCP was estimated to 11h. In the autopsy cases, femoral blood concentrations ranged from 0.05μg/g to 0.38μg/g. 3-MeO-PCP was the sole finding in the case with the highest concentration and the cause of death was established as intoxication with 3-MeO-PCP. In the remaining six autopsy cases, other medications and drugs of abuse were present as well.Despite being scheduled in January 2015, 3-MeO-PCP continues to be abused in Sweden. Exposure to 3-MeO-PCP may cause severe adverse events and even death, especially if the user does not receive life-supporting treatment.

Background: The aim of this study was to validate a translated Swedish version of the lymphoedema-specific quality of life questionnaire (LYMQOL) in a cohort of Swedish cancer patients with secondary lymphoedema of the limbs after cancer treatment. Material and methods: We recruited 102 patients with lymphoedema of the arms or legs after cancer treatment who were visiting lymphoedema therapists at the departments of oncology at the university hospitals in Linköping and Umeå. The LYMQOL questionnaires were translated forward and backward from English to Swedish. Content and face validity were evaluated. The construct validity was assessed by comparing the LYMQOL with the Short Form Health Survey (SF-36) and the perceived degree of lymphoedema of the limbs, respectively. Reliability was determined through test-retest. The internal consistency was assessed by determining Cronbach’s alpha and by factor analysis. Results: The content and face validity assessments showed that LYMQOL was an easy, clear and not too long questionnaire to use for patients with lymphoedema. Construct validity was high in both versions when compared with the SF-36. The association between the degrees of perceived lymphoedema and the LYMQOL was only significant in the domains Function and Body Image in the arm version, whereas all domains in the leg version were significant. The reliability was good for the arm version (intra-class-correlation coefficients 0.53–0.87) and very good for the leg version (intra-class-correlation coefficients 0.78–0.90). The internal consistency was acceptable to excellent, with Cronbach’s alpha values between 0.79–0.93 (arm-version) and 0.87–0.94 (leg-version). The factor analysis confirmed the usefulness of the four domains in the LYMQOL versions. Conclusions: This study confirmed the validity of the Swedish version of LYMQOL and demonstrated that LYMQOL may be a simple and useful tool for use in clinical practice and scientific contexts for evaluating QoL in patients with lymphoedema of the limbs. Funding Agencies|Swedish Cancer SocietySwedish Cancer Society [CAN 2013/620]; Linkoping University; County Council of Ostergotland

Aim: Claimed intake of alcohol after a traffic incident, called the hip-flask defence, can be objectively assessed by different methods. One of them is the use of two consecutive ethanol concentrations in urine and the ratio between ethanol concentrations in urine and blood. Another one is the concentrations of ethyl glucuronide (EtG) and ethyl sulphate (EtS) in blood and their ratio to ethanol. The experimental basis for both these models is from single dose studies only. The aim of this study was therefore to describe the kinetics of ethanol, EtG and EtS after ingestion of two repeated doses of ethanol and to investigate the usefulness of the different models for the assessment of the hip-flask defence. Methods: Thirty-five subjects ingested a first dose of 0.51 g of ethanol per kilo body weight, and two hours later a second dose (the hip-flask drink) of 0.25, 0.51 or 0.85 g of ethanol per kilo body weight. Ten urine and 17 blood samples were collected and analysed for ethanol, EtG and EtS using fully validated methods. It was investigated if all subjects fulfilled the criteria for recent drinking, according to the two different models, when using the samples collected 180-240 minutes after start of first dose drinking. According to the first model, increase in urinary ethanol concentrations and a ratio UAC/BAC below 1.3 indicated recent drinking. According to the second model, increase in blood EtG concentrations and a ratio ethanol (g/kg)/EtG (mg/L) above 1 indicated recent drinking. Results: All subjects in the high dose group fulfilled all criteria for recent drinking. One subject in the medium dose group and nine subjects in the low dose group failed to show increasing UAC and/or a UAC/ BAC ratio below 1.3. One subject in the low dose group failed to show increasing concentrations of blood EtG, but all subjects showed a ratio ethanol/EtG above 1. Conclusions: The present study showed, by the use of experimental data, that both two models used to investigate the hip-flask defence can be used, but only when the hip-flask dose is sufficiently high. (C) 2020 The Author(s). Published by Elsevier B.V.

Dear Editor,Calcium channel inhibitor and beta blocker overdoses may cause life-threatening circulatory failure that can be challenging to manage. We present a massive overdose of amlodipine and me...

Introduction/Background Development of lymphoedema after treatment of endometrial cancer (EC), is still an unexplored area. The aim of this study was to determine the incidence and clinical presentation of lymphoedema of the legs after surgery for EC including pelvic and para-aortic lymphadenectomy one year postoperatively. Methodology An observational multicentre study conducted in 14 centres in Sweden recruited 262 women. 130 women with high-risk early-stage EC underwent surgery including pelvic and para-aortic lymphadenectomy and 132 with low-risk EC had surgery without lymphadenectomy. Systematic leg circumference measurements enabling calculation of leg volumes were performed on four occasions; preoperatively, 4–6 weeks, 6 months, and 1 year postoperatively. Clinical evaluation of lymphoedema by a lymph therapist was conducted on the same occasion. A 10% increase in volume from baseline was categorised as lymphoedema. Results The incidence of lymphoedema increased from 1.8% at the 4–6 weeks assessment to 15% one year postoperatively when lymphadenectomy had been performed. The corresponding figures in the non-lymphadenectomy group were 1.7% to 9.3%. There was no significant difference in incidence on any occasion between the lymphadenectomy and non-lymphadenectomy group (table 1). In women with more than 10% increase in leg volume, 60.7% was objectively clinically graded as normal by lymph therapists. The distribution of the occurrence of lymphoedema differed significantly between those who had less than 10% increase in leg volume and those who had ≥ 10% (table 2). Conclusion The incidence of lymphoedema in legs caused by lymphadenectomy after surgery for EC seemed to be low when assessed by leg volume measurements. Clinically grading of lymphoedema seemed to be underestimated by lymph therapists especially in those who had ≥ 10% increase in leg volume. This raise concerns about the methods of determining and reporting lymphoedema. Disclosure Nothing to disclose.

Aims The first aim of this study was to provide prevalence suicidal feelings over time (past week, past month, past year and lifetime) in a population-based sample of old to very old adults without dementia. Does prevalence change with rising age? The second aim was to examine the fluctuation of suicidal feelings over time. How does this coincide with depression status? Methods Data were derived from the Gothenburg H70 Birth Cohort Studies (the H70 studies) which are multidisciplinary longitudinal studies on ageing. A representative sample of adults in Gothenburg, Sweden with birth years 1901–1944 were invited to take part in a longitudinal health study on ageing and participated at one or more occasions during 1986–2014. The sample consisted of 6668 observations originating from 3972 participants without dementia between the ages of 70 and 108, including 1604 participants with multiple examination times. Suicidal feelings were examined during a psychiatric interview using the Paykel questions (life not worth living, death wishes, thoughts of taking own life, seriously considered taking life, attempted suicide). Results Prevalence figures for suicidal feelings of any severity were as follows: past week 4.8%, past month 6.7%, past year 11.2% and lifetime 25.2%. Prevalence rates increased with age in the total group and in women but not in men. Suicidal feelings were common in participants with concurrent major or minor depression, but over a third of the participants who reported suicidal feelings did not fulfil criteria for these diagnoses nor did they present elevated mean depressive symptom scores. The majority of participants consistently reported no experience of suicidal feelings over multiple examination times, but fluctuation was more common in women compared with men. Conclusion Suicidal feelings in late-life are uncommon in individuals without depression indicating that such behaviour is not a widespread, normative phenomenon. However, such feelings may occur outside the context of depression.

To improve health care for older persons, we need to learn more about ageing, e.g. identify protective factors and early markers for diseases. The Gothenburg H70 Birth Cohort Studies (the H70 studies) are multidisciplinary epidemiological studies examining representative birth cohorts of older populations in Gothenburg, Sweden. So far, six birth cohorts of 70-year-olds have been examined over time, and examinations have been virtually identical between studies. This paper describes the study procedures for the baseline examination of the Birth cohort 1944, conducted in 2014–16. In this study, all men and women born 1944 on specific dates, and registered as residents in Gothenburg, were eligible for participation (n = 1839). A total of 1203 (response rate 72.2%; 559 men and 644 women; mean age 70.5 years) agreed to participate in the study. The study comprised sampling of blood and cerebrospinal fluid, psychiatric, cognitive, and physical health examinations, examinations of genetics and family history, use of medications, social factors, functional ability and disability, physical fitness and activity, body composition, lung function, audiological and ophthalmological examinations, diet, brain imaging, as well as a close informant interview, and qualitative studies. As in previous examinations, data collection serves as a basis for future longitudinal follow-up examinations. The research gained from the H70 studies has clinical relevance in relation to prevention, early diagnosis, clinical course, experience of illness, understanding pathogenesis and prognosis. Results will increase our understanding of ageing and inform service development, which may lead to enhanced quality of care for older persons. Electronic supplementary material The online version of this article (10.1007/s10654-018-0459-8) contains supplementary material, which is available to authorized users.

Background: Chronic rhinosinusitis with and without nasal polyps (CRSw/sNP) are common conditions decreasing health-related quality of life (HRQOL). Individual symptoms capable of predicting outcome after endoscopic sinus surgery (ESS) are poorly defined, and the indirect costs of CRS is rarely reported in Europe. Methodology: Patients with CRSw/sNP admitted for ESS were prospectively enrolled. Patients completed the 22 Sinonasal Outcome Test (SNOT-22), the short-form 36-item questionnaire (SF-36), a Visual Analogue Scale (VAS) and reported CRS-related absenteeism pre- and post-operatively. Results: 181 patients were included. The SNOT-22 score diminished from 51.8 (48.7-55.0) pre-operatively to 33.0 (29.2-36.8) at 6 months. 64% achieved a clinically important improvement in the SNOT-22. SF-36 scores improved statistically significantly in all domains except Role Emotional. The VAS score halved from 68 (65-71) to 34 (29-39) at 6 months post-operatively. A pre-operative SNOT-22 score over 20 implied a greater chance of score improvement after 6 months. A multivariate model identified individual items associated with SNOT-22. Further, patients that had lees than 12 months of sinus disease derived greatest benefit. CRS-related absenteeism dropped from 8-14 days to 1-7 days 12 months after ESS. Conclusions: This prospective study showed that ESS significantly improved the HRQOL and decreased absenteeism of patients with CRSw/sNP. Shorter duration of disease and Need to blow nose and Blockage/congestion of nose of SNOT-22 were identified as predictive factors for good surgical outcome.

Long-term testosterone replacement therapy is mainly monitored by trough levels of serum testosterone (S-T), while urinary testosterone (U-T) is used by forensic toxicology to evaluate testosterone doping. Testosterone in saliva (Sal-T) may provide additional information and simplify the sample collection. We aimed to investigate the relationships between testosterone measured in saliva, serum and urine during standard treatment with 1,000 mg testosterone undecanoate (TU) every 12th week during 1 year. This was an observational study. Males with primary and secondary hypogonadism (HG; n = 23), subjects with gender dysphoria (GD FtM; n = 15) and a healthy control group of men (n = 32) were investigated. Sal-T, S-T and U-T were measured before and after TU injections. Sal-T was determined with Salimetrics

In postmortem investigations of fatal intoxications it is often challenging to determine which drug/s caused the death. To improve the interpretation of postmortem blood concentrations of sedative and hypnotic drugs and/or clonazepam, all medico-legal autopsies in Sweden - where these drugs had been detected in femoral vein blood during 1992-2006 - were identified in the databases of the National Board of Forensic Medicine. For each drug, concentrations in postmortem control cases - where the cause of death was not intoxication and where incapacitation by drugs could be excluded - were compiled as well as the levels found in living subjects; drugged driving cases and therapeutic drug monitoring cases. Subsequently, fatal intoxications were assessed with regards to the primary substances contributing to death, and blood levels were compiled for single and multiple drug intoxications. The postmortem femoral blood levels are reported for 16 sedative and hypnotic drugs, based on findings in 3560 autopsy cases. The cases were classified as single substance intoxications (N = 498), multiple substance intoxications (N = 1555) and postmortem controls (N = 1507). Each autopsy case could be represented more than once in the group of multiple intoxications and among the postmortem controls if more than one of the included substances were detected. The concentration ranges for all groups are provided. Overlap in concentrations between fatal intoxications and reference groups was seen for most substances. However, the concentrations found in single and multiple intoxications were significantly higher than concentrations found in postmortem controls for all substances except alprazolam and triazolam. Concentrations observed among drugged drivers were similar to the concentrations observed among the therapeutic drug monitoring cases. Flunitrazepam was the substance with the highest number of single intoxications, when related to sales. In summary, this study provides reference drug concentrations primarily to be used for improving interpretation of postmortem drug levels in obscure cases, but which also may assist in drug safety work and in pharmacovigilance efforts.

To improve the interpretation of fatal intoxications by establishing fatal and non-fatal reference concentrations of metformin in postmortem femoral blood and to further evaluate risk factors associated with fatal metformin intoxication.All forensic autopsies in Sweden where metformin was detected in femoral blood 2011-2016 were identified in the National Board of Forensic Medicine databases (NFMD). The cases were classified as single substance intoxications, A (n = 22), multiple substance intoxications, B (N = 7) and postmortem controls, C (N = 13). The control group consisted of cases where metformin was detected, but the cause of death excluded the incapacitation by metformin or other substances. Strict inclusion criteria were used, and all postmortem cases were assessed by two independent reviewers. All other cases where the inclusion criteria of groups A-C where not met formed group O (N = 78). The forensic findings logged in the NFMD where linked to national registers whereby information on comorbidities, dispensed drugs and clinical data could be obtained.The mean age was 66 ± 10 years in the total study population and did not differ between the groups. The proportion of men was 64% in group A, 71% in B, 77% in C and 74% in group O. The median values of metformin in group A (48.5 μg/g; range 13.0-210 μg/g) and B (21.0 μg/g; range 4.40-95.0 μg/g) were significantly (p 0.001 and p = 0.015 respectively) higher than those of the control group C (2.30 μg/g ; range 0.70-21.0 μg/g). The median concentration of metformin in group A and B was also significantly higher than in group O (4.60 μg/g; range 0.64-54.0 μg/g) (p 0.001 and p = 0.040 respectively). The results suggest that intoxication with metformin as a cause of death should be considered when the postmortem femoral blood level exceeds about 10 μg/g, although higher levels may be seen in postmortem in cases without incapacitation. The metformin intoxication was confirmed to be intentional in 23% (n = 5) of the single intoxications. Underlying factors identified as important for the remaining fatal metformin intoxications included living alone, any contraindication for the use of metformin, known alcohol abuse and a history of stroke or cardiovascular disease.The reported post mortem femoral blood concentrations of metformin can hopefully contribute to a better interpretation of results in suspected poisonings and obscure cases. Living in a single household, history of cardiovascular disease and contraindications, predominantly alcohol abuse, were associated with fatal metformin intoxication.

The national clinical final examination (NCFE) plays an important role in order to measure the level of knowledge and performance of nursing students. Our findings indicate that the design of the NCFE is beneficial for the students' clinical reasoning and problem solution in the caring situa- tion. The aim of this study was to investigate the experiences of the NCFE from lecturers who cor- rected the written part examination. A further aim was to study the lectures and the RN during observation in the bedside part of the examination. The NCFE is divided into two parts: a theoreti- cal (written) part and a practical (bedside) part. In nursing education it is essential to assess nursing competencies for the future professional role such as the assessment of clinical compe- tence that has become central to evaluate what outcomes are assessed. In addition, it provides a valuable approach to measure the level of knowledge and performance of nursing students. Fu- ture development of the NCFE is necessary regarding the degree to which the examination meets learning objectives and educational results.

Background: According to both in vitro and in vivo data P-glycoprotein (P-gp) may restrict the uptake of several antidepressants into the brain, thus contributing to the poor success rate of current antidepressant therapies. The therapeutic activity of citalopram resides in the Senantiomer, whereas the R-enantiomer is practically devoid of serotonin reuptake potency. To date, no in vivo data are available that address whether the enantiomers of citalopram and its metabolites are substrates of P-gp. Methods: P-gp knockout (abcb1ab (-/-)) and wild-type (abcb1ab (+/+)) mice underwent acute (single-dose) and chronic (two daily doses for 10 days) treatment with citalopram (10 mg/kg) or escitalopram (5 mg/kg). Serum and brain samples were collected 1-6 h after the first or last i.p. injection for subsequent drug analysis by an enantioselective HPLC method. Results: In brain, 3-fold higher concentrations of S- and R-citalopram, and its metabolites, were found in abcb1ab (-/-) mice than in abcb1ab (+/+) mice after both acute and chronic citalopram treatments. After escitalopram treatment, the S-citalopram brain concentration was 3-5 times higher in the knockout mice than in controls. Conclusions: The results provide novel evidence that the enantiomers of citalopram are substrates of P-gp. Possible clinical and toxicological implications of this finding need to be further elucidated.

Over-consumption of alcohol and/or abuse of other drugs are closely linked to attempted or completed suicides. In this retrospective 10-year study (2001-2010), we compared the toxicology findings in hanging suicides (n = 4551) with drug poisoning (intoxication) suicides (n = 2468). The mean age of hanging deaths was 49 ± 19 y (±SD) and 80% were male, compared with a mean age of 52 ± 17 y and 47% males for the intoxication deaths. Poly-drug use was more common in poisoning suicides with an average of 3.6 drugs/case compared with 1.8 drugs/case in hangings. Moreover, 31% of hangings were negative for alcohol and/or drugs. Alcohol was detected (>0.20 g/L) in femoral blood in 30% of hanging suicides (mean 1.39 g/L) and 36% of drug poisonings (mean 1.39 g/L). The median BACs did not depend on the person's age or gender (p > 0.05). Ethanol, paracetamol, citalopram, diazepam, propiomazine, alimemazine and zopiclone were amongst the top-ten drugs detected in both methods of suicide. With the exception of ethanol, the concentrations of drugs in blood were considerably higher in the poisoning deaths, as might be expected. Regardless of the method of suicide, antidepressants and/or antipsychotics were common findings, which could implicate mental health as a significant suicide risk factor. Language: en

OBJECTIVE: To assess trends in the use of antidepressants among young suicides after the warning that these drugs might increase the risk of suicide. METHOD: Individual data of all 845 suicides in the 10- to 19-year age group in Sweden in the time period 1992-2003 (baseline), and in 2004-2010 (after the warning). Outcome data are prescriptions of antidepressants prior to death and detections of antidepressants in post-mortem toxicology. RESULTS: After the warning, suicide in this age group increased for five consecutive years (60.5%). The increase occurred among individuals not treated with antidepressants. CONCLUSION: This study provides further support for the hypothesis that the warning, contrary to its intention, may have increased young suicides by leaving a number of suicidal young persons without treatment with antidepressants. Language: en

NMR spectroscopy is uniquely suited for atomic resolution studies of biomolecules such as proteins, nucleic acids and metabolites, since detailed information on structure and dynamics are encoded in positions and line shapes of peaks in NMR spectra. Unfortunately, accurate determination of these parameters is often complicated and time consuming, in part due to the need for different software at the various analysis steps and for validating the results. Here, we present an integrated, cross-platform and open-source software that is significantly more versatile than the typical line shape fitting application. The software is a completely redesigned version of PINT (https://pint-nmr.github.io/PINT/). It features a graphical user interface and includes functionality for peak picking, editing of peak lists and line shape fitting. In addition, the obtained peak intensities can be used directly to extract, for instance, relaxation rates, heteronuclear NOE values and exchange parameters. In contrast to most available software the entire process from spectral visualization to preparation of publication-ready figures is done solely using PINT and often within minutes, thereby, increasing productivity for users of all experience levels. Unique to the software are also the outstanding tools for evaluating the quality of the fitting results and extensive, but easy-to-use, customization of the fitting protocol and graphical output. In this communication, we describe the features of the new version of PINT and benchmark its performance. Electronic supplementary material The online version of this article (doi:10.1007/s10858-017-0141-6) contains supplementary material, which is available to authorized users.

Jonatan Hedlund *, Johan Ahlner , Marianne Kristiansson , Joakim Sturup a,b National Board of Forensic Medicine, Department of Forensic Psychiatry, PO Box 4044, SE-141 04 Huddinge, Sweden Karolinska Institutet, Department of Clinical Neuroscience, SE-171 77 Stockholm, Sweden National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Artillerigatan 12, SE-587 58 Linkoping, Sweden d Linkoping University, SE-581 83 Linkoping, Sweden

Background Reference concentrations of drugs in post-mortem femoral blood furnishes useful information when poisoning (intoxication) deaths are investigated. However, few publications compare the concentrations of drugs in single-drug fatalities with multi-drug intoxications. This article attempts to fill this gap in knowledge. Methods We searched a national forensic toxicology database (TOXBASE) and found N =13,963 deaths attributed by pathologists to intoxication by drugs (poisoning). The manner of death, whether accidental, suicidal or undetermined intent, was also available. To compare drug concentrations in living and deceased persons, we used information from people arrested for driving under the influence of drugs (DUID). Results The percentage of drug intoxication deaths classified as undetermined intent decreased and accidental overdose deaths increased during the study period. In 2010 manner of death was considered accidental, suicidal or undetermined, in 41%, 30% and 28% of victims, respectively. Most of the deceased had taken multiple drugs (mean three drugs/case) and four or more drugs were identified in 35% of deaths. In single-drug fatalities ethanol (1585), morphine (114), citalopram (28), propoxyphene (51), flunitrazepam (70), propiomazine (46), tramadol (20) and zopiclone (15) were most prevalent. Alprazolam and diazepam were common findings in multi-drug deaths, although these benzodiazepines were rarely encountered in mono-drug intoxication deaths. Median blood concentrations were appreciably higher (2–10 fold) in single-drug fatalities compared with multi-drug deaths. The blood concentrations in DUID suspects were mostly lower than in the multi-drug poisoning deaths. Conclusion This compilation of femoral blood concentrations of drugs in poisoning deaths provides a useful reference material, because we have distinguished between mono-drug intoxication deaths and poisoning with multiple-drugs.

Most patients with advanced cancer experience severe pain and are often treated with opiates. Cancer patients are especially susceptible to opportunistic infections due to treatment with immunosuppressive and cytostatic drugs. Since opiates have been demonstrated to have immunomodulatory effects, it is of clinical importance to evaluate potential differences between commonly used opiates with regard to their effect on the immune system. The aim of this study was to evaluate the effect of morphine, tramadol, fentanyl and ketobemidone on the functioning of the immune system with special reference to TNF and IL-8 release. Method. U-937 cells were preincubated with different concentrations of opioids followed by stimulation with LPS 100 μg/ml for three hours. The effect of opioids on the levels of cytokine mRNA was studied using RT-PCR. Erk and Akt phosphorylation was also measured by Western blot. Results. All opioids with the exception of fentanyl were capable of inhibiting TNF release from U-937 cells. Morphine had no effect on IL-8 release but the effect of other opiates was almost the same as the effect on TNF. All opioids with the exception of fentanyl were capable of inhibiting production of mRNA for TNF and IL-8. The observed effects of opiates were not always reversible by naloxone, suggesting that the effects might be mediated by other receptors or through a non-receptor mediated direct effect. Although preliminary evidence suggests the involvement of Erk and Akt pathways, further studies are needed to unravel the intracellular pathways involved in mediating the effects of opiates. Our data suggests that the order of potency with regard to inhibition of cytokine release is as follows: tramadol > ketobemidone > morphine > fentanyl. Conclusion. Further studies are needed to understand the clinical implications of the observed immunosuppressive effects of tramadol and ketobemidone and to improve opioid treatment strategies in patients with cancer.

The concentration of free-morphine was determined in peripheral (femoral) blood from heroin-related deaths and compared with the concentration in venous blood from impaired drivers. The presence of 6-MAM in blood or urine served as a biomarker for recent use of heroin. Males dominated over females (p0.001) in both the autopsy cases (88%) and the drivers (91%), although their mean age was about the same 33-35 y (p0.05). Concentrations of free-morphine in blood were not associated with age of heroin users in Sweden (p0.05). The median concentration of free-morphine was higher in autopsy cases (0.24 mg/L, N=766) compared with apprehended drivers with 6-MAM in blood (0.15 mg/L, N=124, p0.05), and appreciably higher than in drivers with 6-MAM in urine but not in blood (0.03 mg/L, N=1823, p0.001). The free-morphine concentration was above 0.20mg/L in 65% of autopsy cases, 36% of drivers with 6-MAM in blood but only 1.4% of drivers with 6-MAM in urine. Poly-drug deaths had about the same concentrations of free-morphine in blood (0.24 mg/L, N=703) as heroin-only deaths (0.25 mg/L, N=63). The concentration of morphine in drug overdose deaths (median 0.25 mg/L, N=669) was about the same as in traumatic deaths among heroin users (0.23 mg/L, N=97). However, the concentration of morphine was lower when the deceased had consumed alcohol (0.18 mg/L, N=104) compared with taking a benzodiazepine (0.32 mg/L, N=94). The concentration distributions of free-morphine in blood in heroin-related deaths overlapped with the concentrations in impaired drivers, which makes the interpretation of toxicology results difficult without knowledge about tolerance to opiates in any individual case.

Concentrations of d,l-methadone were determined in blood samples from people arrested for driving under the influence of drugs (DUID), users of illicit drugs, and methadone-related deaths. In drug overdose deaths (N = 346), mean (median) and highest concentrations of methadone in femoral blood were 0.53 mg/L (0.40 mg/L) and 6.7 mg/L, compared with 0.46 mg/L (0.30 mg/L) and 3.7 mg/L in non-poisoning deaths (N = 157) (p < 0.05). In DUID suspects and users of illicit drugs (N = 909), the blood-methadone concentrations were much lower, 0.23 mg/L (0.20 mg/L) and 1.1 mg/L (p < 0.001). The median concentration of methadone in blood decreased as the number of coingested drugs increased in the overdose deaths: 0.5 mg/L with methadone the only drug compared with 0.2 mg/L with 6-9 other drugs present (p < 0.001). These coingested drugs were mainly benzodiazepines (diazepam, alprazolam, flunitrazepam) and amphetamines; THC and morphine (from heroin) were the major illicit drugs. The overlap in blood-methadone concentrations in living cases and autopsy cases makes it difficult to conclude that methadone overdose was the cause of death. Adverse drug-drug interactions and varying degrees of tolerance to opiates complicate the interpretation.

Chronic painful wounds, a major health problem, have a detrimental impact on the quality of life due to associated pain. Some clinical reports have suggested that local administration of morphine could be beneficial. The aim of this study was to evaluate the analgesic effect of topically applied morphine on chronic painful leg ulcers. Twenty-one patients were randomly assigned to receive either morphine or placebo in a randomised, placebo-controlled, crossover pilot study. Each patient was treated four times in total. Pain was measured by the visual analogue score (VAS) before application of gel, directly after and after 2, 6, 12 and 24 hours. Although an overall, clinically relevant, reduction of pain was observed upon treatment with morphine, the difference was not statistically significant. Morphine reduced pain scores more than placebo on treatment occasions 1 and 2. The difference was statistically significant only 2 hours after dressing on the first treatment occasion. Thus, our study did not demonstrate a consistent and globally significant difference in nociception in patients treated with morphine. However, the relatively small number of patients included in our study and other methodological limitations makes it difficult for us to draw general conclusions regarding efficacy of topically applied morphine as an effective treatment for some painful ulcers. Further studies are warranted to evaluate the value of topically applied morphine in the treatment of patients with chronic painful leg ulcers.

Zopiclone is a short-acting hypnotic drug used for treatment of insomnia and its stability has been described in some detail. However, data especially on short-term pre-analytical stability is missing. This study investigated zopiclone stability differences between spiked and authentic whole blood from subjects dosed with zopiclone. In this way influence from physiological factors such as drug interactions, matrix composition and plasma protein levels were minimized. Nine volunteers participated in the study. Whole blood was obtained before and after oral administration of 10 mg Imovane®. Aliquots of 1 g of authentic and spiked blood were after initial measuring, stored at 20 °C during 5 days, 5 or −20 °C during 3 months, and zopiclone was measured by gas chromatography with nitrogen phosphorus detection. The results showed no stability differences between authentic and spiked blood but confirmed the very short stability in whole blood at ambient temperature. In summary, the stability was less than 1 day at 20 °C, less than 2 weeks at 5 °C but stable for 3 months at −20 °C. This study demonstrates the importance of controlling pre-analytical conditions from sampling to analysis to avoid misinterpretation of toxicological results.

Over a 10-year period (1998-2007) all deaths in Sweden classified by forensic pathologists as fatal drug poisonings (N = 6894) were retrieved from a toxicology database (TOXBASE) belonging to the National Board of Forensic Medicine. The deaths were further classified as suicides N = 2288 (33%), undetermined N = 2260 (33%) and accidental N = 2346 (34%). The average age (± SD) of all victims was 49.1 ± 15.9 years and men 47.4 ± 15.6 years were 5-year younger than women 52.2 ± 15.8 years (p < 0.01). Most of the deceased (78%) were poly-drug users although a single drug (mono-intoxications) was found in 22% of all poisoning deaths (p < 0.001). The number of drugs in blood samples varied from 1 to 12 with a median of 3-4 per case. Mono-intoxication deaths were mostly ethanol-related (N = 976) and the mean and median blood-alcohol concentration (BAC) was 3.06 g/L and 3.10 g/L, respectively. The BAC decreased as the number of additional drugs in blood increased from 2.15 g/L with one drug to 1.25 g/L with 6 or more drugs. The mean (median) concentrations of non-alcohol drugs in mono-intoxication deaths were morphine (N = 93) 0.5mg/L (0.2mg/L), amphetamine (N = 39) 2.0mg/L (1.2mg/L), dextropropoxyphene (N = 33) 3.9 mg/L (2.9 mg/L), dihydro-propiomazine (N = 32) 1.6 mg/L (1.0mg/L) and 7-amino-flunitrazepam (N = 28), 0.4 mg/L (0.3mg/L). Elevated blood morphine in these poisoning deaths mostly reflected abuse of heroin as verified by finding 6-monoacetyl morphine (6-MAM) in the blood samples. When investigating drug poisoning deaths a comprehensive toxicological analysis is essential although the results do not reveal the extent of prior exposure to drugs or the development of pharmacological tolerance. The concentrations of drugs determined in post-mortem blood are one element in the case. The autopsy report, the police investigation, the findings at the scene and eye-witness statements should all be carefully considered when the cause and manner of death are determined.

Objective: Ecological studies have demonstrated a substantial decrease in suicide in parallel with an increasing use of antidepressants. To investigate on the individual level the hypothesis that antidepressant medication was a causal factor. Method: Data on the toxicological detection of antidepressants in 18 922 suicides in Sweden 1992-2003 were linked to registers of psychiatric hospitalization as well as registers with sociodemographic data. Results: The probability for the toxicological detection of an antidepressant was lowest in the non-suicide controls, higher in suicides, and even higher in suicides that had been psychiatric in-patients but excluding those who had been in-patients for the treatment of depression. Conclusion: The finding that in-patient care for depression did not increase the probability of the detection of antidepressants in suicides is difficult to explain other than by the assumption that a substantial number of depressed individuals were saved from suicide by postdischarge treatment with antidepressant medication. Language: en

ESPEN 2018 Abstract Submission Topic: Nutritional epidemiology Abstract Submission Identifier: ESPEN18-ABS-1511 ALCOHOL AND DIETARY INTAKE AMONG 70-YEAR-OLDS – RESULTS FROM THE GOTHENBURG H70 BIRTH ...

Zopiclone is a common drug in forensic cases and it is frequently analyzed in biological materials using different analytical methods. Zopiclone is unstable in certain solvents and depending on storage conditions unstable in biological fluids; however its stability in human whole blood has not yet been established in detail. Therefore, the following investigation was performed to study the stability of zopiclone in both spiked and authentic human blood. First, spiked blood samples were stored at -20 degrees C, 5 degrees C and 20 degrees C and the degradation of zopiclone was investigated. Second, authentic and spiked blood samples were stored at 5 degrees C and differences in zopiclone stability were studied. Third, processed sample stability and effect of freeze/thaw cycles were evaluated. Analyses were performed by GC-NPD and zopiclone concentrations were measured at selected time intervals. The study showed that zopiclone degrades in human blood depending on time and temperature and may not be detected after long-term storage. 2-amino-5-chloropyridine was identified as the primary degradation product from zopiclone. At refrigerator temperature zopiclone was stable less than 1 month in both spiked and authentic human blood samples. The best storage condition was at -20 degrees C even at short storage times, as freeze-thaw had no influence on the results. In butyl acetate extracts, zopiclone was stable at least 2 days when kept in the autosampler at ambient temperature. We conclude that preanalytical factors have great impact on analytical results and should be addressed when interpreting whole blood zopiclone concentrations.

Caffeine is widely available in beverages and in different over-the-counter products, including tablets containing 100 mg caffeine. Because intentional fatal intoxications with caffeine occur, the maximum quantity of caffeine tablets that can be bought over the counter in a single purchase was restricted from 250 to 30 in Sweden in the year 2004. The objective of this article was to study the effect of this decision on the number of fatal caffeine intoxications.In Sweden 95% of all cases undergoing forensic autopsy are screened for a number of drugs including caffeine. All cases during January 1993-September 2009 with a caffeine concentration above 80 microg/g blood were recorded.During the study period toxicological investigations were performed in 83,580 forensic autopsies. Caffeine contributed to the fatal outcome in 20 cases (0.02%). Thirteen (65%) of these fatalities occurred before the introduction of the sales restriction. However, no fatal intoxications where caffeine contributed to the cause of death was recorded between May 2007 and September 2009.Overdoses of tablets containing caffeine can be fatal, suicides as well as accidents occur. Restricting the maximum quantity of caffeine tablets available over the counter seemed to be effective in preventing suicides because of caffeine although some time elapsed until the effect was noted. Further monitoring is required to ensure that the observed lower caffeine mortality is a sustained effect.

BACKGROUND: Tramadol is a weak opioid analgesic, which is generally considered to be safe. However, conflicting data exist on the dependence potential of tramadol. OBJECTIVE: The aim of this study ...

Enalapril 40 mg or tolerated dose was given once daily to 21 patients with congestive heart failure (CHF), NYHA class III, in addition to treatment with digoxin and/or diuretics. After an 8-week open period, 19 patients were randomized to continue enalapril or to receive a placebo in a double-blind manner. After the first enalapril dose of 10 mg, maximal reduction of blood pressure (BP) occurred after 4 hours (mean 34/17 mmHg; p less than 0.001). No further reduction was found after higher doses. After the open period significant improvement was shown as judged by NYHA class (p less than 0.01), stroke volume (p less than 0.05), maximal working capacity (p less than 0.05), heart volume (p less than 0.01) and maximum rate pressure product (RPPmax) (p less than 0.001). Urinary aldosterone markedly decreased (p less than 0.01), whereas serum potassium and serum creatinine slightly increased (p less than 0.05). At the end of the blind period enalapril was superior to placebo concerning NYHA class (p less than 0.01), heart volume (p less than 0.05) and RPPmax (p less than 0.05). Other parameters, including aldosterone in urine, did not differ between the groups. Carry-over effects may have diminished the differences between enalapril and placebo. Diarrhoea (n = 5) and hypotension (n = 5) were the most common side-effects. Overall, enalapril was well tolerated and seems to be useful in single daily doses in the treatment of CHF.

According to statistics provided by the Swedish National Road Administration (Vägverket), a total of 1403 drivers were killed in road-traffic crashes in Sweden between 2003 and 2007. Forensic autopsies were performed in approximately 97% of all deaths and specimens of blood and urine were sent for toxicological analysis. In 60% of cases (N=835) the toxicology results were negative and 83% of these victims were men. The blood-alcohol concentration (BAC) was above the legal limit for driving (0.2g/L) in 22% of cases (N=315) at mean, median and highest concentrations of 1.7 g/L, 1.7 g/L and 4.9 g/L, respectively. The proportions of male to female drivers with BAC0.2g/L were 93% vs 7% compared with 83% vs 17% for those with drugs other than alcohol in blood. Drivers with a punishable BAC were over-represented in single vehicle crashes compared with multiple vehicle crashes (67% vs 33%). The opposite held for drivers who had taken a prescription drug (39% vs 61%) and also for drug-negative cases (31% vs 69%). Drugs other than alcohol were identified in 253 cases (18%); illicit drugs only in 39 cases (2.8%), both licit and illicit in 28 cases (2.0%) and in 186 cases (13.3%) one or more therapeutic drugs were present. Amphetamine was the most common illicit drug identified at mean, median and highest concentrations of 1.5mg/L, 1.1mg/L and 5.0mg/L, respectively (N=39). Blood specimens contained a wide spectrum of pharmaceutical products (mean 2.4 drugs/person), comprising sedative-hypnotics (N=93), opiates/opioids (N=69) as well non-scheduled substances, such as paracetamol (N=78) and antidepressants (N=93). The concentrations of these substances in blood were mostly in the therapeutic range. Despite an appreciable increase (12-fold) in number of arrests made by the police for drug-impaired driving after a zero-tolerance law was introduced (July 1999), alcohol still remains the psychoactive substance most frequently identified in the blood of drivers killed in road-traffic crashes.

Human peripheral vein (v. saphena magna) was exposed in vitro to glyceryl trinitrate (GTN) 0.1 mM for 1 h. The subsequent relaxant effect of GTN (10nM-0.1 mM) on vessels contracted by serotonin (0.25 microM) was significantly reduced on vessels preexposed to GTN as compared to control vessels, indicating a development of partial tolerance as far as the vascular smooth muscle relaxant effect is concerned. The impaired relaxant effect was paralleled by a reduced increment of intracellular cyclic GMP. This is, in turn, probably a consequence of both a diminished guanylate cyclase activity and an elevated phosphodiesterase activity in the GTN-tolerant vessels. The relaxant activity as well as the level of intracellular cyclic GMP were restored in GTN-tolerant vessels by dipyridamole (5 microM), an agent with phosphodiesterase inhibiting properties.

Mirtazapine is a tetracyclic antidepressant drug available as a racemic mixture of S(+)- and R(−)-mirtazapine. These enantiomers have different pharmacological properties, and both contribute to the clinical and adverse effects of the drug. Cytochrome P450 (CYP) 2D6 has been implicated in the metabolism of S(+)-mirtazapine. However, the effect of CYP2D6 on serum concentrations of the enantiomers of mirtazapine and its metabolites has not been assessed in patients on long-term treatment. The main objective of the study was to evaluate the effect of the CYP2D6 genotype on enantiomeric steady-state trough serum concentrations of mirtazapine and its metabolites N-desmethylmirtazapine and 8-hydroxymirtazapine. The effects of sex, age and smoking behaviour were also assessed. The study included 95 patients who had depression according to the Diagnostic and Statistical Manual of Mental Disorders — 4th Edition and were treated for 4 weeks with a daily dose of mirtazapine 30 mg. The serum concentrations of the enantiomers of mirtazapine and its metabolites were analysed by liquid chromatography-mass spectrometry, and the subjects were genotyped for CYP2D6 alleles *3, *4, *5 and *6 and gene duplication. Three subjects (3%) were classified as ultrarapid metabolizers (UMs), 56 (59%) as homozygous extensive metabolizers (EMs), 30 (32%) as heterozygous EMs and 6 (6%) as poor metabolizers (PMs) of CYP2D6. The median trough serum concentrations of S(+)-mirtazapine were higher in PMs (59 nmol/L, p = 0.016) and in heterozygous EMs (39 nmol/L, p = 0.013) than in homozygous EMs (28 nmol/L). PMs and heterozygous EMs also had higher mirtazapine S(+)/ R(−) ratios (0.4) than homozygous EMs (0.3, p = 0.015 and 0.004, respectively). The S(+)- N-desmethylmirtazapine concentration was higher in PMs (16 nmol/L) than in homozygous EMs (7 nmol/L, p = 0.043). There was an association between the CYP2D6 genotype and the ratio between S(+)-8-hydroxymirtazapine and S(+)-mirtazapine, with a significantly higher ratio in homozygous EMs than in heterozygous EMs (0.11 vs 0.05, p = 0.007). The influence of the CYP2D6 genotype on S(+)-mirtazapine, the mirtazapine S(+)/ R(−) ratio and S(+)- N-desmethylmirtazapine remained significant after correction for the influence of sex, age and smoking. Smokers had significantly lower concentrations of S(+)-mirtazapine (23 vs 39 nmol/L, p = 0.026) and R(−)- N-desmethylmirtazapine (39 vs 51 nmol/L, p = 0.036) and a significantly lower mirtazapine S(+)/R(−) ratio (0.28 vs 0.37, p = 0.014) than nonsmokers, and the effect of smoking remained significant after multivariate analysis. This study is the first to show the impact of the CYP2D6 genotype on steady-state serum concentrations of the enantiomers of mirtazapine and its metabolites. Our results also support the role of CYP1A2 in the metabolism of mirtazapine, with lower serum concentrations in smokers than in nonsmokers.

There is limited information on the pharmacokinetics ofziprasidone (ZIP) in naturalistic clinical settings. The objective of this study was to investigate the concentrations of ZIP and its active metabolite S-methyl-dihydroziprasidone (SMDZ), and the dose-normalized concentrations, using routine therapeutic drug monitoring (TDM) data. A high-performance liquid chromatographic method for determining serum concentrations of these substances for routine clinical use was established at the TDM Laboratory in Linköping, Sweden. This analytical service was available to all physicians in Sweden. Between January 2001 and December 2004, 545 analyses, representing samples from 370 patients, were performed. The median daily ZIP dose was 120 mg (range 20 -320 mg). In all, 121 steady-state trough specimens with essential clinical information were included in the pharmacokinetic evaluation. The median (25th to 75th percentile) serum concentration of ZIP was 125 nmol/L (82-188 nmol/L). The SMDZ:ZIP ratio decreased with increasing serum concentration of ZIP. The median (25th to 75th percentile) dose-normalized concentrations (nmol L(-1) mg(-1) d(-1) forZIPand SMDZ were 1.13 (0.74-1.77) and 0.62 (0.45-0.86), respectively,with SMDZ:ZIP ratio of 0.57 (0.42-0.79). The overall coefficients of variation for dose-normalized serum concentrations of ZIP, SMDZ, andSMDZ:ZIP ratio were 62%, 56%, and 57%, respectively (n = 121). Smoking women had lower normalized ZIP concentrations than nonsmoking women. Twenty-eight patients with repeated eligible TDM analyses were studied for intraindividual variance over time. In summary, great interindividual and intraindividual differences in ZIPconcentrations were observed. TDM of ZIP maybe used for individual dose adjustments and monitoring medication adherence.