Rising incidence of breast cancer among young women in Sweden.

The national Swedish cancer registry was used to analyse the age-specific time trends in breast cancer incidence in Sweden from 1970 to 1984. The analysis included both a calendar year and a birth cohort approach to estimate time trends in disease occurrence. According to the birth cohort approach there was a statistically significant increase in the incidence with an average annual increase of the incidence of 3.2% (P = 0.0114), 3.4% (P = 0.0002) and 2.2% (P = 0.0264) in the age groups 25-29, 30-34 and 35-39, respectively. Possible causes of the observed increasing incidence are discussed

Novel Rhizosphere Soil Alleles for the Enzyme 1-Aminocyclopropane-1-Carboxylate Deaminase Queried for Function with an In Vivo Competition Assay

ABSTRACT Metagenomes derived from environmental microbiota encode a vast diversity of protein homologs. How this diversity impacts protein function can be explored through selection assays aimed to optimize function. While artificially generated gene sequence pools are typically used in selection assays, their usage may be limited because of technical or ethical reasons. Here, we investigate an alternative strategy, the use of soil microbial DNA as a starting point. We demonstrate this approach by optimizing the function of a widely occurring soil bacterial enzyme, 1-aminocyclopropane-1-carboxylate (ACC) deaminase. We identified a specific ACC deaminase domain region (ACCD-DR) that, when PCR amplified from the soil, produced a variant pool that we could swap into functional plasmids carrying ACC deaminase-encoding genes. Functional clones of ACC deaminase were selected for in a competition assay based on their capacity to provide nitrogen to Escherichia coli in vitro . The most successful ACCD-DR variants were identified after multiple rounds of selection by sequence analysis. We observed that previously identified essential active-site residues were fixed in the original unselected library and that additional residues went to fixation after selection. We identified a divergent essential residue whose presence hints at the possible use of alternative substrates and a cluster of neutral residues that did not influence ACCD performance. Using an artificial ACCD-DR variant library generated by DNA oligomer synthesis, we validated the same fixation patterns. Our study demonstrates that soil metagenomes are useful starting pools of protein-coding-gene diversity that can be utilized for protein optimization and functional characterization when synthetic libraries are not appropriate

Health economic analysis of ticagrelor in patients with acute coronary syndromes intended for non-invasive therapy

Objective: To investigate the cost effectiveness of ticagrelor versus clopidogrel in patients with acute coronary syndromes (ACS) in the Platelet Inhibition and Patient Outcomes (PLATO) study who were scheduled for non-invasive management. Methods: A previously developed cost effectiveness model was used to estimate long-term costs and outcomes for patients scheduled for non-invasive management. Healthcare costs, event rates and health-related quality of life under treatment with either ticagrelor or clopidogrel over 12 months were estimated from the PLATO study. Long-term costs and health outcomes were estimated based on data from PLATO and published literature sources. To investigate the importance of different healthcare cost structures and life expectancy for the results, the analysis was carried out from the perspectives of the Swedish, UK, German and Brazilian public healthcare systems. Results: Ticagrelor was associated with lifetime quality-adjusted life-year (QALY) gains of 0.17 in Sweden, 0.16 in the UK, 0.17 in Germany and 0.13 in Brazil compared with generic clopidogrel, with increased healthcare costs of €467, €551, €739 and €574, respectively. The cost per QALY gained with ticagrelor was €2747, €3395, €4419 and €4471 from a Swedish, UK, German and Brazilian public healthcare system perspective, respectively. Probabilistic sensitivity analyses indicated that the cost per QALY gained with ticagrelor was below conventional threshold values of cost effectiveness with a high probability. Conclusions: Treatment of patients with ACS scheduled for 12 months’ non-invasive management with ticagrelor is associated with a cost per QALY gained below conventional threshold values of cost effectiveness compared with generic clopidogrel. Trial registration number NCT000391872

Impact of presentation and transfer delays on complete ST-segment resolution before primary percutaneous coronary intervention: Insights from the ATLANTIC trial

Aims: The aim of this study was to identify predictors of complete ST-segment resolution (STR) pre-primary percutaneous coronary intervention (PCI) in patients enrolled in the ATLANTIC trial. Methods and results: ECGs recorded at the time of inclusion (pre-hospital [pre-H]-ECG) and in the catheterisation laboratory before angiography (pre-PCI-ECG) were analysed by an independent core laboratory. Complete STR was defined as 6570%. Complete STR occurred pre-PCI in 12.8% (204/1, 598) of patients and predicted lower 30-day composite MACCE (OR=0.10, 95% CI: 0.002-0.57, p=0.001) and total mortality (OR=0.16, 95% CI: 0.004-0.95, p=0.035). Independent predictors of complete STR included the time from index event to pre-H-ECG (OR=0.94, 95% CI: 0.89-1.00, p=0.035), use of heparins before pre- PCI-ECG (OR=1.75, 95% CI: 1.25-2.45, p=0.001) and time from pre-H-ECG to pre-PCI-ECG (OR=1.09, 95% CI: 1.03-1.16, p=0.005). In the pre-H ticagrelor group, patients with complete STR had a significantly longer delay between pre-H-ECG and pre-PCI-ECG compared to patients without complete STR (median 53 [44-73] vs. 49 [38.5-61] mins, p=0.001); however, this was not observed in the control group (in-hospital ticagrelor) (50 [40-67] vs. 49 [39-61] mins, p=0.258). Conclusions: Short patient delay, early administration of anticoagulant and ticagrelor if a long transfer delay is expected may help to achieve reperfusion prior to PCI. Pre-H treatment may be beneficial in patients with longer transfer delays, allowing the drug to become biologically active. ClinicalTrials.gov Identifier: NCT01347580

Pre-hospital administration of ticagrelor in diabetic patients with ST-elevation myocardial infarction undergoing primary angioplasty: A sub-analysis of the ATLANTIC trial

Objective: We investigated, in the contemporary era of ST-elevation myocardial infarction (STEMI) treatment, the influence of diabetes mellitus (DM) on cardiovascular outcomes, and whether pre-hospital administration of ticagrelor may affect these outcomes in a subgroup of STEMI patients with DM. Background: DM patients have high platelet reactivity and a prothrombotic condition which highlight the importance of an effective antithrombotic regimen in this high-risk population. Methods: In toal 1,630 STEMI patients enrolled in the ATLANTIC trial who underwent primary percutaneous coronary intervention (PCI) were included. Multivariate analysis was used to explore the association of DM with outcomes and potential treatment-by-diabetes interaction was tested. Results: A total of 214/1,630 (13.1%) patients had DM. DM was an independent predictor of poor myocardial reperfusion as reflected by less frequent ST-segment elevation resolution ( 6570%) after PCI (OR 0.59, 95% CI 0.43\u20130.82, P < 0.01) and was an independent predictor of the composite 30-day outcomes of death/new myocardial infarction (MI)/urgent revascularization/definite stent thrombosis (ST) (OR 2.80, 95% CI 1.62\u20134.85, P < 0.01), new MI or definite acute ST (OR 2.46, 95% CI 1.08\u20135.61, P = 0.03), and definite ST (OR 10.00, 95% CI 3.54\u201328.22, P < 0.01). No significant interaction between pre-hospital ticagrelor vs in-hospital ticagrelor administration and DM was present for the clinical, electrocardiographic and angiographic outcomes as well as for thrombolysis in myocardial infarction major bleeding. Conclusions: DM remains independently associated with poor myocardial reperfusion and worse 30-day clinical outcomes. No significant interaction was found between pre-hospital vs in-hospital ticagrelor administration and DM status. Further approaches for the treatment of DM patients are needed. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01347580

Are non-responders in a quitline evaluation more likely to be smokers?

BACKGROUND: In evaluation of smoking cessation programs including surveys and clinical trials the tradition has been to treat non-responders as smokers. The aim of this paper is to assess smoking behaviour of non-responders in an evaluation of the Swedish national tobacco cessation quitline a nation-wide, free of charge service. METHODS: A telephone interview survey with a sample of people not participating in the original follow-up. The study population comprised callers to the Swedish quitline who had consented to participate in a 12 month follow-up but had failed to respond. A sample of 84 (18% of all non-responders) was included. The main outcome measures were self-reported smoking behaviour at the time of the interview and at the time of the routine follow-up. Also, reasons for not responding to the original follow-up questionnaire were assessed. For statistical comparison between groups we used Fischer's exact test, odds ratios (OR) and 95% confidence intervals (CI) on proportions and OR. RESULTS: Thirty-nine percent reported to have been smoke-free at the time they received the original questionnaire compared with 31% of responders in the original study population. The two most common reasons stated for not having returned the original questionnaire was claiming that they had returned it (35%) and that they had not received the questionnaire (20%). Non-responders were somewhat younger and were to a higher degree smoke-free when they first called the quitline. CONCLUSION: Treating non-responders as smokers in smoking cessation research may underestimate the true effect of cessation treatment

Mortality in GOLD stages of COPD and its dependence on symptoms of chronic bronchitis

BACKGROUND: The GOLD classification of COPD severity introduces a stage 0 (at risk) comprising individuals with productive cough and normal lung function. The aims of this study were to investigate total mortality risks in GOLD stages 0–4 with special focus on stage 0, and furthermore to assess the influence of symptoms of chronic bronchitis on mortality risks in GOLD stages 1–4. METHOD: Between 1974 and 1992, a total of 22 044 middle-aged individuals participated in a health screening, which included a spirometry as well as recording of respiratory symptoms and smoking habits. Individuals with comorbidity at baseline (diabetes, stroke, cancer, angina pectoris, or heart infarction) were excluded from the analyses. Hazard ratios (HR 95% CI) of total mortality were analyzed in GOLD stages 0–4 with individuals with normal lung function and without symptoms of chronic bronchitis as a reference group. HR:s in smoking individuals with symptoms of chronic bronchitis within the stages 1–4 were calculated with individuals with the same GOLD stage but without symptoms of chronic bronchitis as reference. RESULTS: The number of deaths was 3674 for men and 832 for women based on 352 324 and 150 050 person-years respectively. The proportion of smokers among men was 50% and among women 40%. Self reported comorbidity was present in 4.6% of the men and 6.6% of the women. Among smoking men, Stage 0 was associated with an increased mortality risk, HR; 1.65 (1.32–2.08), of similar magnitude as in stage 2, HR; 1.41 (1.31–1.70). The hazard ratio in stage 0 was significantly higher than in stage 1 HR; 1.13 (0.98–1.29). Among male smokers with stage 1; HR: 2.04 (1.34–3.11), and among female smokers with stage 2 disease; HR: 3.16 (1.38–7.23), increased HR:s were found in individuals with symptoms of chronic bronchitis as compared to those without symptoms of chronic bronchitis. CONCLUSION: Symptoms fulfilling the definition of chronic bronchitis were associated with an increased mortality risk among male smokers with normal pulmonary function (stage 0) and also with an increased risk of death among smoking individuals with mild to moderate COPD (stage 1 and 2)

Marital status and occupation in relation to short-term case fatality after a first coronary event - a population based cohort

<p>Abstract</p> <p>Background</p> <p>Although marital status and low occupation level has been associated with mortality, the relationship with case fatality rates (CFR) after a coronary event (CE) is unclear. This study explored whether incidence of CE and short-term CFR differ between groups defined in terms of marital status and occupation, and if this could be explained by biological and life-style risk factors.</p> <p>Methods</p> <p>Population-based cohort study of 33,224 subjects (67% men), aged 27 to 61 years, without history of myocardial infarction, who were enrolled between 1974 and 1992. Incidence of CE, and CFR (death during the first day or within 28 days after CE, including out-of-hospital deaths) was examined over a mean follow-up of 21 years.</p> <p>Results</p> <p>A total of 3,035 men (6.0 per 1000 person-years) and 507 women (2.4 per 1000) suffered a first CE during follow-up. CFR (during the 1^stday) was 29% in men and 23% in women. After risk factor adjustments, unmarried status in men, but not in women, was significantly associated with increased risk of suffering a CE [hazard ratios (HR) 1.10, 95% CI: 0.97-1.24; 1.42: 1.27-1.58 and 1.77: 1.31-2.40 for never married, divorced and widowed, respectively, compared to married]. Unmarried status, in both gender, was also related with an increased CFR (1^stday), taking potential confounders into account (odds ratio (OR) 2.14, 95% CI: 1.63-2.81; 1.91: 1.50-2.43 and 1.49: 0.77-2.89 for never married, divorced and widowed, respectively, compared to married men. Corresponding figures for women was 2.32: 0.93-5.81; 1.87: 1.04-3.36 and 2.74: 1.03-7.28. No differences in CFR (1^stday) were observed between occupational groups in neither gender.</p> <p>Conclusions</p> <p>In this population-based Swedish cohort, short-term CFR was significantly related to unmarried status in men and women. This relationship was not explained by biological-, life-style factors or occupational level.</p