Fatal Intoxications with Zopiclone-A Cause for Concern?

INTRODUCTION: Zopiclone, a controlled substance prescribed for insomnia, has become a common toxicological finding in forensic autopsy cases. This study investigated the role and extent of zopiclone use in fatal intoxications in Sweden. METHODS: All forensic autopsy cases positive for zopiclone in femoral blood during 2012-2020 were selected. Among these cases, fatalities caused by intoxication according to the cause of death certificates issued by the forensic pathologist were identified. Intoxications where zopiclone contributed to the cause of death were included in the study. The Swedish Prescribed Drug Register was utilized to examine whether the included cases were prescribed zopiclone or not. RESULTS: In total 7320 fatal intoxications underwent a forensic autopsy during the study period, 573 of them were caused by zopiclone. Among the zopiclone fatalities, 87% (n = 494) had a prescription for zopiclone, and 8% (n = 43) were monointoxications. Most fatalities, 62% (n = 354) were suicides, and zopiclone was involved in about 17% (n = 354) of all intoxication suicides in Sweden. Women were significantly (p < 0.01) overrepresented in suicides with zopiclone, comprising 56% (n = 291) of fatalities. The median age was 55 years among zopiclone intoxications compared with 44 years amongst all fatal intoxications. CONCLUSION: This study demonstrates that the toxicity of zopiclone can be lethal both in combination with other substances and on its own. Most individuals dying in fatal zopiclone intoxications were prescribed zopiclone, which potentially indicates that a more restrictive prescribing rate could prevent future intoxication deaths, especially when caring for patients with an increased suicide risk.

Do P2Y12 receptor inhibitors prescribed poststroke modify the risk of cognitive disorder or dementia? Protocol for a target trial using multiple national Swedish registries.

INTRODUCTION: The target of a class of antiplatelet medicines, P2Y12R inhibitors, exists both on platelets and on brain immune cells (microglia). This protocol aims to describe a causal (based on a counterfactual model) approach for analysing whether P2Y12R inhibitors prescribed for secondary prevention poststroke may increase the risk of cognitive disorder or dementia via their actions on microglia, using real-world evidence. METHODS AND ANALYSIS: This will be a cohort study nested within the Swedish National Health and Medical Registers, including all people with incident stroke from 2006 to 2016. We developed directed acyclic graphs to operationalise the causal research question considering potential time-independent and time-dependent confounding, using input from several experts. We developed a study protocol following the components of the target trial approach described by Hernan et al and describe the data structure that would be required in order to make a causal inference. We also describe the statistical approach required to derive the causal estimand associated with this important clinical question; that is, a time-to-event analysis for the development of cognitive disorder or dementia at 1, 2 and 5-year follow-up, based on approaches for competing events to account for the risk of all-cause mortality. Causal effect estimates and the precision in these estimates will be quantified. ETHICS AND DISSEMINATION: This study has been approved by the Ethics Committee of the University of Gothenburg and Confidentiality Clearance at Statistics Sweden with Dnr 937-18, and an approved addendum with Dnr 2019-0157. The analysis and interpretation of the results will be heavily reliant on the structure, quality and potential for bias of the databases used. When we implement the protocol, we will consider and document any biases specific to the dataset and conduct appropriate sensitivity analyses. Findings will be disseminated to local stakeholders via conferences, and published in appropriate scientific journals.

Oxycodone-Related Deaths: The Significance of Pharmacokinetic and Pharmacodynamic Drug Interactions.

BACKGROUND AND OBJECTIVES: Oxycodone is frequently prescribed as well as detected in postmortem cases. Concurrent use of pharmacodynamically or pharmacokinetically interacting drugs can cause adverse effects or even fatal intoxication. The aims of this study were to investigate differences in prescriptions for and toxicological findings of pharmacodynamically and pharmacokinetically interacting drugs in fatal oxycodone-related intoxications and other causes of death. We also aimed to investigate the differences in prevalence of oxycodone prescriptions, and the detected postmortem oxycodone concentrations between fatal oxycodone-related intoxications and other causes of death. METHODS: Forensic autopsy cases (2012-2018) where oxycodone was identified in femoral blood (n = 1236) were included. Medical history and prescription data were retrieved from national databases and linked to the forensic toxicology findings. RESULTS: Oxycodone-related deaths were found to have higher blood concentrations of oxycodone (median 0.30 µg/g vs. 0.05 µg/g) and were less likely to have a prescription for oxycodone (OR 0.62) compared to nonintoxication deaths. Pharmacodynamically interacting drugs were prescribed in 79% and found in blood in 81% of the cases. Pharmacokinetically interacting drugs were rarely prescribed (1%). Oxycodone-related deaths were more likely to have prescriptions for a pharmacodynamically interacting drug (OR 1.7) and more often have co-findings of one or multiple pharmacodynamically interacting drugs (OR 5.6). CONCLUSION: The results suggest that combined use of oxycodone and pharmacodynamically interacting drugs is associated with oxycodone-related death and that non-medical use of oxycodone is a potential risk factor for oxycodone-related intoxication.

False negative results in testosterone doping in forensic cases: Sensitivity of the urinary detection criteria T/E and T/LH.

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.

Late-adolescent risk factors for suicide and self-harm in middle-aged men: explorative prospective population-based study.

BACKGROUND: Recent reports show alarmingly high rates of suicide in middle-aged men, yet there are few long-term prospective studies that focus on suicidal behaviour in men in this age group. AIMS: To prospectively explore associations of potential risk factors at age 18 with suicide and self-harm in middle-aged men. METHOD: A population-based Swedish longitudinal cohort study of male conscripts with no history of self-harm at enlistment in 1968-1989 (n = 987 583). Conscription examinations included measures of cognitive performance, stress resilience, psychiatric diagnoses, body mass index (BMI), cardiovascular fitness and muscle strength. Suicides and self-harm at age 45-65 years were identified in the National Hospital Register and Swedish Cause of Death Register. Risks were calculated using Cox proportional hazards models. RESULTS: Low stress resilience (cause-specific hazard ratio CHR = 2.31, 95% CI 1.95-2.74), low cognitive ability (CHR = 2.01, 95% CI 1.71-2.37) as well as psychiatric disorders and low cardiovascular fitness in late adolescence were associated with increased risk for suicide in middle-aged men. Similar risk estimates were obtained for self-harm. In addition, high and low BMI as well as low muscle strength were associated with increased risk of self-harm. Associations also remained significant after exclusion of men with self-harm before age 45. CONCLUSIONS: This prospective study provides life-course perspective support that psychological and physical characteristics in late adolescence may have long-lasting consequences for suicidal behaviour in middle-aged men, a very large population at heightened risk of suicide.

Cardiovascular fitness and risk of migraine: a large, prospective population-based study of Swedish young adult men.

OBJECTIVES: To examine the longitudinal relationship between cardiovascular fitness in young adult men and future risk of migraine and to estimate eventual differential effects among categories of body mass index (BMI) and blood pressure. DESIGN: National, prospective, population-based cohort study. SETTING: Sweden 1968-2014. PARTICIPANTS: 18-year-old Swedish men (n=1 819 828) who underwent mandatory military conscription examinations during the years 1968-2005. PRIMARY AND SECONDARY OUTCOMES: The primary outcome was the first dispensation of prescribed migraine-specific medication, identified using the Swedish Prescribed Drug Register. The secondary outcome was documented migraine diagnosis from the Swedish National Hospital Register. RESULTS: During follow-up, 22 533 men filled a prescription for migraine-specific medication. After confounding adjustment, compared with high cardiovascular fitness, low and medium fitness increased the risk of migraine-specific medication (risk ratio (RR)low: 1.29, 95% CI 1.24 to 1.35; population attributable fraction: 3.6%, 95% CI 1.7% to 5.3% and RRmedium: 1.15, 95% CI 1.12 to 1.19; population attributable fraction: 8.0%, 95% CI 4.0% to 11.7%). To assess potential effect measure modification, stratified analyses of these association by levels of BMI and blood pressure showed that lower fitness levels increased risk of migraine across all groups except among underweight men or men with high diastolic blood pressure. CONCLUSIONS: Young men with a lower cardiovascular fitness had a higher long-term risk of developing pharmacological prescription-requiring migraine. This study contributes with information regarding risk factors for migraine in men, an understudied population in migraine research.

Late-life suicidal behaviours among new users of antidepressants: a prospective population-based study of sociodemographic and gender factors in those aged 75 and above.

OBJECTIVE: To investigate sociodemographic and gender factors associated with suicide and suicide attempts among new users of antidepressants aged 75 and above. DESIGN: Register-based cohort study. SETTING: National population-based cohort of Swedish residents aged ≥75 years. PARTICIPANTS: 185 225 patients who initiated antidepressant medication between 1 January 2007 and 31 December 2013 were followed until 31 December 2014. MAIN OUTCOME MEASURES: Suicide and suicide attempts. Fine and Gray regression models were used to analyse the sociodemographic factors (age, country of birth, marital status, education level, last occupation, income and social allowance) associated with suicidal behaviours in the entire cohort and by gender. RESULTS: During follow-up, 295 suicides and 654 suicide attempts occurred. Adjusted sub-hazard ratios (aSHRs) for suicide were lower among older age groups (aSHR 0.73, 95% CI 0.53 to 0.99 for those 85-89 years; and aSHR 0.53, 95% CI 0.33 to 0.86 for those ≥90 years). A similar pattern was observed for suicide attempts. Suicide attempts were more common among those born in foreign countries (aSHR 1.58, 95% CI 1.16 to 2.15 for those born in another Nordic country; and aSHR 1.43, 95% CI 1.06 to 1.93 for those born in non-Nordic countries). In the gender-stratified analyses, being single or divorced, and born in another Nordic country was associated with a higher risk of suicide among men. Educational and occupational history and being born in a non-Nordic country influenced risk of suicidal behaviours in women. CONCLUSION: Suicidal behaviours occurred more commonly among new users who were 'younger' old adults and those with foreign background, suggesting that those groups might require greater support when initiating antidepressant therapy. Our findings suggest the need for gender-specific, multifaceted approaches to the prevention of suicidal behaviours in late life.

Antidepressants and suicidal behaviour in late life: a prospective population-based study of use patterns in new users aged 75 and above.

PURPOSE: To investigate associations between antidepressant use patterns and risk of fatal and non-fatal suicidal behaviours in older adults who initiated antidepressant therapy. METHOD: A national population-based cohort study conducted among Swedish residents aged ≥ 75 years who initiated antidepressant treatment. Patients who filled antidepressant prescriptions between January 1, 2007 and December 31, 2013 (N = 185,225) were followed until December 31, 2014. Sub-hazard ratios of suicides and suicide attempts associated with use patterns of antidepressants, adjusting for potential confounders such as serious depression were calculated using the Fine and Gray regression models. RESULTS: During follow-up, 295 suicides and 654 suicide attempts occurred. Adjusted sub-hazard ratios (aSHRs) were increased for both outcomes in those who switched to another antidepressant (aSHR for suicide 2.42, 95% confidence interval 1.65 to 3.55, and for attempt 1.76, 1.32 to 2.34). Elevated suicide risks were also observed in those who concomitantly filled anxiolytics (1.54, 1.20 to 1.96) and hypnotics (2.20, 1.69 to 2.85). Similar patterns were observed for the outcome suicide attempt. Decreased risk of attempt was observed among those with concomitant use of anti-dementia drugs (0.40, 0.27 to 0.59). CONCLUSION: Switching antidepressants, as well as concomitant use of anxiolytics or hypnotics, may constitute markers of increased risk of suicidal behaviours in those who initiate antidepressant treatment in very late life. Future research should consider indication biases and the clinical characteristics of patients initiating antidepressant therapy.

Comparison of Annoyance from Railway Noise and Railway Vibration.

The aim of this study is to compare vibration exposure to noise exposure from railway traffic in terms of equal annoyance, i.e., to determine when a certain noise level is equally annoying as a corresponding vibration velocity. Based on questionnaire data from the Train Vibration and Noise Effects (TVANE) research project from residential areas exposed to railway noise and vibration, the dose response relationship for annoyance was estimated. By comparing the relationships between exposure and annoyance for areas both with and without significant vibration exposure, the noise levels and vibration velocities that had an equal probability of causing annoyance was determined using logistic regression. The comparison gives a continuous mapping between vibration velocity in the ground and a corresponding noise level at the facade that are equally annoying. For equivalent noise level at the facade compared to maximum weighted vibration velocity in the ground the probability of annoyance is approximately 20% for 59 dB or 0.48 mm/s, and about 40% for 63 dB or 0.98 mm/s.

Psychosocial job conditions, fear avoidance beliefs and expected return to work following acute coronary syndrome: a cross-sectional study of fear-avoidance as a potential mediator.

BACKGROUND: Despite improvements in treatment, acute coronary syndrome remains a substantial cause for prolonged sick absences and premature retirement. Knowledge regarding what benefits return to work is limited, especially the effect of psychological processes and psychosocial work factors. The purposes of this cross-sectional study were two-fold: to examine associations between adverse psychosocial job conditions and fear-avoidance beliefs towards work, and to determine whether such beliefs mediated the relationship between work conditions and expected return to work in acute coronary syndrome survivors. METHODS: Study inclusion criteria: acute myocardial infarction or unstable angina diagnosis, below 65 years of age, being a resident in the West county of Sweden and currently working. In all, 509 individuals (21.8 % women) accepted study participation and for whom all data of study interest were available for analysis. Psychosocial work variables; job demand-control and effort-reward imbalance, were assessed with standard questionnaire batteries. Linear regression models were used to investigate relationships between psychosocial factors and fear-avoidance, and to evaluate mediator effects for fear-avoidance. Both total sample and gender stratified analyses were calculated. RESULTS: Fear-avoidance beliefs about work were associated to psychosocial job environments characterized by high strain (ß 1.4; CI 1.2-1.6), active and passive work and high effort-reward imbalance (ß 0.6; CI 0.5-0.7). Further, such beliefs also mediated the relationship between adverse work conditions and expected time for return to work. However, these results were only observed in total sample analyses or among or male participants. For women only high strain was linked to fear-avoidance, and these relationships became non-significant when entering chosen confounders. CONCLUSIONS: This cross-sectional study showed that acute coronary syndrome survivors, who laboured under adverse psychosocial work conditions, held fear-avoidance beliefs towards their workplace. Furthermore, these beliefs mediated the relationships between - high strained or high effort-reward imbalanced work - and expected return to work. However, mentioned results were primarily found among men, which could results from few female study participants or gender differences in return to work mechanisms. Still, an earlier return to work might be promoted by interventions focusing on improved psychosocial work conditions and cognitive behavioural therapy targeting fear-avoidance beliefs.

Regression models for log-normal data: comparing different methods for quantifying the association between abdominal adiposity and biomarkers of inflammation and insulin resistance.

We compared six methods for regression on log-normal heteroscedastic data with respect to the estimated associations with explanatory factors (bias and standard error) and the estimated expected outcome (bias and confidence interval). Method comparisons were based on results from a simulation study, and also the estimation of the association between abdominal adiposity and two biomarkers; C-Reactive Protein (CRP) (inflammation marker,) and Insulin Resistance (HOMA-IR) (marker of insulin resistance). Five of the methods provide unbiased estimates of the associations and the expected outcome; two of them provide confidence intervals with correct coverage.