Drug development for major chronic health conditions-aligning with growing public health needs: Proceedings from a multistakeholder think tank.

The global pharmaceutical industry portfolio is skewed towards cancer and rare diseases due to more predictable development pathways and financial incentives. In contrast, drug development for major chronic health conditions that are responsible for a large part of mortality and disability worldwide is stalled. To examine the processes of novel drug development for common chronic health conditions, a multistakeholder Think Tank meeting, including thought leaders from academia, clinical practice, non-profit healthcare organizations, the pharmaceutical industry, the Food and Drug Administration (FDA), payors as well as investors, was convened in July 2022. Herein, we summarize the proceedings of this meeting, including an overview of the current state of drug development for chronic health conditions and key barriers that were identified. Six major action items were formulated to accelerate drug development for chronic diseases, with a focus on improving the efficiency of clinical trials and rapid implementation of evidence into clinical practice.

Night work and breast cancer risk in a cohort of female healthcare employees in Stockholm, Sweden.

OBJECTIVES: Night work has been classified as probably carcinogenic to humans by the International Agency for Research on Cancer, but epidemiological evidence was considered limited due to variability in findings and potential bias. This study aimed to investigate the risk of breast cancer in a cohort with detailed and registry-based data on night work. METHODS: The cohort comprised 25 585 women (nurses and nursing assistants) employed 1 year or more between 2008 and 2016 in the healthcare sector in Stockholm. Information on work schedules was obtained from employment records. Breast cancer cases were identified from the national cancer register. HRs were estimated by a discrete time proportional hazards model, adjusting for age, country of birth, profession and childbirth. RESULTS: There were 299 cases of breast cancer, 147 in premenopausal and 152 in postmenopausal women. The adjusted HR of postmenopausal breast cancer in association with ever versus never working nights was 1.31 (95% CI 0.91 to 1.85). Eight or more years of night work was associated with an increased risk of postmenopausal breast cancer, HR=4.33 (95% CI 1.45 to 10.57), based on five cases only, though. CONCLUSIONS: This study is limited by a short period of follow-up and a lack of information on night work before 2008. Most exposure metrics showed no association with breast cancer risk, but there was an elevated risk of postmenopausal breast cancer in women after 8 or more years of night work.

Maternal smoking during pregnancy and type 1 diabetes in the offspring: a nationwide register-based study with family-based designs.

BACKGROUND: Maternal smoking during pregnancy was reported to be associated with a reduced risk of type 1 diabetes in the offspring. We investigated whether this association is consistent with a causal interpretation by accounting for familial (shared genetic and environmental) factors using family-based, quasi-experimental designs. METHODS: We included 2,995,321 children born in Sweden between 1983 and 2014 and followed them for a diagnosis of type 1 diabetes until 2020 through the National Patient, Diabetes and Prescribed Drug Registers. Apart from conducting a traditional cohort study, we performed a nested case-control study (quasi-experiment) comparing children with type 1 diabetes to their age-matched siblings (or cousins). Information on maternal smoking during pregnancy was retrieved from the Swedish Medical Birth Register. Multivariable adjusted Cox proportional hazards regression and conditional logistic regression were used. RESULTS: A total of 18,617 children developed type 1 diabetes, with a median age at diagnosis of 9.4 years. The sibling and cousin comparison design included 14,284 and 7988 of these children, respectively. Maternal smoking during pregnancy was associated with a 22% lower risk of offspring type 1 diabetes in the full cohort (hazard ratio 0.78, 95% confidence interval [CI] 0.75-0.82). The corresponding odds ratio was 0.78 (95% CI 0.69-0.88) in the sibling and 0.72 (95% CI 0.66-0.79) in the cousin comparison analysis. CONCLUSIONS: This nationwide, family-based study provides support for a protective effect of maternal smoking on offspring type 1 diabetes. Mechanistic studies are needed to elucidate the underlying pathways behind this link.

Outcome at age 7 of epilepsy presenting in the first 2 years of life. A population-based study.

OBJECTIVE: Existing data suggest that epilepsy presenting in the first few years of life carries a worse prognosis than later onset. However, studies are few and methods differ, making interpretations of data uncertain. This study analyzes outcome at age 7 and potential prognostic factors in a well-characterized population-based cohort with epilepsy onset during the first 2 years of life. METHODS: An incidence cohort of 116 prospectively identified cases of epilepsy with seizure onset before age 2 years was described in Stödberg et al. (2020). Cases were originally retrieved from the Stockholm Incidence Registry of Epilepsy (SIRE), which registered all cases with a first unprovoked epileptic seizure from September 1, 2001, in Northern Stockholm. Data on treatment and outcome at age 7 years were collected from electronic medical records and through interviews with parents. Outcome and potential prognostic factors were analyzed with descriptive statistics and multivariable log binomial regression analysis. RESULTS: Eleven children (9.5%) died before age 7. Polytherapy was common. Epilepsy surgery was performed in two children. At age 7 years, 61 of 116 children (53%) had been seizure-free for the last 2 years or longer. Intellectual disability was diagnosed in 57 of 116 children (49%), autism spectrum disorder in 13 (11%), and cerebral palsy in 28 (24%). West syndrome had a similar seizure remission rate but a worse cognitive outcome. There was no difference in outcome between first and second year onset. Six predictors, including etiology, remained associated with two or more outcome variables after regression analysis. SIGNIFICANCE: About half of children with infantile-onset epilepsy will become seizure-free and half of them will have intellectual disability. Etiology was confirmed as a major independent predictor of outcome. Our study contributes to a more firm knowledge base when counseling parents of infants diagnosed with epilepsy.

Shift and night work during pregnancy and preterm birth-a cohort study of Swedish health care employees.

BACKGROUND: Previous studies of preterm birth (PTB) concerning night work have been inconclusive and partly limited by imprecise data on working schedules. This study investigated the risk of PTB in relation to detailed, registry-based data on working hours. METHODS: In a register-based prospective cohort study, we identified 4970 singleton births with information on PTB from the Swedish Medical Birth Register of health care employees in Stockholm. Day-by-day information on working hours 2008-16 was obtained from a computerized employee register. Odds ratios (ORs) of PTB according to work hour characteristics were analysed by logistic regression adjusted for mother's age, stature, body mass index (BMI), parity, smoking habits, education, profession and country of birth. RESULTS: There was an increased risk of PTB among those who frequently worked night shifts (>25 times) [OR, 1.62; 95% confidence interval (CI), 1.03-2.53] and who ever worked ≥3 consecutive night shifts (OR, 1.43; 95% CI, 1.03-1.99) during the first trimester. Frequently (> 8 times) working 3 or more consecutive nights, and frequently (>18 times) having quick returns from night shifts (<28 h) during the first trimester showed 3-4 fold increased risk of PTB. Moreover, working frequent (>20 times) long shifts (≥10 h) (OR 1.63; 95% CI, 1.07-2.49) during the first trimester and working any Week >40 h (OR 2.05; 95% CI, 1.31-3.22) during the third trimester were associated with PTB. CONCLUSIONS: In this cohort of Swedish health care employees with registry-based data on working hours, night work, especially working frequent consecutive nights, and quick returns from night shifts during the first trimester were associated with increased risk of PTB among pregnant women.

Occupational exposure to respirable crystalline silica and acute myocardial infarction among men and women in Sweden.

OBJECTIVES: Occupational exposure to respirable crystalline silica (RCS) is common. The study aimed to assess the risk for acute myocardial infarction (AMI) after long-term exposure to RCS and to explore differences in risk between men and women. METHODS: The cohort included all manual workers identified from the Swedish National Census in 1980 using data on job titles and demography altogether from five censuses from 1960 to 1990, in total 605 246 men and 480 607 women. Information on AMI was obtained from nationwide registers from 1992 to 2006. Exposure to RCS was assessed with a job-exposure matrix. HRs and 95% CIs were estimated by Cox regression, adjusted for age, socioeconomic status and urbanisation index. RESULTS: Among manual workers ever exposed to RCS, the adjusted risk of AMI was HR 1.29 (95% CI 1.15 to 1.46) in women, and HR 1.02 (95% CI 1.00 to 1.04) in men. In the highest quartile of cumulative exposure, the risk of AMI was HR 1.66 (95% CI 1.27 to 2.18) for women, and HR 1.06 (95% CI 1.03 to 1.10) for men, respectively. The risk of AMI increased with cumulative exposure to RCS both in women (p=0.001) and in men (p=0.016). An interaction analysis showed that the relative risk from exposure to RCS was statistically significantly lower in men than in women at similar exposure levels. CONCLUSIONS: Occupational exposure to RCS was related to the risk of AMI. Women were more sensitive to exposure to RCS than men.

Occupational exposure to particles and increased risk of developing chronic obstructive pulmonary disease (COPD): A population-based cohort study in Stockholm, Sweden.

OBJECTIVES: Chronic Obstructive Pulmonary Disease (COPD) is a common respiratory disorder. Next to tobacco smoking, occupational exposure is the most important risk factor for COPD in high-income countries. To enable preventative measures, more knowledge is needed on which specific occupational exposures that are related to risk of developing COPD in men and women. METHODS: A population-based cohort was formed from subjects responding to the Stockholm Public Health Surveys in 2002, 2006, and 2010, followed up until 2014. The dataset was linked to a quantitative job exposure matrix via occupational titles from the 1990 nation-wide Population and housing census. We identified COPD among subjects having medication for COPD and/or reporting a physician's diagnosis of COPD. The gender-specific risks to develop COPD from occupational particle-exposure were estimated by proportional hazards regression model, adjusted for age and individual data on tobacco-smoking. RESULTS: Men exposed to respirable crystalline silica (RCS) (HR 1.46, CI 1.13-1.90), gypsum and insulation material (HR 1.56, CI 1.18-2.05), diesel exhaust (HR 1.18, CI 0.99-1.41) and high levels of particles from asphalt/bitumen (HR 1.71, CI 1.06-2.76) as well as welding fumes (HR 1.57, CI 1.12-2.21) had an increased smoking-adjusted risk for developing COPD. An increased risk was also observed among women highly exposed to various organic particles from soil, leather, plastic, soot, animal, textile, flour (HR 1.53, CI 1.15-2.04). Furthermore, a significant positive exposure-response trend was found among men exposed to RCS, iron dust, gypsum and insulation material, and diesel exhaust. A tendency towards an exposure-response relationship was also seen among both men and women exposed to welding fumes and various organic particles, and among men exposed to particles from asphalt/bitumen. The population attributable fraction for COPD from occupational exposure to particles was 10.6% among men and 6.1% among women. CONCLUSIONS: This study indicates an increased smoking-adjusted risk of developing of COPD due to occupational exposure to particles. A positive exposure-response relationship was found for RCS, gypsum and insulation, diesel exhaust, and welding fumes. Also, exposure to high levels of asphalt/bitumen and various organic particles was associated with a higher risk for COPD. Reduction of these exposures in the work environment are important to prevent future cases of COPD. More studies are needed to investigate exposure-response relationships further, but this study indicates that the European occupational exposure limit (OEL) for RCS needs to be re-evaluated.

Mortality rates and cardiovascular disease burden in type 2 diabetes by occupation, results from all Swedish employees in 2002-2015.

OBJECTIVE: To identify occupations where employees with type 2 diabetes have a high risk of cardiovascular disease (CVD) and mortality, and their prevalence of CVD risk factors. This study can contribute in the creation of targeted interventions at the workplace. RESEARCH DESIGN AND METHODS: This nationwide registry-based study included all employees with type 2 diabetes born in Sweden in 1937-1979 (n = 180,620) and followed up in 2002-2015. We calculated age-standardized incidence (per 100,000 person-years) of all-cause and CVD mortality, ischemic heart disease (IHD) and stroke across the 30 most common occupations. Information on prognostic factors was retrieved from the National Diabetes Register. RESULTS: In males with type 2 diabetes, mortality rates were highest in manufacturing workers (1782) and machine operators (1329), and lowest in specialist managers (633). The risk of death at age 61-70 years was 21.8% in manufacturing workers and 8.5% in managers. In females with type 2 diabetes, mortality rates were highest in manufacturing workers (1150) and cleaners (876), and lowest in writers and artists (458); the risk of death at age 61-70 years was 12.4% in manufacturing workers and 4.3% in writers and artists. The same occupations also had relatively high incidences of CVD mortality, IHD and stroke. Occupational groups with poor prognosis had high prevalence of CVD risk factors including poor glycemic control, smoking and obesity. CONCLUSIONS: Manufacturing workers, machine operators and cleaners with type 2 diabetes have two to three times higher mortality rates than managers, writers and artists with type 2 diabetes. Major health gains would be made if targeted workplace interventions could reduce CVD risk factors in these occupations.

Pharmacologic treatment and SUDEP risk: A nationwide, population-based, case-control study.

OBJECTIVE: We conducted a nationwide case-control study in Sweden to test the hypothesis that antiepileptic drugs (AEDs) mono- or polytherapy, adherence, antidepressants, neuroleptics, ß-blockers, and statins are associated with sudden unexpected death in epilepsy (SUDEP) risk. METHODS: Included were 255 SUDEP cases and 1,148 matched controls. Information on clinical factors and medications came from medical records and the National Patient and Prescription Registers. The association between SUDEP and medications was assessed by odds ratios (ORs) with 95% confidence intervals (CIs) adjusted for potential risk factors including type of epilepsy, living conditions, comorbidity, and frequency of generalized tonic-clonic seizures (GTCS). RESULTS: Polytherapy, especially taking 3 or more AEDs, was associated with a substantially reduced risk of SUDEP (OR 0.31, 95% CI 0.14-0.67). Combinations including lamotrigine (OR 0.55, 95% CI 0.31-0.97), valproic acid (OR 0.53, 95% CI 0.29-0.98), and levetiracetam (OR 0.49, 95% CI 0.27-0.90) were associated with reduced risk. No specific AED was associated with increased risk. Regarding monotherapy, although numbers were limited, the lowest SUDEP risk was seen in users of levetiracetam (0.10, 95% CI 0.02-0.61). Having nonadherence mentioned in the medical record was associated with an OR of 2.75 (95% CI 1.58-4.78). Statin use was associated with a reduced SUDEP risk (OR 0.34, 95% CI 0.11-0.99) but selective serotonin reuptake inhibitor use was not. CONCLUSION: These results provide support for the importance of medication adherence and intensified AED treatment for patients with poorly controlled GTCS in the effort to reduce SUDEP risk and suggest that comedication with statins may reduce risk.

Incidence and prevalence of type 2 diabetes by occupation: results from all Swedish employees.

AIMS/HYPOTHESIS: The workplace is a potentially important arena for prevention of type 2 diabetes and the first step is to identify occupations where the disease is common and/or risk is high. Therefore, our aim was to analyse incidence and prevalence of type 2 diabetes across all occupational groups in Sweden. METHODS: This nationwide study included all Swedish citizens born between 1937 and 1979 and gainfully employed between 2001 and 2013 (N = 4,550,892), and followed for a diagnosis of diabetes from 2006 to 2015 (n = 201,717) through national registers. Prevalence in 2013 (mean age 51 years; range 35-67) and age-standardised incidence (per 1000 person-years) were analysed across the 30 most common occupations among men and women. Information on BMI, physical fitness and smoking was obtained through the National Conscription (mean age 18) and Medical Birth Registers (mean age 29). RESULTS: Prevalence of type 2 diabetes was 5.2% in men and 3.2% in women; in men it was highest among motor vehicle drivers (8.8%) and in women it was highest among manufacturing workers (6.4%). Incidence varied dramatically across occupational groups. In men, it was highest among manufacturing workers (9.41) and professional drivers (9.32) and lowest among university teachers (3.44). In women, incidence was highest in manufacturing workers (7.20) and cleaners (6.18) and lowest in physiotherapists (2.20). We found major differences in the prevalence of being overweight and smoking and in the level of physical fitness across these occupational groups even at young ages. CONCLUSIONS/INTERPRETATION: Professional drivers, manufacturing workers and cleaners have a threefold increased risk of type 2 diabetes compared with university teachers and physiotherapists. These differences most likely reflect dramatic differences in the prevalence of lifestyle risk factors. If workplace interventions could reduce weight and increase physical activity among employees in these occupations, major health gains may be made.

Genotypes of HLA, TCF7L2, and FTO as potential modifiers of the association between sweetened beverage consumption and risk of LADA and type 2 diabetes.

PURPOSE: Sweetened beverage consumption is associated with type 2 diabetes (T2D) and LADA. We investigated to what extent this association is mediated by BMI and whether it is modified by genotypes of HLA, TCF7L2 rs7903146, or FTO rs9939609. METHODS: Swedish case-control data including incident cases of LADA (n = 386) and T2D (n = 1253) with matched population-based controls (n = 1545) was used. We estimated adjusted ORs of diabetes (95% CI) in relation to sweetened beverage intake (per daily 200 mL serving) and genotypes. The impact of BMI was estimated using causal mediation methodology. Associations with HOMA-IR and HOMA-B were explored through linear regression. RESULTS: Sweetened beverage intake was associated with increased risk of LADA (OR 1.15, 95% CI 1.03-1.29) and T2D (OR 1.21, 1.11-1.32). BMI was estimated to mediate 17% (LADA) and 56% (T2D) of the total risk. LADA was associated with risk variants of HLA (3.44, 2.63-4.50) and TCF7L2 (1.27, 1.00-1.61) but not FTO. Only among non-carriers of high-risk HLA genotypes was sweetened beverage intake associated with risk of LADA (OR 1.32, 1.06-1.56) and HOMA-IR (beta = 0.162, p = 0.0047). T2D was associated with TCF7L2 and FTO but not HLA, and the risk conferred by sweetened beverages appeared modified by FTO (OR 1.45, 95% CI 1.21-1.73 in non-carriers). CONCLUSIONS: Our findings suggest that sweetened beverages are associated with LADA and T2D partly through mediation by excess weight, but possibly also through other mechanisms including adverse effects on insulin sensitivity. These effects seem more pronounced in individuals without genetic susceptibility.

Commonly used estimates of the genetic contribution to disease are subject to the same fallacies as bad luck estimates.

The scientific debate following the initial formulation of the "bad luck" hypothesis in cancer development highlighted how measures based on analysis of variance are inappropriately used for risk communication. The notion of "explained" variance is not only used to quantify randomness, but also to quantify genetic and environmental contribution to disease in heritability coefficients. In this paper, we demonstrate why such quantifications are generally as problematic as bad luck estimates. We stress the differences in calculation and interpretation between the heritability coefficient and the population attributable fraction, the estimated fraction of all disease events that would not occur if an intervention could successfully prevent the excess genetic risk. We recommend using the population attributable fraction when communicating results regarding the genetic contribution to disease, as this measure is both more relevant from a public health perspective and easier to understand.

Interaction Between Overweight and Genotypes of HLA, TCF7L2, and FTO in Relation to the Risk of Latent Autoimmune Diabetes in Adults and Type 2 Diabetes.

OBJECTIVE: We investigated potential interactions between body mass index (BMI) and genotypes of human leukocyte antigen (HLA), TCF7L2-rs7903146, and FTO-rs9939609 in relation to the risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes. METHODS: We pooled data from two population-based studies: (i) a Swedish study with incident cases of LADA [positive for glutamic acid decarboxylase autoantibodies (GADA); n = 394) and type 2 diabetes (negative for GADA; n = 1290) and matched controls without diabetes (n = 2656) and (ii) a prospective Norwegian study that included incident cases of LADA (n = 131) and type 2 diabetes (n = 1901) and 886,120 person-years of follow-up. Analyses were adjusted for age, sex, physical activity, and smoking. Interaction between overweight (BMI ≥ 25 kg/m2) and HLA/TCF7L2/FTO high-risk genotypes was assessed by attributable proportion due to interaction (AP). RESULTS: The combination of overweight and high-risk genotypes of HLA, TCF7L2, and FTO was associated with pooled relative risk (RRpooled) of 7.59 (95% CI, 5.27 to 10.93), 2.65 (95% CI, 1.97 to 3.56), and 2.21 (95% CI, 1.60 to 3.07), respectively, for LADA, compared with normal-weight individuals with low/intermediate genetic risk. There was a significant interaction between overweight and HLA (AP, 0.29; 95% CI, 0.10 to 0.47), TCF7L2 (AP, 0.31; 95% CI, 0.09 to 0.52), and FTO (AP, 0.38; 95% CI, 0.15 to 0.61). The highest risk of LADA was seen in overweight individuals homozygous for the DR4 genotype [RR, 26.76 (95% CI, 15.42 to 46.43); AP, 0.58 (95% CI, 0.32 to 0.83) (Swedish data)]. Overweight and TCF7L2 also significantly interacted in relation to type 2 diabetes (AP, 0.26; 95% CI, 0.19 to 0.33), but no interaction was observed with high-risk genotypes of HLA or FTO. CONCLUSIONS: Overweight interacts with HLA high-risk genotypes but also with genes associated with type 2 diabetes in the promotion of LADA.

Postprandial levels of GLP-1, GIP and glucagon after 2 years of weight loss with a Paleolithic diet: a randomised controlled trial in healthy obese women.

Objective To investigate how weight loss by different diets impacts postprandial levels of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon. Methods In this single-centre, parallel group 2-year trial, 70 healthy postmenopausal obese women were randomised to the Paleolithic diet or a healthy control diet based on Nordic Nutrition Recommendations. Both diets were without calorie restriction. The primary outcome was the change in fat mass. Here, secondary analyses on GLP-1, GIP and glucagon measured during an OGTT are described. Results In the Paleolithic diet group, mean weight loss compared to baseline was 11% at 6 months and 10% at 24 months. In the control diet group, mean weight loss was 6% after 6 and 24 months (P = 0.0001 and P = 0.049 for the comparison between groups at 6 and 24 months respectively). Compared to baseline, the mean incremental area under the curve (iAUC) for GLP-1 increased by 34 and 45% after 6 and 24 months in the Paleolithic diet group and increased by 59% after 24 months in the control diet group. The mean iAUC for GIP increased only in the Paleolithic diet group. The area under the curve (AUC) for glucagon increased during the first 6 months in both groups. The fasting glucagon increase correlated with the ß-hydroxybutyrate increase. Conclusions Weight loss caused an increase in postprandial GLP-1 levels and a further rise occurred during weight maintenance. Postprandial GIP levels increased only after the Paleolithic diet. Reduced postprandial glucagon suppression may be caused by a catabolic state.

Tobacco and type 2 diabetes: is the association explained by genetic factors?

BACKGROUND: Smoking and use of Swedish smokeless tobacco (snus) are associated with increased risk of type 2 diabetes (T2D). Our aim was to estimate the unique and shared genetic components of these traits and to what extent the association is explained by shared genetic factors. METHODS: We used twins of the Swedish Twin Registry who responded to a questionnaire between 1998 and 2006 (n = 40 247) and were followed until 2015 in the National Prescription and Patient Registries. We estimated hazard ratios (HRs) and odds ratios (ORs) for the association between smoking/snus use and T2D (n = 2130) and used structural equation models to estimate genetic and environmental variance components and genetic correlations. RESULTS: Current smokers [HR 1.69, 95% confidence interval (CI), 1.49-1.92] and snus users (HR 1.19, 95% CI 1.01-1.41) had an increased risk of T2D. In within-pair analyses of monozygotic twins, corresponding ORs were 1.36, 95% CI 0.75-2.46 (smoking) and 1.54, 95% CI 0.80-2.99 (snus). Heritability was 43% (95% CI 36-51) for ever smoking, 58% (95% CI 44- 70) for ever snus use and 66% (95% CI 59-72) for T2D. The genetic correlation with T2D was 18% (95% CI 1-35) for smoking and -6% (95% CI -24 to 4) for snus use, indicating that only a small fraction of the genetic influence is shared. CONCLUSIONS: We could confirm that consumers of snus and cigarettes are at increased risk of T2D. Both snus use and smoking have strong genetic components, which appears to be attributable primarily to genes that are distinct from those promoting T2D.

Risk for injuries and accidents in epilepsy: A prospective population-based cohort study.

OBJECTIVE: To study the risk for injuries/accidents in people with newly diagnosed epileptic seizures in relation to comorbidities. METHODS: Between September 1, 2001, and August 31, 2008, individuals in northern Stockholm with incident unprovoked seizures (epilepsy; n = 2,130) were included in a registry. For every epilepsy patient, 8 individuals matched for sex and inclusion year (n = 16,992) were randomly selected as references from the population of the catchment area. Occurrence of injuries/accidents was monitored through the national patient and cause of death registers until December 31, 2013. These registers also provided information on comorbidities (e.g., brain tumor, stroke, psychiatric disease, diabetes mellitus). RESULTS: Injury/accident was demonstrated in 1,033 epilepsy cases and 6,202 references (hazard ratio [HR] 1.71, 95% confidence interval 1.60-1.83). The excess risk was seen mainly during the first 2 years after diagnosis. Sex and educational status had no significant effect on HR. The risk was normal in children but increased in adults. Highest HR was seen for drowning, poisoning, adverse effect of medication, and severe traumatic brain injury. Compared to references without comorbidities, HR was 1.17 (1.07-1.28) in epilepsy without comorbidities, 4.52 (4.18-4.88) in references with comorbidities, and 7.15 (6.49-7.87) in epilepsy with comorbidities. CONCLUSION: Presence of comorbidities should be considered when counseling patients with newly diagnosed epilepsy concerning risk for injuries/accidents. Early information is important, as the risk is highest during the first 2 years following seizure onset.

Cancer incidence in Stockholm firefighters 1958-2012: an updated cohort study.

OBJECTIVES: Previous studies on firefighters indicate an increased risk of cancer although findings regarding which cancer sites are in excess have been inconsistent. The aim of this study was to investigate the cancer incidence among Swedish firefighters. METHODS: This updated cohort study included 1080 men who worked at least 1 year as a firefighter in the city of Stockholm, Sweden during 1931-1983. First-time diagnoses of cancer were identified through the Swedish Cancer Registry from 1958 until 2012. Employment as a firefighter was determined from the annual fire station enrolment records. Standardized incidence ratios were calculated using the Stockholm population as reference. RESULTS: Firefighters in Stockholm had a low overall risk of cancer (SIR = 0.81 95% CI 0.71-0.91). However, firefighters were at an increased risk of stomach cancer (SIR = 1.89 95% CI 1.25-2.75). Firefighters had significantly low risks for prostate cancer (SIR = 0.68 95% CI 0.52-0.87) and malignant melanoma of the skin (SIR = 0.30 95% CI 0.06-0.88). There was a statistically significant trend of increasing overall risk of cancer with increasing employment duration, although there was still no excess of cancer overall in any of the categories of employment duration. CONCLUSION: Stockholm firefighters had an increased risk of stomach cancer but a low overall risk of cancer. The trend of increasing overall risk of cancer with increasing employment duration could potentially be related to the carcinogenic exposures at work.

Cancer incidence in female laboratory employees: extended follow-up of a Swedish cohort study.

OBJECTIVES: Work in chemical laboratories is associated with exposure to chemicals, of which some are known or suspected carcinogens. A cohort study of laboratory workers in Stockholm followed until 1992 showed an excess of hematolymphatic malignancies in chemical laboratories and an excess of breast cancer among women working for more than 10 years in such laboratories. The follow-up of this cohort has now been extended by 20 years. METHODS: The cohort comprised 2245 female laboratory workers who are employed for >1 year from 1950 to 1989. Information on employment periods and type of laboratory ('chemical' or 'non-chemical') was obtained from employee registers. Cancer diagnoses from 1958 to 2012 were obtained from the Swedish Cancer Registry. RESULTS: There were 383 cases of cancer (SIR=0.93 (95% CI 0.84 to 1.02)). The risk of breast cancer was elevated, of borderline statistical significance, among those who had worked for at least 10 years in chemical laboratories (SIR=1.41 (95% CI 0.99 to 1.95) 36 cases). The breast cancer risk was especially high in women who had worked for more than 10 years in chemical labs before 1970 (SIR=3.76 (95% CI 1.72 to 7.14), nine cases). There was no excess of breast cancer in non-chemical labs (SIR=0.77 (95% CI 0.54 to 1.07), 35 cases). The number of hematolymphatic cancer was no longer significantly elevated. CONCLUSIONS: The increased risk of breast cancer, as well as the earlier noted excess of hematolymphatic malignancies, may be related to exposure to carcinogenic chemicals/organic solvents (eg, benzene) used in chemical laboratories, especially during earlier periods.

Population pharmacokinetics of ticagrelor and AR-C124910XX in patients with prior myocardial infarction
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OBJECTIVE: The population pharmacokinetics of ticagrelor and its active metabolite AR-C124910XX were characterized following ticagrelor 60 mg or 90 mg twice daily oral long-term treatment in 4,426 patients with a history of myocardial infarction. METHODS: The ticagrelor and AR-C124910XX plasma concentration-time data were described by one-compartment models with first-order absorption or metabolite formation and elimination. RESULTS: Systemic exposure to ticagrelor and AR-C124910XX were stable over time. Ticagrelor apparent clearance (CL/F) was 17 L/h for the 60-mg and 15.4 L/h for the 90-mg dose. The CL/F of AR-C124910XX was 11.1 L/h for the 60-mg and 9.95 L/h for the 90-mg dose. Both ticagrelor and AR-C124910XX CL/F were independently influenced by body weight, sex, age, smoking, and Japanese ethnicity. Female sex and age > 75 years were the only categorical covariates, having more than 20% effect on AR-C124910XX CL/F. Ticagrelor CL/F was 6% higher and 11% lower, whereas AR-C124910XX CL/F was 26% higher and 34% lower for patients weighing 110 and 50 kg, respectively, compared with an 83 kg patient. CONCLUSIONS: The small differences in exposure to both ticagrelor and AR-C124910XX between demographic subgroups were in accordance with the consistent efficacy and safety outcomes observed across the population. The results were similar to those observed previously in patients with acute coronary syndromes.
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