The nationwide case-cohort study in pharmacoepidemiology: a study of iatrogenic anaphylaxis and agranulocytosis

Drug safety is an important palt of postmarketing surveillance. In ancient times, people were already aware of the fact that drugs could have side effects. The oldest drugs were mainly of plant and animal origin, but also mercury, arsenic and antimony were used, the toxic effects of which were well known. In 1224 Frederick II, Emperor of Hohenstaufen ordered inspection of drugs and mixtures prepared by apothecaries and in 1518 the Royal college of Physicians was founded, whose Fellows were also concemed with quality control of drugs. The first drug to be banned because of its toxicity was antimony in the 17th century. It was used again, however, after it cured Louis XIV from typhoid fever. One of the first descriptions of an intoxication to a drug which is still in use today, was made by William Withering in 1785. He described digitalis intoxication as follows: "The Foxglove, when given in very large and quickly repeated doses, occasions sickness, vomiting, purging, giddiness, confused vision, objects appearing green or yellow, increased secretion of urine with frequent motions to patt with it, and sometimes inability to retain it; slow pulse, even as low as 35 in a minute, cold sweats, convulsions, syncope and death"

High prevalence of impaired awareness of hypoglycemia and severe hypoglycemia among people with insulin-treated type 2 diabetes: The Dutch Diabetes Pearl Cohort

Objective People with type 2 diabetes on insulin are at risk for hypoglycemia. Recurrent hypoglycemia can cause impaired awareness of hypoglycemia (IAH), and increase the risk for severe hypoglycemia. The aim of this study was to assess the prevalence and determinants of self-reported IAH and severe hypoglycemia in a Dutch nationwide cohort of people with insulin-treated type 2 diabetes. Research design and methods Observational study of The Dutch Diabetes Pearl, a cohort of people with type 2 diabetes treated in primary, secondary and tertiary diabetes care centers. The presence of IAH and the occurrence of severe hypoglycemia in the past year, defined as an event requiring external help to re

Susceptibility to chronic mucus hypersecretion, a genome wide association study

Background: Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations. Methods: GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and meta-analysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (≥20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP). Results: A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25x10-6, OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3x10 -9) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture. Conclusions: Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH

The association between various smoking behaviors, cotinine biomarkers and skin autofluorescence, a marker for advanced glycation end product accumulation.

Background: Skin autofluorescence, a biomarker for advanced glycation end products (AGEs) accumulation, has been shown to predict diabetes-related cardiovascular complications and is associated with several environmental and lifestyle factors. In the present study, we examined the association between various smoking behaviors and skin autofluorescence, as well as the association between several cotinine biomarkers and skin autofluorescence, using both epidemiological and metabolomics data. Methods: In a cross-sectional study, we evaluated participants from the LifeLines Cohort Study and the Qatar Metabolomics Study on Diabetes (QMDiab). In the LifeLines Cohort Study smoking behavior and secondhand smoking were assessed in 8,905 individuals including 309 individuals (3.5%) with type 2 diabetes. In QMDiab, cotinine biomarkers were measured in saliva, plasma and urine in 364 individuals of whom 188 (51%) had type 2 diabetes. Skin autofluorescence was measured non-invasively in all participants using the AGE Reader. Results: Skin autofluorescence levels increased with a higher number of hours being exposed to secondhand smoking. Skin autofluorescence levels of former smokers approached levels of never smokers after around 15 years of smoking cessation. Urinary cotinine N-oxide, a biomarker of nicotine exposure, was found to be positively associated with skin autofluorescence in the QMDiab study (p = 0.03). Conclusions: In the present study, we have demonstrated that secondhand smoking is associated with higher skin autofluorescence levels whereas smoking cessation has a beneficial effect on skin autofluorescence. Finally, urinary cotinine N-oxide might be used as an alternative way for questionnaires to examine the effect of (environmental) tobacco smoking on skin autofluorescence

Comined effects of smoking and alcohol on metabolic syndrome: the lifelines cohort study

Introduction - The development of metabolic syndrome (MetS) is influenced by environmental factors such as smoking and alcohol consumption. We determined the combined effects of smoking and alcohol on MetS and its individual components. Methods - 64,046 participants aged 18–80 years from the LifeLines Cohort study were categorized into three body mass index (BMI) classes (BMI1 drink/day) and tobacco showed higher triglycerides levels. Up to 2 drinks/day was associated with a smaller waist circumference in overweight and obese individuals. Consumption of >2 drinks/day increased blood pressure, with the strongest associations found for heavy smokers. The overall metabolic profile of wine drinkers was better than that of non-drinkers or drinkers of beer or spirits/mixed drinks. Conclusion - Light alcohol consumption may moderate the negative associations of smoking with MetS. Our results suggest that the lifestyle advice that emphasizes smoking cessation and the restriction of alcohol consumption to a maximum of 1 drink/day, is a good approach to reduce the prevalence of MetS. Figure

Influence of storage and inter- and Intra-assay variability on the measurement of inflammatory biomarkers in population-based biobanking.

BACKGROUND: In the present study, we examined the effect of sample storage on the reproducibility of several inflammatory biomarkers, including high-sensitivity C-reactive protein (hsCRP), high-sensitivity interleukin-6 (hsIL6), and high-sensitivity tumor necrosis factor alpha (hsTNFα). In addition, we assessed inter- and intra-assay variability between collaborating biobanks. METHODS: In total, 240 fasting plasma samples were obtained from the LifeLines biobank. Samples had been stored for less than 2 or more than 4 years at -80°C. Measurements were performed at three different laboratories. hsCRP was measured by immunonephelometry and ELISA, hsIL6, and hsTNFα samples were measured with ELISAs from two different manufacturers. For confirmation, similar analyses were performed on samples obtained from a subpopulation of 80 obese individuals. Passing-Bablok regression analysis and Bland-Altman plots were used to compare the results. RESULTS: We observed good stability of samples stored at -80°C. hsCRP measured on the day of blood draw was similar to levels measured after more than 4 years of storage. There were small interlaboratory differences with the R&D ELISAs for hsIL6 and hsTNFα. We found a linear correlation between the Bender Medsystems ELISA and the R&D ELISA for hsIL6, with significantly higher levels measured with the R&D ELISA. Over 90% of hsTNFα samples measured with the IBL ELISA were below the detection limit of 0.13 ng/L, rendering this assay unsuitable for large-scale analysis. Similar results were found in the confirmation study. CONCLUSION: In summary, plasma hsCRP showed good stability in samples stored for either less than 2 years or more than 4 years at -80°C. Both the R&D and Bender Medsystems for hsIL6 measurement yielded similar results. The IBL hsTNFα assay is not suited for use in biobanking samples. Assays for the measurement of inflammatory biomarker assays should be rigorously tested before large sample sets are measured

Skin autofluorescence is related to tobacco smoke and nicotine exposure.

Clinical epidemiolog

Supplementary Material for: Hydrocortisone Dose Influences Pain, Depressive Symptoms and Perceived Health in Adrenal Insufficiency: A Randomized Controlled Trial

<br><strong><em>Background:</em></strong> There is a major lack of randomized controlled trials (RCTs) evaluating the effects of hydrocortisone (HC) substitution therapy in patients with secondary adrenal insufficiency. Therefore, we evaluated the effects of two different replacement doses of HC on health-related quality of life (HRQoL) in a RCT. <b><i>Methods:</i></b> This RCT with a double-blind cross-over design was performed at the University Medical Center Groningen. Forty-seven patients (29 men, age 51 ± 14 years, range 19-73 years) with secondary adrenal insufficiency participated. Patients received both a lower and a higher dose of HC (0.2-0.3 and 0.4-0.6 mg/kg body weight/day) for 10 weeks in random order. HRQoL was assessed with a daily mood and symptom checklist (Patient Health Questionnaire-15 [PHQ-15], Generalized Anxiety Disorder-7 [GAD-7], Patient Health Questionnaire-9 [PHQ-9]) and with questionnaires assessing general well-being (RAND 36-Item Health Survey [RAND-36]), mood (Hospital Anxiety and Depression Scale [HADS]) and fatigue (Multidimensional Fatigue Inventory-20 [MFI-20]). ClinicalTrials.gov identifier: NCT01546922. <b><i>Results:</i></b> Patients receiving the higher dose of HC reported significantly fewer symptoms of depression (p = 0.016 and p = 0.045 for HADS and PHQ-9, respectively), less general and mental fatigue (p = 0.004 and p = 0.003, respectively, both MFI-20), increased motivation (p = 0.021, MFI-20), better physical functioning (p = 0.041), better general health (p = 0.013) and more vitality (p = 0.025) (all RAND-36). In addition, while on the higher dose, fewer somatic symptoms (p = 0.022) and less pain (p < 0.001) (both PHQ-15) were experienced. <b><i>Conclusions:</i></b> On the higher dose of HC, patients reported a better HRQoL on various domains as compared to the lower dose of HC. The fact that a higher dose of HC may improve patient well-being should be taken into consideration when individualizing the HC substitution dose

High prevalence of impaired awareness of hypoglycemia and severe hypoglycemia among people with insulin-treated type 2 diabetes: The Dutch Diabetes Pearl Cohort

Contains fulltext : 218277.pdf (publisher's version ) (Open Access)OBJECTIVE: People with type 2 diabetes on insulin are at risk for hypoglycemia. Recurrent hypoglycemia can cause impaired awareness of hypoglycemia (IAH), and increase the risk for severe hypoglycemia. The aim of this study was to assess the prevalence and determinants of self-reported IAH and severe hypoglycemia in a Dutch nationwide cohort of people with insulin-treated type 2 diabetes. RESEARCH DESIGN AND METHODS: Observational study of The Dutch Diabetes Pearl, a cohort of people with type 2 diabetes treated in primary, secondary and tertiary diabetes care centers. The presence of IAH and the occurrence of severe hypoglycemia in the past year, defined as an event requiring external help to recover, were assessed using the validated Dutch version of the Clarke questionnaire. In addition, clinical variables were collected including age, diabetes duration, hemoglobin A1c, ethnicity and education. RESULTS: 2350 people with type 2 diabetes on insulin were included: 59.1% men, mean age 61.1+/-10.4 years, mean diabetes duration 14.8+/-9.2 years and 79.5% on basal-bolus therapy. A total of 229 patients (9.7%) were classified as having IAH and 742 patients (31.6%) reported severe hypoglycemia. Increased odds for IAH were found with complex insulin regimens and lower odds with having a partner and body mass index >/=30 kg/m(2). Severe hypoglycemia was associated with complex insulin regimens, non-Caucasian ethnicity and use of psychoactive drugs, and inversely with metformin use. CONCLUSIONS: In this nationwide cohort, almost one out of ten people with type 2 diabetes on insulin had IAH and >30% had a history of severe hypoglycemia in the past year