Case report on postmortem fentanyl measurement after overdose with more than 67 fentanyl patches.

PURPOSE: Fentanyl is an analgesic that is frequently prescribed, which resulted in non-intentional as well as intentional misuse and deaths. Here, we present a postmortem case of a patient who clearly died of a fentanyl overdose due to an extensive number of fentanyl patches combined with oral intake of fentanyl and cocaine. We aimed to show how postmortem analysis can be used to interpret postmortem fentanyl concentrations in unique cases like the one we present. CASE DESCRIPTION: A 23-year-old male was found dead in his bedroom with 67 non-prescribed patches of fentanyl on his body. In the room, there also were fentanyl tablets of 100 µg and cocaine powder, which had possibly also been taken by the deceased. To confirm the cause of death, urine and subclavian blood were retrieved to perform a standard postmortem toxicology screening. The toxicological screening revealed the presence of several drugs, including cocaine, fentanyl, lidocaine and paracetamol. Further analysis of the quantitative postmortem values of fentanyl with ultra-performance liquid chromatography-tandem mass spectrometry revealed a fentanyl concentration of 57.9 µg/L. Considering several issues around postmortem drug analyses, this value seemed to be in line with concentrations found in previously reported postmortem cases. CONCLUSION: We were able to confirm the expected cause of death with an extensive toxicological screening in combination with the circumstantial evidence. We identified fentanyl as most important cause for the fatal outcome in this specific case and simultaneously contributed to the limited availability of knowledge on postmortem fentanyl concentrations.

Chronic hepatitis B and C infections in the Netherlands: estimated prevalence in risk groups and the general population.

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are usually asymptomatic for decades, thus targeted screening can prevent liver disease by timely diagnosis and linkage to care. More robust estimates of chronic HBV and HCV infections in the general population and risk groups are needed. Using a modified workbook method, the total number of ever chronically infected individuals in the Netherlands in 2016 was determined using population size and prevalence estimates from studies in the general and high-risk population. The estimated 2016 chronic HBV infection prevalence is 0.34% (low 0.22%, high 0.47%), corresponding to approximately 49 000 (low 31 000, high 66 000) HBV-infected individuals aged 15 years and older. The estimated ever-chronic HCV infection prevalence is 0.16% (low 0.06%, high 0.27%), corresponding to approximately 23 000 (low 8000, high 38 000) ever-chronic HCV-infected individuals. The prevalence of chronic HBV and HCV infections in the Netherlands is low. First-generation migrants account for most infections with 81% and 60% of chronic HBV and HCV infections, respectively. However, about one-fifth of HCV infections is found in the general population at low risk. This method can serve as an example for countries in need of more accurate prevalence estimates, to help the design and evaluation of prevention and control policies.

Strategies for achieving viral hepatitis C micro-elimination in the Netherlands.

The Netherlands is striving to achieve national elimination of the hepatitis C virus (HCV) as one of the first countries worldwide. The favorable HCV epidemiology with both low prevalence and incidence, together with access to care and treatment, present excellent conditions to further build on towards this objective. The Dutch national plan on viral hepatitis, introduced in 2016, defines targets in the HCV healthcare cascade and provides a structural framework for the development of elimination activities. Since many different stakeholders are involved in HCV care in the Netherlands, focus has been placed on micro-elimination initiatives as a pragmatic and efficient approach. These numerous micro-eliminations projects have brought the Netherlands closer to HCV elimination. In the near future, efforts specifically have to be made in order to optimize case-finding strategies and to successfully accomplish the nationwide implementation of the registration and monitoring system of viral hepatitis mono-infections, before this final goal can be reached. The upcoming years will then elucidate if the Dutch' hands on approach has resulted in sufficient progress against HCV and if the Netherlands will lead the way towards nationwide HCV elimination.

[Leading cause of death in young Dutch people: the cigarette]. / Doodsoorzaak nr. 1 bij jonge Nederlanders: de sigaret.

OBJECTIVE: To investigate the impact of smoking on premature death in the Netherlands and the difference between causes of death for smokers and non-smokers. DESIGN: Observational cohort study. METHOD: Data on smoking behaviour were obtained from 40,000 people who participated in the CBS (Statistics Netherlands) health survey between 2001-2006. These data were linked to data on death and cause of death for the 10 years following this questionnaire. Hazard ratios were calculated for premature deaths among smokers, classified into smoking intensity, and ex-smokers as compared with those who had never smoked. These data were used to estimate cumulative death of smokers versus non-smokers. RESULTS: The hazard ratio for premature death was 3.8 (95% CI: 3.2-4.5) for heavy smokers, 2.6 (95% CI: 2.2-3.0) for moderate smokers and 1.7 (95% CI: 1.3-2.3) for light smokers. Lifelong heavy smokers had a chance of 23% of dying before the age of 65. For moderate and light smokers and for non-smokers, the chance was respectively 16, 11 and 7%. For half of all people who died relatively young, cancer was the underlying cause of death. This was mainly lung cancer for smokers. Heavy smokers are estimated to have lost 13 years of life, moderate smokers 9 and light smokers 5. Smoking cessation at any age still benefited health. Ex-smokers who had quit before an approximate age of 35 had the same life expectancy as lifelong non-smokers. CONCLUSION: An estimated four in ten premature deaths can be attributed to smoking in the Netherlands. Cancer is the predominant cause of death amongst smokers. Smoking cessation increases life expectancy. Therefore, the earlier a smoker stops, the better.

Herziene richtlijn 'Behandeling van tabaksverslaving en stoppen met roken ondersteuning'.

- The revised guideline 'Treatment of tobacco addiction and smoking cessation support' offers health professionals a framework to provide evidence-based care to patients who smoke, which should aid in reducing smoking prevalence and smoke-related morbidity and mortality.- Four topics of the guideline have been revised: behavioural interventions, pharmacotherapy, e-health interventions and e-cigarettes. For the other topics, the recommendations from the 2009 version remain unaltered.- It is important that health professionals offer a made-to-measure smoking cessation advice and apply a fit-for-purpose smoking cessation intervention.- Nicotine replacement therapy remains the first-line pharmacotherapy intervention and is most effective when combined with behavioural intervention.- E-health interventions are particularly effective when they are personalised and of an interactive nature, and when text messaging is incorporated.- At present, e-cigarettes are not recommended as an aid to smoking cessation.

The estimated future disease burden of hepatitis C virus in the Netherlands with different treatment paradigms.

BACKGROUND & AIMS: Prevalence of hepatitis C virus (HCV) infection in the Netherlands is low (anti-HCV prevalence 0.22%). All-oral treatment with direct-acting antivirals (DAAs) is tolerable and effective but expensive. Our analysis projected the future HCV-related disease burden in the Netherlands by applying different treatment scenarios. METHODS: Using a modelling approach, the size of the HCV-viraemic population in the Netherlands in 2014 was estimated using available data and expert consensus. The base scenario (based on the current Dutch situation) and different treatment scenarios (with increased efficacy, treatment uptake, and diagnoses) were modelled and the future HCV disease burden was predicted for each scenario. RESULTS: The estimated number of individuals with viraemic HCV infection in the Netherlands in 2014 was 19,200 (prevalence 0.12%). By 2030, this number is projected to decrease by 4 5% in the base scenario and by 85% if the number of treated patients increases. Furthermore, the number of individuals with hepatocellular carcinoma and liver-related deaths is estimated to decrease by 19% and 27%, respectively, in the base scenario, but may both be further decreased by 68% when focusing on treatment of HCV patients with a fibrosis stage of ≥ F2. CONCLUSIONS: A substantial reduction in HCV-related disease burden is possible with increases in treatment uptake as the efficacy of current therapies is high. Further reduction of HCV-related disease burden may be achieved through increases in diagnosis and preventative measures. These results might inform the further development of effective disease management strategies in the Netherlands.

Historical epidemiology of hepatitis C virus (HCV) in select countries - volume 2.

Chronic hepatitis C virus (HCV) infection is a leading cause of liver related morbidity and mortality. In many countries, there is a lack of comprehensive epidemiological data that are crucial in implementing disease control measures as new treatment options become available. Published literature, unpublished data and expert consensus were used to determine key parameters, including prevalence, viremia, genotype and the number of patients diagnosed and treated. In this study of 15 countries, viremic prevalence ranged from 0.13% in the Netherlands to 2.91% in Russia. The largest viremic populations were in India (8 666 000 cases) and Russia (4 162 000 cases). In most countries, males had a higher rate of infections, likely due to higher rates of injection drug use (IDU). Estimates characterizing the infected population are critical to focus screening and treatment efforts as new therapeutic options become available.

Strategies to manage hepatitis C virus (HCV) infection disease burden - volume 2.

The hepatitis C virus (HCV) epidemic was forecasted through 2030 for 15 countries, and the relative impact of two scenarios was considered: (i) increased treatment efficacy while holding the treated population constant and (ii) increased treatment efficacy and increased annual treated population. Increasing levels of diagnosis and treatment, in combination with improved treatment efficacy, were critical for achieving substantial reductions in disease burden. In most countries, the annual treated population had to increase several fold to achieve the largest reductions in HCV-related morbidity and mortality. This suggests that increased capacity for screening and treatment will be critical in many countries. Birth cohort screening is a helpful tool for maximizing resources. In most of the studied countries, the majority of patients were born between 1945 and 1985.

The present and future disease burden of hepatitis C virus (HCV) infections with today's treatment paradigm - volume 2.

Morbidity and mortality attributable to chronic hepatitis C virus (HCV) infection are increasing in many countries as the infected population ages. Models were developed for 15 countries to quantify and characterize the viremic population, as well as estimate the number of new infections and HCV related deaths from 2013 to 2030. Expert consensus was used to determine current treatment levels and outcomes in each country. In most countries, viremic prevalence has already peaked. In every country studied, prevalence begins to decline before 2030, when current treatment levels were held constant. In contrast, cases of advanced liver disease and liver related deaths will continue to increase through 2030 in most countries. The current treatment paradigm is inadequate if large reductions in HCV related morbidity and mortality are to be achieved.

Cerebrovascular risk factors do not contribute to genetic variance of cognitive function: the ERF study.

Impaired cognition in later life may result from Alzheimer's disease-related pathology, but also from vascular pathology. We studied to what extent vascular risk explained heritability of cognition in 780 individuals, related in one extended pedigree in a genetically isolated population, in the ERF study. Heritability was estimated using variance components modelling (SOLAR). Univariate analyses included models with and without vascular disease; bivariate analyses included both cognitive and vascular traits, such as blood pressure, serum glucose or lipids. Heritability for immediate and delayed recall, recognition, semantic fluency, Trail making B and Stroop tests was significant, with estimates from 0.16 to 0.36. Vascular factors did not affect cognitive functions, except immediate recall and the Stroop test. Heritability estimates did not change significantly when adjusted for vascular disease. We found no genetic correlation between cognition and vascular traits. Therefore, in this population vascular disease is mildly associated with cognitive dysfunction, and in those with vascular disease, the underlying genetic risk factors are not likely to account for the genetic variation in cognition at adult age.

Heritability of the function and structure of the arterial wall: findings of the Erasmus Rucphen Family (ERF) study.

BACKGROUND AND PURPOSE: Using 930 individuals connected in a single pedigree from an isolated population, participants of the Erasmus Rucphen Family (ERF) study, we investigated the heritability of carotid-femoral pulse wave velocity (PWV), carotid intima media thickness (IMT), and carotid plaque score. METHODS: PWV was measured between the carotid and femoral arteries as an indicator of aortic stiffness. Common carotid IMT and plaque score, quantifying alterations in arterial wall structure, were measured by ultrasonography. RESULTS: All 3 traits were significantly associated with classic cardiovascular risk factors. Age- and gender-adjusted heritability estimates were 0.36 for PWV, 0.41 for carotid IMT, and 0.28 for plaque score. After adjustment for appropriate risk factors, the heritabilities were 0.26, 0.35, and 0.21 for PWV, IMT, and plaque score, respectively. All heritability estimates were statistically significant (P<0.001). Taking into account different proportions of variance associated with covariates for each trait, genetic factors explained &12% of the total variability for each of the phenotypes. CONCLUSIONS: To our knowledge, this is the first report on the heritability of PWV. The heritability estimates of IMT and plaque score were similar to those in previous reports. We conclude that genetic factors significantly contribute to arterial structure and function in this isolated population, presenting the opportunity to locate susceptibility genes related to cardiovascular disorders.

Mortality from Creutzfeldt-Jakob disease and related disorders in Europe, Australia, and Canada.

BACKGROUND: An international study of the epidemiologic characteristics of Creutzfeldt-Jakob disease (CJD) was established in 1993 and included national registries in France, Germany, Italy, the Netherlands, Slovakia, and the United Kingdom. In 1997, the study was extended to Australia, Austria, Canada, Spain, and Switzerland. METHODS: Data were pooled from all participating countries for the years 1993 to 2002 and included deaths from definite or probable CJD of all etiologic subtypes. RESULTS: Four thousand four hundred forty-one cases were available for analysis and included 3,720 cases of sporadic CJD, 455 genetic cases, 138 iatrogenic cases, and 128 variant cases. The overall annual mortality rate between 1999 and 2002 was 1.67 per million for all cases and 1.39 per million for sporadic CJD. Mortality rates were similar in all countries. There was heterogeneity in the distribution of cases by etiologic subtype with an excess of genetic cases in Italy and Slovakia, of iatrogenic cases in France and the UK, and of variant CJD in the UK. CONCLUSIONS: This study has established overall epidemiologic characteristics for Creutzfeldt-Jakob disease (CJD) of all types in a multinational population-based study. Intercountry comparisons did not suggest any relative change in the characteristics of sporadic CJD in the United Kingdom, and the evidence in this study does not suggest the occurrence of a novel form of human bovine spongiform encephalopathy infection other than variant CJD. However, this remains a possibility, and countries currently unaffected by variant CJD may yet have cases.

Predictors of survival in sporadic Creutzfeldt-Jakob disease and other human transmissible spongiform encephalopathies.

A collaborative study of human transmissible spongiform encephalopathies has been carried out from 1993 to 2000 and includes data from 10 national registries, the majority in Western Europe. In this study, we present analyses of predictors of survival in sporadic (n = 2304), iatrogenic (n = 106) and variant Creutzfeldt-Jakob disease (n = 86) and in cases associated with mutations of the prion protein gene (n = 278), including Gerstmann-Sträussler-Scheinker syndrome (n = 24) and fatal familial insomnia (n = 41). Overall survival for each disease type was assessed by the Kaplan-Meier method and the multivariate analyses by the Cox proportional hazards model. In sporadic disease, longer survival was correlated with younger age at onset of illness, female gender, codon 129 heterozygosity, presence of CSF 14-3-3 protein and type 2a prion protein type. The ability to predict survival based on patient covariates is important for diagnosis and counselling, and the characterization of the survival distributions, in the absence of therapy, will be an important starting point for the assessment of potential therapeutic agents in the future.

Octapeptide repeat insertions in the prion protein gene and early onset dementia.

OBJECTIVES: The most common familial early onset dementia mutations are found in the genes involved in Alzheimer's disease; the amyloid precursor protein (APP) and the presenilin 1 and 2 (PSEN1 and 2) genes; the prion protein gene (PRNP) may be involved. METHODS: Following identification of a two-octapeptide repeat insertion in PRNP, we conducted a meta-analysis to investigate the relation of number of PRNP octapeptide repeats with age at disease onset and duration of illness; identifying 55 patients with PRNP octapeptide repeat insertions. We used a linear mixed effects model to assess the relation of number of repeats with age at disease onset, and studied the effect of the number of inserted octapeptide repeats on disease duration with a Cox proportional hazards regression analysis. RESULTS: We found an increasing number of repeats associated with younger age at onset (p < 0.001). Duration of the disease decreased significantly with the length of the octapeptide repeat (p < 0.001) when adjusting for age at onset. CONCLUSIONS: Our findings show significant inverse associations of the length of the PRNP octapeptide repeat with age at disease onset and disease duration in the spongiform encephalopathies.

Sporadic Creutzfeldt-Jakob disease and surgery: a case-control study using community controls.

BACKGROUND: The cause of sporadic Creutzfeldt-Jakob disease (CJD) is unknown. Previous studies found a link with a history of surgery but had methodologic problems. OBJECTIVE: To help elucidate medical and associated risk factors for sporadic CJD as part of the 1993 to 1995 European Union collaborative studies of CJD. METHODS: Medical and associated risk factors from 326 patients with sporadic CJD, taken from population-based studies performed between 1993 and 1995 in France, Germany, the Netherlands, and the UK, were compared with 326 community controls recruited by telephone in 2000. RESULTS: A history of surgery was significantly associated with the risk of sporadic CJD (odds ratio [OR]: 1.8; 95% CI: 1.2 to 2.6), which was not dependent on the number of surgical procedures, and was stronger in females (OR: 2.5; 95% CI: 1.5 to 4.0). Gynecologic (OR: 1.5; 95% CI: 1.0 to 2.3) and "other" operations (any operation other than neurologic, eye, ear, gallbladder, gastrointestinal, and gynecologic operations, tonsillectomy, and appendectomy) (OR: 1.5; 95% CI: 1.1 to 2.1) were associated with risk of CJD. Tonsillectomy (OR: 0.3; 95% CI: 0.2 to 0.5) and appendectomy (OR: 0.6; 95% CI: 0.4 to 0.8) were observed less frequently in cases. An increased risk was also found with a history of ear piercing in females (OR: 1.6; 95% CI: 1.1 to 2.5) and psychiatric visit(s) (OR: 2.6; 95% CI: 1.5 to 4.3). CONCLUSIONS: These results support the hypothesis that cases of sporadic CJD may result from hitherto unrecognized surgical contamination events. However, because of the limits of the study design, the rarity of the disease, and the potential for bias, the results should be interpreted with caution.

Creutzfeldt-Jakob disease 38 years after diagnostic use of human growth hormone.

A 47 year old man is described who developed pathology proven Creutzfeldt-Jakob disease (CJD) 38 years after receiving a low dose of human derived growth hormone (hGH) as part of a diagnostic procedure. The patient presented with a cerebellar syndrome, which is compatible with iatrogenic CJD. This is the longest incubation period described so far for iatrogenic CJD. Furthermore, this is the first report of CJD after diagnostic use of hGH. Since the patient was one of the first in the world to receive hGH, other cases of iatrogenic CJD can be expected in the coming years.

[Creutzfeldt-Jakob disease: diagnosis, incidence, prevention and treatment]. / Ziekte van Creutzfeldt-Jakob: diagnostiek, incidentie, preventie en behandeling.

Creutzfeldt-Jakob disease (CJD) is a rare, neurodegenerative disorder belonging to the spongiform encephalopathies. A variant form (vCJD) is most likely the result of infection with the agent that causes bovine spongiform encephalopathy (BSE). Diagnostic information can be obtained by EEG, testing cerebrospinal fluid for the presence of the 14-3-3 protein, MRI, brain biopsy, tonsil biopsy, and postmortem brain examination. Some tests, such as MRI and postmortem brain examination, can be used to distinguish between CJD and vCJD. Pathological prions in a tonsil biopsy are only found with vCJD. In the Netherlands, there are four known cases of iatrogenic CJD. On the basis of certain exposure to BSE via the food chain, cases of vCJD are also to be expected. Chloropromazine and mepacrine are known to inhibit the formation of pathological prion conformations, but clinical trials have not yet been carried out.

The first two patients with dura mater associated Creutzfeldt-Jakob disease in the Netherlands.

Creutzfeldt-Jakob disease (CJD) can be transmitted through human growth hormone or gonadotrophin administration, dura mater or cornea transplantation, depth EEG monitoring and the use of contaminated neurosurgical instruments. We describe the first two dura mater associated CJD cases in the Netherlands. Ten and fourteen years before the onset of symptoms both patients received a Lyodura implantation. Findings are discussed in light of the growing epidemic of CJD among dura mater recipients.

Influence of the prion protein and the apolipoprotein E genotype on the Creutzfeldt-Jakob Disease phenotype.

We investigated the risk associated with the codon 129 polymorphism in the prion protein gene (PRNP) and apolipoprotein E gene (APOE) isoforms for development of Creutzfeldt-Jakob disease (CJD) (n=126) and the possible influences on the disease pathology and its most important clinical characteristics. The PRNP M129V (PRNP129) polymorphism was determined using both DNA extracted from formalin fixed and paraffin embedded brain tissue (n=59) and leukocyte extracted DNA (n=67). In the latter group also the PRNP open reading frame and the APOE genotype were analysed and compared to a neurologically unaffected, age and sex matched control group (n=79). We found that methionine homozygosity of the PRNP129 increases the risk for developing CJD. PRNP129 also influenced the prion accumulation patterns in brain. The APOE 4 allele was an independent risk factor for developing CJD. We further observed a significant dose dependent APOE 4 effect on the number and type of amyloid-beta plaques in the brain of CJD patients.