Analysis of antibiotic use patterns in Danish hospitals 2015-2021 using an adapted version of the who aware classification.

BACKGROUND: AWaRe is a tool to categorise and guide antibiotic use. Antibiotics are classified in three groups: Access, Watch and Reserve. The Access group contains first choice antibiotics for 25 of the most common infections. Antibiotics in the Watch and Reserve groups should be restricted to cases that cannot be effectively treated with drugs from the Access group. OBJECTIVES: The primary aim of this study was to evaluate and adapt the WHO 2019 AWaRe classification for use with antibiotic usage data in Danish hospitals. The secondary aim was to study the usefulness of the abxaware; software package for visualisation and analysis of temporal trends in antibiotic use patterns. METHODS: We obtained data on purchases of antibiotics in Danish hospitals from January 2015 to July 2021. Sixty-seven unique drugs had been purchased. To better correspond with Danish guidelines, we moved two drugs one AWaRe level upwards. To help aggregate antibiotics according to AWaRe and visualise use patterns, we developed an R package, abxaware. RESULTS: After adding two drugs that were not included in the original AWaRe classification nearly all antibiotics (>99%) used in Danish hospitals were covered. The abxaware software package for R is a useful tool to help aggregate, visualise and analyse antibiotic use patterns. CONCLUSIONS: With minor modifications, we adapted the AWaRe classification to cover most antibiotics used in Danish hospitals and to reflect Danish treatment guidelines. The abxaware package is a useful tool to aggregate and plot antibiotic usage data according to the AWaRe classification and to test for non-random variation in the percentage use of Access antibiotics.

Air pollution from traffic and risk for lung cancer in three Danish cohorts.

BACKGROUND: Air pollution is suspected to cause lung cancer. The purpose was to investigate whether the concentration of nitrogen oxides (NOx) at the residence, used as an indicator of air pollution from traffic, is associated with risk for lung cancer. METHODS: We identified 679 lung cancer cases in the Danish Cancer Registry from the members of three prospective cohorts and selected a comparison group of 3,481 persons from the same cohorts in a case-cohort design. Residential addresses from January 1, 1971, were traced in the Central Population Registry. The NOx concentration at each address was calculated by dispersion models, and the time-weighted average concentration for all addresses was calculated for each person. We used Cox models to estimate incidence rate ratios after adjustment for smoking (status, duration, and intensity), educational level, body mass index, and alcohol consumption. RESULTS: The incidence rate ratios for lung cancer were 1.30 [95% confidence interval (95% CI), 1.07-1.57] and 1.45 (95% CI, 1.12-1.88) for NOx concentrations of 30 to 72 and >72 microg/m3, respectively, when compared with <30 microg/m3. This corresponds to a 37% (95% CI, 6-76%) increase in incidence rate ratio per 100 microg/m3 NOx. The results showed no significant heterogeneity in the incidence rate ratio for lung cancer between cohorts or between strata defined by gender, educational level, or smoking status. CONCLUSION: The study showed a modest association between air pollution from traffic and the risk for lung cancer. IMPACT: This study points at traffic as a source of carcinogenic air pollution and stresses the importance of strategies for reduction of population exposure to traffic-related air pollution.

Bulky DNA adducts as risk indicator of lung cancer in a Danish case-cohort study.

Little is known of the predictive value of the levels of DNA adducts in terms of cancer risk. We examined the association between bulky DNA adducts and risk of lung cancer in a population-based cohort, comprising of 25,717 men and 27,972 women aged 50-64 years at entry. We included 245 cases (137 men and 108 women) with lung cancer and a comparison group of 255 individuals (137 men and 118 women), matched on sex, age and smoking duration. Bulky adducts in white blood cells collected at enrollment and stored at -150 degrees C were analyzed by (32)P-postlabeling method, using the butanol enrichment procedure. The median level of bulky DNA adducts was 0.196 adduct/10(8) nucleotides (5-95 percentiles: 0.094-0.595) among current smokers who were later diagnosed with lung cancer and 0.163 adduct/10(8) nucleotides (5-95 percentiles: 0.091-0.455) among current smokers in the comparison group. The smoking adjusted incidence rate ratios (IRR) for lung cancer in relation to one log unit (natural logarithm) difference in adduct levels were 1.22 (95% CI 0.85-1.74), 1.33 (95% CI 0.89-1.98) and 0.76 (95% CI 0.39-1.47) among all, current and former smokers, respectively. Current smokers with bulky DNA adduct levels above the median had a significant higher lung cancer rate than those with adduct levels below the median (IRR = 1.61; 95% CI 1.04-2.49). The results are compatible with previous studies, suggesting a slightly higher risk of lung cancer with higher levels of adducts among smokers. Our results indicate that bulky DNA adducts may have a weak association with lung cancer risk.

Physical activity and risk for lung cancer in a Danish cohort.

Physical activity might reduce the risk for lung cancer by various mechanisms, but the evidence is inconclusive. We therefore examined the relationship between physical activity and risk for lung cancer in a large population-based Danish cohort with detailed information about number of hours per week spent on specific physical activities as well as lifetime smoking patterns. Between 1993 and 1997, a total of 57,053 persons aged 50-64 years agreed to participate in the cohort. After exclusions of persons with cancer diagnosis before invitation and persons for whom data regarding study variables were missing, 26,070 men and 28,352 women remained for study. By 31 December 2002, lung cancer had been diagnosed in 194 men and 175 women. A questionnaire registered average number of hours per week spent on each of 6 types of leisure time physical activity. Level of occupational physical activity was registered in 5 categories. Cox's proportional hazard model stratified according to age at entry (1-year intervals) was adjusted for smoking, school education, possible occupational exposure to lung carcinogens and intake of fruit and vegetables. No significant association was found between number of hours per week spent on 6 types of physical activity during leisure time and the incidence rate ratio (IRR) for lung cancer. For each type of activity, the IRR of lung cancer was lower for active compared to nonactive women, whereas for men lower IRRs were only observed for sports and gardening. Higher levels of occupational physical activity had no protective effect; the lowest IRR was found for sitting work. Our study shows no convincing protective effect of physical activity on lung cancer risk.

Two regions in chromosome 19q13.2-3 are associated with risk of lung cancer.

Lung cancer is the most common fatal cancer among Danish men, and the incidence rate is increasing among women. In a case-cohort study, we have investigated the occurrence of lung cancer in relation to a high-risk haplotype, previously identified for breast cancer among post-menopausal women, and in relation to the closely linked polymorphisms XPD Asp312Asn and Lys751Gln. Among 54220 members of a Danish prospective cohort study aged 50-64 at entry, 265 lung cancer cases were identified and a sub-cohort comprising 272 individuals was used for comparison. Among women in the 50-55 year age interval, homozygous carriers of the high-risk haplotype were at increased risk of lung cancer (RR=7.02, 95% CI=1.88-26.18). In the 56-60 year and 61-70 year age intervals, no associations were observed. Among men, no statistically significant associations were found in any age interval. Female homozygous carriers of the variant allele of XPD Lys751Gln were at significantly increased risk of lung cancer in the two younger age-intervals (50-55 years: RR=5.60, 95% CI=1.18-26.45, 56-60 years: RR=10.60, 95% CI=1.50-75.64). Among men, carriers of the variant allele of XPD Lys751Gln had a non-significantly increased risk of lung cancer in the youngest age interval (RR=6.38, 95% CI=0.74-54.90). When the polymorphisms in XPD Asp312Asn and Lys751Gln were mutually adjusted, XPD Asp312Asn was not associated with increased risk of cancer. We found no interaction between genotypes and duration of smoking. In conclusion, two regions of chromosome 19q13.2-3 seem to be associated with risk of lung cancer.

Augmented intrinsic activity of Factor VIIa by replacement of residues 305, 314, 337 and 374: evidence of two unique mutational mechanisms of activity enhancement.

Coagulation Factor VIIa (FVIIa) lacks the ability to spontaneously complete the conversion to a fully active enzyme after specific cleavage of an internal peptide bond (Arg152-Ile153) in the zymogen. Recently, several variants of FVIIa with enhanced intrinsic activity have been constructed. The in vitro characterization of these variants has shed light on molecular determinants that put restrictions on FVIIa in favour of a zymogen-like conformation and warrants continued efforts. Here we describe a new FVIIa variant with high intrinsic activity containing the mutations Leu305-->Val, Ser314-->Glu, Lys337-->Ala, and Phe374-->Tyr. The variant, called FVIIa(VEAY), processes a tripeptidyl substrate very efficiently because of an unprecedented, 5.5-fold lowering of the K(m) value. Together with a 4-fold higher substrate turnover rate this gives the variant a catalytic efficiency 22 times that of wild-type FVIIa, which is reflected in a considerably enhanced susceptibility to inhibition by antithrombin and other inhibitors. For instance, the affinity of FVIIa(VEAY) for the S1 probe and inhibitor p -aminobenzamidine is represented by an 8-fold lower K(i) value compared with that of FVIIa. Activation of Factor X in solution occurs about 10 times faster with FVIIa(VEAY) than with FVIIa, due virtually exclusively to an increased kcat value. The high activity of FVIIa(VEAY) is not accompanied by an increased burial of the N-terminus of the protease domain. A comparison of the kinetic parameters and molecular properties of FVIIa(VEAY) with those of the previously described mutant V158D/E296V/M298Q-FVIIa (FVIIa(IIa)), and the locations of the substitutions in the two variants, reveals what appear to be two profoundly different structural mechanisms dictating improvements in enzymic performance.