Long-term 4-year safety of saxagliptin in drug-naive and metformin-treated patients with Type 2 diabetes.

AIMS: To evaluate the safety of saxagliptin ± metformin over 4 years in patients with Type 2 diabetes mellitus. METHODS: Drug-naive (n = 401; study 11) or metformin-treated (n = 743; study 14) adults with HbA(1c) of 53-86 mmol/mol (7.0-10%) were enrolled in two randomized, placebo-controlled, double-blind trials of saxagliptin 2.5, 5 or 10 mg/day. Patients rescued during or completing 24 weeks of treatment could continue in a 42-month long-term blinded phase, for which the primary goal was assessment of safety and tolerability. Between-group efficacy was not evaluated in the long-term phase of study 11. Time to rescue or discontinuation because of inadequate glycaemic control, change from baseline in HbA(1c) and percentages of patients achieving HbA(1c) < 53 mmol/mol (< 7.0%) were assessed in study 14. RESULTS: No new safety findings were noted during the long-term phase. Most adverse events were mild or moderate, with slightly greater frequency of upper respiratory infections with saxagliptin. Hypoglycaemic event rates were similar with saxagliptin and placebo. In study 14, time to rescue or discontinuation because of inadequate glycaemic control was longer with saxagliptin plus metformin than for placebo plus metformin. From baseline to week 154, HbA(1c) decreased with saxagliptin but increased with placebo. CONCLUSION: Saxagliptin monotherapy or add-on to metformin is generally safe and well tolerated, with no increased risk of hypoglycaemia, for up to 4 years.

Associations of traffic related air pollutants with hospitalisation for first acute myocardial infarction: the HEAPSS study.

BACKGROUND: Acute myocardial infarction (AMI) is the leading cause of death attributed to cardiovascular diseases. An association between traffic related air pollution and AMI has been suggested, but the evidence is still limited. OBJECTIVES: To evaluate in a multicentre study association between hospitalisation for first AMI and daily levels of traffic related air pollution. METHODS: The authors collected data on first AMI hospitalisations in five European cities. AMI registers were available in Augsburg and Barcelona; hospital discharge registers (HDRs) were used in Helsinki, Rome and Stockholm. NO2, CO, PM10 (particles <10 microm), and O3 were measured at central monitoring sites. Particle number concentration (PNC), a proxy for ultrafine particles (<0.1 microm), was measured for a year in each centre, and then modelled retrospectively for the whole study period. Generalised additive models were used for statistical analyses. Age and 28 day fatality and season were considered as potential effect modifiers in the three HDR centres. RESULTS: Nearly 27,000 cases of first AMI were recorded. There was a suggestion of an association of the same day CO and PNC levels with AMI: RR = 1.005 (95% CI 1.000 to 1.010) per 0.2 mg/m3 and RR = 1.005 (95% CI 0.996 to 1.015) per 10000 particles/cm3, respectively. However, associations were only observed in the three cities with HDR, where power for city-specific analyses was higher. The authors observed in these cities the most consistent associations among fatal cases aged <75 years: RR at 1 day lag for CO = 1.021 (95% CI 1.000 to 1.048) per 0.2 mg/m3, for PNC = 1.058 (95% CI 1.012 to 1.107) per 10000 particles/cm3, and for NO2 = 1.032 (95% CI 0.998 to 1.066) per 8 microg/m3. Effects of air pollution were more pronounced during the warm than the cold season. CONCLUSIONS: The authors found support for the hypothesis that exposure to traffic related air pollution increases the risk of AMI. Most consistent associations were observed among fatal cases aged <75 years and in the warm season.

Road traffic noise and annoyance--an increasing environmental health problem.

Traffic noise, which is steadily increasing, is considered to be an important environmental health problem. The aim of this study was to estimate the degree of annoyance and sleep disturbance related to road traffic noise in residential settings in an urban community. The study is based on a questionnaire on environmentally related health effects distributed to a stratified random sample of 1000 individuals, 19-80 years old, in a municipality with heavy traffic in the county of Stockholm. The response rate was 76%. The individual noise exposure was estimated using evaluated noise dispersion models and local noise assessments. Frequent annoyance was reported by 13% of subjects exposed to Leq 24 hr >50 dBA compared to 2% among those exposed to <50 dBA, resulting in a difference of 11% (95% Confidence Interval (CI) 7%, 15%). Sometimes or frequently occurring sleep disturbance was reported by 23% at Leq 24 hr >50 dBA and by 13% at levels <50 dBA, a difference of 11% (95% CI 4%, 18%). A positive exposure- response relation was indicated for annoyance as well as for sleep disturbances when classifying the individuals into four different exposure categories (< 45, 46- 50, 51-55 and >55 dBA Leq 24 hr). There was some habituation to noise for problems related to sleep but not for annoyance. The prevalence of both annoyance and sleep problems was higher when bedroom windows were facing streets. People living in apartments had more sleep problems compared to people living in detached or semi-detached houses. In conclusion traffic noise exposure, even at low levels, was associated with annoyance and sleep disturbance. Access to a quiet side seemed to be a major protective factor for noise related problems.

NO2, as a marker of air pollution, and recurrent wheezing in children: a nested case-control study within the BAMSE birth cohort.

AIMS: To investigate the association between air pollution, including with NO2, and recurrent wheezing during the first two years of life. METHODS: A birth cohort (BAMSE) comprised 4089 children, for whom information on exposures, symptoms, and diseases was available from parental questionnaires at ages 2 months, and 1 and 2 years. NO2 was measured during four weeks in and outside the dwellings of children with recurrent wheezing and two age matched controls, in a nested case-control study (540 children). RESULTS: Conditional logistic regression showed an OR of 1.60 (95% CI 0.78 to 3.26) among children in the highest quartile of outdoor NO2 exposure in relation to those in the lowest quartile, adjusted for potential confounders. The corresponding OR for indoor NO2 was 1.51 (95% CI 0.81 to 2.82). An interaction with environmental tobacco smoke (ETS) was indicated with an OR of 3.10 (95% CI 1.32 to 7.30) among children exposed to the highest quartile of indoor NO2 and ETS. The association between NO2 and recurrent wheezing appeared stronger in children who did not fulfil the criteria for recurrent wheezing until their second year. CONCLUSIONS: Although the odds of increased recurrent wheezing are not statistically significantly different from one, results suggest that exposure to air pollution including NO2, particularly in combination with exposure to ETS, increases the risk of recurrent wheezing in children.

Strategies for preventing wheezing and asthma in small children.

OBJECTIVE: To assess the effects of living in agreement with allergy preventive guidelines on wheezing and asthma at 2 years of age. DESIGN: Prospective birth cohort study (BAMSE). Questionnaires on heredity and environmental factors were answered when the child was 2 months, and detailed questionnaires on symptoms at 1 and 2 years of age. PARTICIPANTS: 4089 children, born during 1994-1996. SETTING: Child Health Centres in central and north-western parts of Stockholm, Sweden. MAIN OUTCOME MEASURES: Wheezing and asthma up to the age of 2. RESULTS: The effects of preventive guidelines regarding breastfeeding, maternal tobacco smoke and home dampness on wheezing and asthma were assessed in multiple logistic regression models. The cumulative incidence of recurrent wheezing at 2 years of age was 12.6% and of asthma 6.8% among those with a lifestyle in agreement with all guidelines and 24.1 and 17.9%, respectively, in families exposed to at least two of the three risk factors. Among children with no heredity, family lifestyle according to the guidelines gave a twofold reduction of asthma (5.3 vs. 10.5%), while the group with heredity had a threefold reduction (9.1 vs. 27.3%). The attributable fraction for asthma associated with the guidelines was 23% in total and 33% among those with heredity. CONCLUSION: In this observational study, family lifestyle according to preventive guidelines is associated with an important reduction of recurrent wheezing and asthma at 2 years of age, especially among children with allergic heredity. A follow-up will determine whether there still a risk reduction of both symptoms and disease.

Increased prevalence of hypertension in a population exposed to aircraft noise.

OBJECTIVES: To investigate whether there is a relation between residential exposure to aircraft noise and hypertension. METHODS: The study population comprised two random samples of subjects aged 19-80 years, one including 266 residents in the vicinity of Stockholm Arlanda airport, and another comprising 2693 inhabitants in other parts of Stockholm county. The subjects were classified according to the time weighted equal energy and maximum aircraft noise levels at their residence. A questionnaire provided information on individual characteristics including history of hypertension. RESULTS: The prevalence odds ratio for hypertension adjusted for age, sex, smoking, and education was 1.6 (95% confidence interval (95% CI) 1.0 to 2.5) among those with energy averaged aircraft noise levels exceeding 55 dBA, and 1.8 (95% CI 1.1 to 2.8) among those with maximum aircraft noise levels exceeding 72 dBA. An exposure-response relation was suggested for both exposure measures. The exposure to aircraft noise seemed particularly important for older subjects and for those not reporting impaired hearing ability. CONCLUSIONS: Community exposure to aircraft noise may be associated with hypertension.

Environmental tobacco smoke and myocardial infarction among never-smokers in the Stockholm Heart Epidemiology Program (SHEEP).

An increased risk for myocardial infarction (MI) related to environmental tobacco smoke (ETS) exposure has previously been reported, but several aspects of the association are still uncertain. We studied the MI risk associated with ETS exposure among 334 nonfatal never-smoking MI cases and 677 population controls, 45-70 years of age, in Stockholm County. A postal questionnaire with a telephone follow-up provided information on ETS exposure and other potential risk factors for MI. After adjustment for age, gender, hospital catchment area, body mass index, socioeconomic status, job strain, hypertension, diet, and diabetes mellitus, the odds ratio for MI was 1.58 (95% confidence interval = 0.97-2.56) for an average daily exposure of 20 cigarettes or more from the spouse. Combined exposure from spouse and work showed an increasing odds ratio for MI, up to 1.55 (95% confidence interval = 1.02-2.34) in the highest category of weighted duration, that is, more than 90 "hour-years" of exposure (1 "hour-year" = 365 hours, or 1 hour per day for 1 year). In addition, more recent exposure appeared to convey a higher risk. Our data confirm an increased risk of MI from exposure to ETS and suggest that intensity of spousal exposure, combined exposure from spouse and work, and time since last exposure are important.

Using geographic information systems to assess individual historical exposure to air pollution from traffic and house heating in Stockholm.

A specific aim of a population-based case-control study of lung cancer in Stockholm, Sweden, was to use emission data, dispersion models, and geographic information systems (GIS) to assess historical exposure to several components of ambient air pollution. Data collected for 1,042 lung cancer cases and 2,364 population controls included information on residence from 1955 to the end of follow-up for each individual, 1990-1995. We assessed ambient air concentrations of pollutants from road traffic and heating throughout the study area for three points in time (1960, 1970, and 1980) using reconstructed emission data for the index pollutants nitrogen oxides (NO(x)/NO(2)) and sulfur dioxide together with dispersion modeling. NO(2) estimates for 1980 compared well with actual measurements, but no independently measured (study-external) data were available for SO(2), precluding similar validation. Subsequently, we used linear intra- and extrapolation to obtain estimates for all other years 1955-1990. Eleven thousand individual addresses were transformed into geographic coordinates through automatic and manual procedures, with an estimated error of < 100 m for 90% of the addresses. Finally, we linked annual air pollution estimates to annual residence coordinates, yielding long-term residential exposure indices for each individual. There was a wide range of individual long-term average exposure, with an 11-fold interindividual difference in NO(2) and an 18-fold difference in SO(2). The 30-year average for all study subjects was 20 microg/m(3) NO(2) from traffic and 53 microg/m(3) SO(2) from heating. The results indicate that GIS can be useful for exposure assessment in environmental epidemiology studies, provided that detailed geographically related exposure data are available for relevant time periods.

Worsening of asthma in children allergic to cats, after indirect exposure to cat at school.

Exposure to cat allergen at school might exacerbate symptoms in asthmatic children with cat allergy. To study this, we identified 410 children, 6-12 yr of age, who were being treated for asthma (inhaled steroids and beta-agonists), were allergic to cats, and had no cat at home. Peak expiratory flow (PEF), asthma symptoms, medication, fever and/or sore throat, and contact with furred pets were recorded twice daily during the last week of summer holidays and the second and third weeks of school. The number of cat owners in each class was recorded. Ninety-two children with asthma reported no contact with furred pets. Among these, children who attended classes with > 18% (median value) cat owners reported significantly decreased PEF, more days with asthma symptoms, and increased use of medication after school started. Those in classes with < or = 18% cat owners reported no change. Children in classes with many cat owners ran a 9-fold increased risk of exacerbated asthma after school start compared with children in classes with few cat owners, after adjusting for age, sex, and fever and/or sore throat. Thus, asthma symptoms, PEF, and the use of asthma medication in children with cat allergy may be affected by indirect cat exposure at school.

Self-diagnosed dermatitis in adults. Results from a population survey in Stockholm.

In a population-based survey of public health issues in Stockholm, Sweden, self-reported hand eczema, history of childhood eczema, nickel allergy, occurrence of skin symptoms on the face and intolerance to cosmetics and hygiene products, were investigated. A postal questionnaire was sent to 15,000 inhabitants aged 19-80 years. The response rate was 73%. The 1-year prevalence of hand eczema was 8% (females 10%, males 6%). History of childhood eczema was reported by 15% and, of these, 42% also stated positively that they had had hand eczema at some time. Hypersensitivity to nickel was owned to 15% of the females and 3% of the males. Of the nickel-sensitive, 30% reported ever having had hand eczema. The combination of nickel allergy and history of childhood eczema resulted in a cumulative prevalence of hand eczema of 56%. Females reported more hand-washings per day than did males, and a relation between number of hand-washings and hand eczema was found. Self-reported 1-year prevalence of skin symptoms on the face was 14% and, of these, 33% also owned to hypersensitivity to cosmetics. Dermatitis appears to be a common health problem. This fact should be made clear to those who give priority and allocate resources to health problems, e.g., by participation of dermatologists in performing population-based surveys.

Urban air pollution and lung cancer in Stockholm.

We conducted a population-based case-control study among men 40-75 years of age encompassing all cases of lung cancer 1985-1990 among stable residents of Stockholm County 1950-1990. Questionnaires to subjects or next-of-kin (primarily wives or children) elicited information regarding smoking and other risk factors, including occupational and residential histories. A high response rate (>85%) resulted in 1,042 cases and 2,364 controls. We created retrospective emission databases for NOx/NO2 and SO2 as indicators of air pollution from road traffic and heating, respectively. We estimated local annual source-specific air pollution levels using validated dispersion models and we linked these levels to residential addresses using Geographical Information System (GIS) techniques. Average traffic-related NO2 exposure over 30 years was associated with a relative risk (RR) of 1.2 (95% confidence interval 0.8-1.6) for the top decile of exposure, adjusted for tobacco smoking, socioeconomic status, residential radon, and occupational exposures. The data suggested a considerable latency period; the RR for the top decile of average traffic-related NO2 exposure 20 years previously was 1.4 (1.0-2.0). Little association was observed for SO2. Occupational exposure to asbestos, diesel exhaust, and other combustion products also increased the risk of lung cancer. Our results indicate that urban air pollution increases lung cancer risk and that vehicle emissions may be particularly important.

Fel d 1 and Can f 1 in settled dust and airborne Fel d 1 in allergen avoidance day-care centres for atopic children in relation to number of pet-owners, ventilation and general cleaning.

BACKGROUND: Special day-care centres for atopic children have been established in Sweden. OBJECTIVE: To study concentrations of cat (Fel d 1) and dog (Can f 1) allergens in settled dust and airborne cat allergen in day-care centres in relation to pet ownership among children and staff, ventilation and general cleaning. METHODS: Twelve allergen avoidance day-care centres and 22 conventional day-care centres were included in the study. Settled dust was collected and analysed with ELISA. Airborne cat allergen levels were measured in eight allergen avoidance and seven conventional centres with a personal air sampler and analysed with an amplified ELISA. Air change rate per hour (ACH) was measured. A questionnaire which focused on keeping of cat and dog among staff and children and frequency of general cleaning was used. RESULTS: In the allergen avoidance day-care centres neither children nor staff reported ownership of cats or dogs, compared with 21/22 of the conventional centres in which children and staff kept furred animals. Fel d 1 and Can f 1 were found in settled dust in all day-care centres. In the allergen avoidance compared with the conventional centres the concentrations of Fel d 1 and Can f 1 were lower, Fel d 1: median 0. 64 microg/g vs 5.45 microg/g and Can f 1: 0.39 microg/g vs 2.51, both P < 0.001, and airborne Fel d 1 was also lower in the allergen avoidance centres compared with the control centres, 1.51 ng/m3 vs 15.8 ng/m3, P = 0.002. A correlation was found between airborne and settled Fel d 1, rs = 0.75, P < 0.001. Furthermore, a correlation was found between increased ACH and decreased levels of Fel d 1 in the air in the day-care centres with no cat-owners, rs = - 0.86, P = 0.007. No relation was found between levels of cat or dog allergen and amount of general cleaning. CONCLUSION: Not keeping pets seems to reduce children's exposure to pet-allergen in their 'working environment'. Additionally, appropriate ventilation seems to reduce Fel d 1 in the air in day-care centres.