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.

Admission glucose as a prognostic marker for all-cause mortality and cardiovascular disease.

BACKGROUND: Diabetes and prediabetes are known risk factors for cardiovascular disease and associated with increased mortality risk. Whether patients with a random elevated blood glucose level but no history of diabetes are at a higher mortality and cardiovascular risk is not entirely known. METHODS: A retrospective cohort study where patients (18-80 years) with no history of diabetes between 2006 and 2016 attending the emergency department (ED) in Sweden were included. Based on the first (index) blood glucose level patients were categorized into four groups: hypoglycemia (< 3.9 mmol/L), normal glucose tolerance (NGT) (3.9-7.8 mmol/L), dysglycemia (7.8-11.1 mmol/L), and hyperglycemia (> 11.1 mmol/L). Data was collected from four nationwide registers (National Patient Register, National Cause of Death Register, Prescribed Drug Register and Statistics Sweden). Cox regression was used to calculate adjusted hazard ratios (HR) with 95% confidence intervals (CI) for all-cause mortality and cardiovascular outcomes using NGT as reference. RESULTS: 618,694 patients were included during a mean follow-up time of 3.9 years. According to the index blood glucose level: 1871 (0.3%) had hypoglycemia, 525,636 (85%) had NGT, 77,442 (13%) had dysglycemia, and 13,745 (2%) patients had hyperglycemia, respectively. During follow-up 44,532 (7.2%) deaths occurred. After multiple adjustments, mortality risk was highest in patients with hypoglycemia HR 2.58 (2.26-2.96) followed by patients with hyperglycemia HR 1.69 (1.63-1.76) and dysglycemia HR 1.16 (1.13-1.19). Risk for cardiovascular events: i.e., myocardial infarction, stroke and heart failure, were highest among patients with hyperglycemia HR 2.28 (2.13-2.44), HR 1.62 (1.51-1.74) and HR 1.60 (1.46-1.75), respectively. CONCLUSION: Patients with disturbed blood glucose level at ED admission have a higher mortality risk than patients with NGT. Patients with hyperglycemia have almost a two folded increased long-term mortality risk and more than a doubled risk for cardiovascular events compared to patients with NGT.

Perinatal risk factors for SUDEP: A population-based case-control study.

Sudden unexpected death in epilepsy (SUDEP) is a leading epilepsy-related cause of death. Researchers have highlighted the similarities between SUDEP and sudden infant death syndrome (SIDS), but perinatal risk factors such as those identified for SIDS have not been assessed previously for SUDEP. We conducted a population-based case-control study of 58 SUDEP individuals and 384 living epilepsy controls born after 1982, utilizing the Swedish Medical Birth Register together with other national health registers and individual medical records to examine if prenatal and perinatal factors are associated with SUDEP risk. We observed a 3-fold SUDEP risk increase for infants who were small for gestational age (SGA) (odds ratio [OR] 3.13; 95% confidence interval [CI] 1.05-9.30) and for those with an Apgar score of 0-6 compared to 9-10 at 10 min (OR 3.22; 95% CI 1.05-9.87). After adjusting for a number of known SUDEP risk factors, we observed that the Apgar score between 0 and 6 after 10 min had a 10-fold increased risk for SUDEP OR 10.37 (95% CI 1.49-72.01) and over a 2-fold risk for those born after the 40th gestational week (OR 2.42; 95% CI 1.03-5.65). The potential mechanisms linking low Apgar score, gestational age, and SGA to SUDEP risk remain to be explored.

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.

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.

Job control, job demands and job strain and suicidal behaviour among three million workers in Sweden.

OBJECTIVE: To investigate the association between job control, job demands and their combination (job strain) and suicide attempts and deaths among male and female workers in Sweden. METHODS: Job control and demands were measured separately for men and women using a job exposure matrix, which was linked to around three million individuals based on their occupational title in 2005. Suicide attempts and deaths were measured in the hospital and cause of death registers from 2006 to 2016. HRs were estimated using discrete proportional hazards models with annually updated age as the time axis. Models were adjusted for sociodemographic, family, health, labour market and childhood factors, as well as the time-varying effects of unemployment, sick leave and family factors during follow-up. RESULTS: Low job control was associated with an increased risk of suicide attempts and deaths among both men and women while high job demands tended to be associated with a decreased risk. The combination of job control and job demands (job strain) reflected the increased risk of low control jobs and the decreased risk of high demand jobs. Associations were attenuated but still present after adjustments. CONCLUSIONS: Low job control is related to suicide attempts and deaths, and this is only partially explained by important covariates measured both prebaseline and during follow-up. Attempts to increase job control among workers may be beneficial in preventing suicide.

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.

Consumption of red meat, genetic susceptibility, and risk of LADA and type 2 diabetes.

PURPOSE: Red meat consumption is positively associated with type 1 (T1D) and type 2 (T2D) diabetes. We investigated if red meat consumption increases the risk of latent autoimmune diabetes in adults (LADA) and T2D, and potential interaction with family history of diabetes (FHD), HLA and TCF7L2 genotypes. METHODS: Analyses were based on Swedish case-control data comprising incident cases of LADA (n = 465) and T2D (n = 1528) with matched, population-based controls (n = 1789; n = 1553 in genetic analyses). Multivariable-adjusted ORs in relation to self-reported processed and unprocessed red meat intake were estimated by conditional logistic regression models. Attributable proportion (AP) due to interaction was used to assess departure from additivity of effects. RESULTS: Consumption of processed red meat was associated with increased risk of LADA (per one servings/day OR 1.27, 95% CI 1.07-1.52), whereas no association was observed for unprocessed red meat. For T2D, there was no association with red meat intake once BMI was taken into account. The combination of high (> 0.3 servings/day vs. less) processed red meat intake and high-risk HLA-DQB1 and -DRB1 genotypes yielded OR 8.05 (95% CI 4.86-13.34) for LADA, with indications of significant interaction (AP 0.53, 95% CI 0.32-0.73). Results were similar for the combination of FHD-T1D and processed red meat. No interaction between processed red meat intake and FHD-T2D or risk variants of TCF7L2 was seen in relation to LADA or T2D. CONCLUSION: Consumption of processed but not unprocessed red meat may increase the risk of LADA, especially in individuals with FHD-T1D or high-risk HLA genotypes.

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.

Disability pensions related to heavy physical workload: a cohort study of middle-aged and older workers in Sweden.

OBJECTIVES: The aim of the study was to examine the associations between heavy physical workload among middle-aged and older workers and disability pension due to any diagnosis, as well as musculoskeletal, psychiatric, cardiovascular or respiratory diagnoses. The population-based design made it possible to examine dose-response and potential gender differences in the associations. METHODS: About 1.8 million men and women aged 44-63 years and registered as living in Sweden in 2005 were followed regarding disability pension during 2006-2016, until ages 55-65 years. Mean values of physical workload and job control, estimated through gender-specific job-exposure matrices (JEMs), were assigned to individuals through their occupational titles in 2005. Exposure values were ranked separately for women and men and divided into quintiles. Associations were analyzed with Cox proportional-hazards regression. RESULTS: The analyses showed robust, dose-response associations between physical workload and disability pension with a musculoskeletal diagnosis in both genders: the adjusted hazard ratio and 95% confidence interval for those with the heaviest exposure was 2.58 (2.37-2.81) in women and 3.34 (2.83-3.94) in men. Dose-response associations were also seen in relation to disability pension with a cardiovascular or a respiratory diagnosis, though the hazard ratios were smaller. Physical workload was not associated with disability pension with a psychiatric diagnosis after adjustment for job control. CONCLUSION: This study of the entire Swedish population of middle-aged and older workers suggests that higher degrees of physical workload may increase the risk of disability pension overall, and specifically with musculoskeletal, cardiovascular or respiratory diagnosis, in both women and men.

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.

Leveraging electronic health records for clinical research.

Electronic health records (EHRs) can be a major tool in the quest to decrease costs and timelines of clinical trial research, generate better evidence for clinical decision making, and advance health care. Over the past decade, EHRs have increasingly offered opportunities to speed up, streamline, and enhance clinical research. EHRs offer a wide range of possible uses in clinical trials, including assisting with prestudy feasibility assessment, patient recruitment, and data capture in care delivery. To fully appreciate these opportunities, health care stakeholders must come together to face critical challenges in leveraging EHR data, including data quality/completeness, information security, stakeholder engagement, and increasing the scale of research infrastructure and related governance. Leaders from academia, government, industry, and professional societies representing patient, provider, researcher, industry, and regulator perspectives convened the Leveraging EHR for Clinical Research Now! Think Tank in Washington, DC (February 18-19, 2016), to identify barriers to using EHRs in clinical research and to generate potential solutions. Think tank members identified a broad range of issues surrounding the use of EHRs in research and proposed a variety of solutions. Recognizing the challenges, the participants identified the urgent need to look more deeply at previous efforts to use these data, share lessons learned, and develop a multidisciplinary agenda for best practices for using EHRs in clinical research. We report the proceedings from this think tank meeting in the following paper.

Evolution over time of SUDEP incidence: A nationwide population-based cohort study.

Prompted by a recent report on declining incidence of sudden unexpected death in epilepsy (SUDEP) following implantation of a vagus nerve stimulator (VNS), we analyzed SUDEP risk over 6 years in a population-based cohort of 60 952 epilepsy patients in Sweden. All deaths from July 1, 2006 through December 31, 2011, were identified. Those with epilepsy mentioned on the death certificate were adjudicated for SUDEP using medical records and autopsy reports. In all, 292 SUDEP cases were identified. Comparing the first years (2006-2007) with the subsequent 4 years (2008-2011), the crude and standardized (to the US 2000 population) incidence of SUDEP (whether or not possible SUDEP was included) was significantly lower during the second time period; Incidence rate ratios based on standardized rates was estimated at 0.76 (95% confidence interval [CI] 0.60-0.97, P = .027) for SUDEP. The incidence of SUDEP decreased by 7% per year during the 6-year follow-up. Our data thus suggest that, for unknown reasons, incidence of SUDEP decreases with duration of follow-up. This has implications for patient counseling as well as for the design of studies attempting to assess the effectiveness of an intervention against SUDEP, which clearly needs to include a control group.

Circumstances of SUDEP: A nationwide population-based case series.

OBJECTIVE: Given the increasing attention being paid to potential strategies for sudden unexpected death in epilepsy (SUDEP) prevention, we analyzed the circumstances of SUDEP and its incidence in relation to time of year, week, and day. METHODS: Prospective case-series based on persons with an International Classification of Diseases (ICD-10) code for epilepsy in the Swedish Patient Registry 1998-2005, who were alive on June 30, 2006 (n = 60 952). Linkage to the National Cause-of-Death Registry identified all deaths from July 2006 through December 2011, with epilepsy mentioned on death certificate, together with all deaths during 2008 (n = 3166). Death certificates, medical charts, autopsy, and police reports were reviewed to identify SUDEP cases and related circumstances. Autopsied non-SUDEP deaths (n = 60) from the study population served as a reference. RESULTS: There were 329 SUDEPs (63% men) of which 167 were definite, 89 probable, and 73 possible. SUDEP cases were younger at death (50.8 years) than non-SUDEP deaths (73.3 years) (P < .001) and more likely to be male (63% vs 55%, P = .0079). Most SUDEP cases died at night (58%), at home (91%), and 65% were found dead in bed. When documented, 70% were found in prone position. In 17%, death was witnessed and in 88% of these, a seizure was observed. Of the 329 SUDEP cases, 71% were living alone and 14% shared a bedroom. Compared to an autopsied non-SUDEP reference group, definite SUDEPs were more likely to die at home, during the night, unwitnessed, in the prone position, to live alone, and more often with a preceding seizure. SIGNIFICANCE: SUDEP cases live alone, die unwitnessed at home at night, with indication of a preceding seizure, supporting the critical role of lack of supervision. These facts need to be considered in the development of preventive strategies.

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.