Understanding the importance of low-molecular weight (ethylene oxide- and propylene oxide-induced) DNA adducts and mutations in risk assessment: Insights from 15 years of research and collaborative discussions.

The interpretation and significance of DNA adduct data, their causal relationship to mutations, and their role in risk assessment have been debated for many years. An extended effort to identify key questions and collect relevant data to address them was focused on the ubiquitous low MW N7-alkyl/hydroxyalkylguanine adducts. Several academic, governmental, and industrial laboratories collaborated to gather new data aimed at better understanding the role and potential impact of these adducts in quantifiable genotoxic events (gene mutations/micronucleus). This review summarizes and evaluates the status of dose-response data for DNA adducts and mutations from recent experimental work with standard mutagenic agents and ethylene oxide and propylene oxide, and the importance for risk assessment. This body of evidence demonstrates that small N7-alkyl/hydroxyalkylguanine adducts are not pro-mutagenic and, therefore, adduct formation alone is not adequate evidence to support a mutagenic mode of action. Quantitative methods for dose-response analysis and derivation of thresholds, benchmark dose (BMD), or other points-of-departure (POD) for genotoxic events are now available. Integration of such analyses of genetox data is necessary to properly assess any role for DNA adducts in risk assessment. Regulatory acceptance and application of these insights remain key challenges that only the regulatory community can address by applying the many learnings from recent research. The necessary tools, such as BMDs and PODs, and the example datasets, are now available and sufficiently mature for use by the regulatory community. Environ. Mol. Mutagen. 60: 100-121, 2019. © 2018 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.

Significant variation in mortality and functional outcome after acute ischaemic stroke between Western countries: data from the tinzaparin in acute ischaemic stroke trial (TAIST).

BACKGROUND: The medical care of patients with acute stroke varies considerably between countries. This could lead to measurable differences in mortality and functional outcome. OBJECTIVE: To compare case mix, clinical management, and functional outcome in stroke between 11 countries. METHODS: All 1484 patients from 11 countries who were enrolled into the tinzaparin in acute ischaemic stroke trial (TAIST) were included in this substudy. Information collected prospectively on demographics, risk factors, clinical features, measures of service quality (for example, admission to a stroke unit), and outcome were assessed. Outcomes were adjusted for treatment assignment, case mix, and service relative to the British Isles. RESULTS: Differences in case mix (mostly minor) and clinical service (many of prognostic relevance) were present between the countries. Significant differences in outcome were present between the countries. When assessed by geographical region, death or dependency were lower in North America (odds ratio (OR) adjusted for treatment group only = 0.52 (95% confidence interval, 0.39 to 0.71) and north west Europe (OR = 0.54 (0.37 to 0.78)) relative to the British Isles; similar reductions were found when adjustments were made for 11 case mix variables and five service quality measures. Similarly, case fatality rates were lower in North America (OR = 0.44 (0.30 to 0.66)) and Scandinavia (OR = 0.50 (0.33 to 0.74)) relative to the British Isles, whether crude or adjusted for case mix and service quality. CONCLUSIONS: Both functional outcome and case fatality vary considerably between countries, even when adjusted for prognostic case mix variables and measures of good stroke care. Differing health care systems and the management of patients with acute stroke may contribute to these findings.

Direct costs during the first year after intracerebral hemorrhage.

OBJECTIVES: Knowledge of resource use and associated costs of treatment, care and rehabilitation at hospitals and in the health care and social service sectors is limited. This study presents data on the total resource use during the first year after spontaneous intracerebral hemorrhage. METHODS: All patients hospitalized because of stroke at a university hospital in Copenhagen, Denmark, during a 1-year period 1994-1995 were included in a database. The patients were followed until 1 year after the stroke, and data on resource use during and after the hospital stay were collected prospectively. This study investigates a subgroup comprising 90 patients with intracerebral hemorrhage. Resource use is described and costs are calculated. RESULTS: The cost of the hospital stay including acute care and rehabilitation had a mean of 90200 DKK (US$16100). The total cost of health care and social services during the first year had a mean of 123200 DKK (US$22000). Costs decreased significantly with age, but when differences of 30 days case fatality between age groups were considered, the association between costs and age disappeared. CONCLUSIONS: The mean cost of treatment, care and rehabilitation during the first year after intracerebral hemorrhage was 123200 DKK, of which the primary hospital stay constituted 73%.

[Attitude of general practitioners to the importance of gender and diet in disease prevention]. / Praktiserende laegers holdning til kønnets og kostens betydning ved sygdomsforebyggelse.

Three hundred and seventy-four general practitioners (GPs) in Denmark filled in a questionnaire on attitudes to include information on gender and diet in the strategy for prevention of coronary heart disease, cancer, osteoporosis, and overweight/underweight. Risk factors for disease in general were ranked as follows: smoking, alcohol, stress, diet, physical exercise, heredity and hygiene. The patients' lack of motivation, insufficient time for each patient, and inadequate knowledge about nutrition were stated as barriers to dietary counselling. The GPs stated that the gender of the patient was important only to the counselling on osteoporosis. Lack of time and insufficient knowledge were perceived as barriers for including gender specific issues in prevention. It is concluded that GPs consider dietary counselling important but lack time and knowledge. The results point at a need for better pre- and postgraduate training in nutrition, and for a better reimbursement system for time spent on prevention.

Costs of health care and social services during the first year after ischemic stroke.

OBJECTIVES: Knowledge of resource use and costs can be useful when evaluating existing services or planning new services. This study investigates the use of health care and social services during the first year after a stroke. Total costs are calculated, costs are compared across subgroups of patients, and resource items of major importance for the total costs are identified. METHODS: The study is based on a database comprising data on all stroke patients admitted to a university hospital in Copenhagen, Denmark, over a 1-year period, 1994-95. Patients were followed for 1 year after the stroke, and data on resource use during and after hospitalization were collected prospectively at interviews. This paper focuses on a subset of 385 patients who were admitted because of cerebral infarct or unspecified stroke. RESULTS: The mean cost, based on all patients, of health care and social services during the first year was 142,900 DKK (US $25,500). The hospital care until the first discharge, including acute care and rehabilitation, cost 101,600 Danish krones (DKK) (US $18,100), i.e., 71% of the total cost. Major resource items after discharge were nursing homes, readmissions, outpatient rehabilitation, and home help. The cost during the first year varied with a number of factors, with the most important being survival and degree of disability. Patients who survived the acute phase and who had severe disability (Barthel Activities of Daily Living [ADL] Index: 0-9) 7-10 days after admission had a total cost during the first year that was five times as high as patients with no disability (Barthel ADL Index: 20). CONCLUSION: Costs of health care and social services during the first year after a stroke vary considerably. Disability as measured with the Barthel ADL Index is a stronger predictor of costs than Scandinavian Stroke Scale scores and other clinical and demographic variables.

[Direct costs of transient cerebral ischemia. A hospital-based study of resource use in Denmark during the first year following transient cerebral ischemic attack]. / Direkte omkostninger ved transitorisk cerebral iskaemi. En hospitalsbaseret undersøgelse af ressourceforbruget i Danmark i patientens første år efter transitorisk cerebral iskaemi.

In order to obtain knowledge of costs of health care and social services for patients who have transient ischaemic attacks (TIA) all patients admitted to a university hospital in Copenhagen, Denmark, with TIA during 12 months in 1994-1995 were included in a database. The patients were followed until one year after admission and data on resource use during and after the hospital stay were collected prospectively at interviews. The cost of the hospital stay had a mean of 10,100 DKK (1,800 US$) and the cost of health care and social services after discharge had a mean of 8,800 DKK (1,600 US$) per person.

Direct costs of transient ischemic attacks: a hospital-based study of resource use during the first year after transient ischemic attacks in Denmark.

BACKGROUND AND PURPOSE: Knowledge of costs of health care and social services for patients who have transient ischemic attacks (TIAs) is scarce. This study investigates the resource use and estimates direct costs during the first year after a TIA. METHODS: All patients admitted to a university hospital in Copenhagen, Denmark, because of TIA during 12 months in 1994-1995 were included in a database. The patients were followed until 1 year after admission, and data on resource use during and after the hospital stay were collected prospectively at interviews. RESULTS: The cost of the hospital stay had a mean of DKr 10100 (US $1800), and the cost of health care and social services after discharge had a mean of DKr 8800 (US $1600). CONCLUSIONS: The total cost of health care and social services during the first year after a TIA had a mean of DKr 18800. The hospital stay and the services after discharge each made up half of the total direct cost.