Regioselective Hydroalkylation of Vinylarenes by Cooperative Cu and Ni Catalysis.

Disclosed here is a dual copper and nickel catalytic system with a silyl hydride source for promoting the linear selective hydroalkylation of vinylarenes. This carbon-carbon bond-forming protocol is applied to couple a variety of functionalized vinylarenes with alkyl halides applying a nickel(II) NNN pincer complex in the presence of an NHC-ligated copper catalyst. This combination allows for a 1 mol % loading of the nickel catalyst leading to turnover numbers of up to 72. Over 40 examples are presented, including applications for pharmaceutical diversification. Labeling experiments demonstrated the regioselectivity of the reaction and revealed that the copper catalyst plays a crucial role in enhancing the rate for formation of the reactive linear alkyl nickel complex. Overall, the presented work provides a complimentary approach for hydroalkylation reactions, whilst providing a preliminary mechanistic understanding of the cooperativity between the copper and nickel complexes.

On-demand synthesis of phosphoramidites.

Automated chemical synthesis of oligonucleotides is of fundamental importance for the production of primers for the polymerase chain reaction (PCR), for oligonucleotide-based drugs, and for numerous other medical and biotechnological applications. The highly optimised automised chemical oligonucleotide synthesis relies upon phosphoramidites as the phosphate precursors and one of the drawbacks of this technology is the poor bench stability of phosphoramidites. Here, we report on the development of an on-demand flow synthesis of phosphoramidites from their corresponding alcohols, which is accomplished with short reaction times, near-quantitative yields and without the need of purification before being submitted directly to automated oligonucleotide synthesis. Sterically hindered as well as redox unstable phosphoramidites are synthesised using this methodology and the subsequent couplings are near-quantitative for all substrates. The vision for this technology is direct integration into DNA synthesisers thereby omitting manual synthesis and storage of phosphoramidites.

Controlled Release of Reactive Gases: A Tale of Taming Carbon Monoxide.

This Personal Account describes the development of air-stable and solid precursors for on-demand release of carbon monoxide. In combination with the development of a two-chamber reactor, COware®, CO liberation can be achieved under safe working conditions, as well as allowing transition metal-mediated carbonylations with stoichiometric carbon monoxide. Particularly appealing is the adaptability of this chemical technology for the preparation of carbon isotope labeled bioactive compounds.

Access to Aryl and Heteroaryl Trifluoromethyl Ketones from Aryl Bromides and Fluorosulfates with Stoichiometric CO.

We report a sequential one-pot preparation of aromatic trifluoromethyl ketones starting from readily accessible aryl bromides and fluorosulfates, the latter easily prepared from the corresponding phenols. The methodology utilizes low pressure carbon monoxide generated ex situ from COgen to generate Weinreb amides as reactive intermediates that undergo monotrifluoromethylation affording the corresponding aromatic trifluoromethyl ketones (TFMKs) in good yields. The stoichiometric use of CO enables the possibility for accessing 13C-isotopically labeled TFMK by switching to the use of 13COgen.

Copper-catalyzed and additive free decarboxylative trifluoromethylation of aromatic and heteroaromatic iodides.

A copper-catalyzed decarboxylative trifluoromethylation of (hetero)aromatic iodides has been developed. Importantly, this new copper-catalyzed reaction operates in the absence of any ligands and metal additives. The protocol shows good functional group tolerance and is compatible with heteroaromatic systems. The reaction proved scalable to a 15 mmol scale with increased yield. Finally, late-stage installation of the trifluoromethyl functionality afforded the N-trifluoroacetamide variant of the antidepressant agent, Prozac, demonstrating the applicability of the developed method.

Observer Agreement and Accuracy of 18F-Sodium Fluoride PET/CT in the Diagnosis of Bone Metastases in Prostate Cancer.

Our aim was to evaluate the interobserver agreement in 18F-sodium fluoride (NaF) PET/CT for the detection of bone metastases in patients with prostate cancer (PCa). Methods:18F-NaF PET/CT scans were retrieved from all patients who participated in 4 recent prospective trials. Two experienced observers independently evaluated the 18F-NaF PET/CT scans on a patient level using a 3-category scale (no bone metastases [M0], equivocal for bone metastases, and bone metastases present [M1]) and on a dichotomous scale (M0/M1). In patients with no more than 10 lesions, the location and number of lesions were recorded. On a patient level, the diagnostic performance was calculated using a sensitivity analysis, in which equivocal lesions were handled as M0 as well as M1. Results:18F-NaF PET/CT scans from 219 patients with PCa were included, of whom 129 patients were scanned for primary staging, 67 for biochemical recurrence, and 23 for metastatic castration-resistant PCa. Agreement between the observers was almost perfect on a patient level (3-category unweighted κ = 0.83 ± 0.05, linear weighted κ = 0.90 ± 0.06, and dichotomous κ = 0.91 ± 0.07). On a lesion level (dichotomous scale), the observers agreed on the number and location of bone metastases in 205 (93.6%) patients. In the remaining 14 patients, the readers disagreed on the number of lesions in 13 patients and the location of bone metastases in 1 patient. A final diagnosis of bone metastases was made for 211 of 219 patients. The sensitivity ranged from 0.86 to 0.92, specificity from 0.83 to 0.97, positive predictive value from 0.70 to 0.93, and negative predictive value from 0.94 to 0.96. Conclusion: The interobserver agreement on 18F-NaF PET/CT for the detection of bone metastases in patients with PCa was very high among trained observers, both on a patient level and on a lesion level. Moreover, the diagnostic performance of 18F-NaF PET/CT was satisfactory, rendering 18F-NaF PET/CT a robust tool in the diagnostic armamentarium.

Single and dual coil shock efficacy and predictors of shock failure in patients with modern implantable cardioverter defibrillators-a single-center paired randomized study.

PURPOSE: Implantable cardioverter defibrillators (ICDs) can treat life-threatening tachyarrhythmia with high-voltage shocks. The aims were to compare the efficacy of single and dual coil shock vectors in modern ICDs and to identify predictors of shock failure. METHODS: This is a single-center paired randomized study including 216 patients with mixed indications and ICDs from four manufacturers. All patients underwent two implant defibrillation tests using single and dual coil vectors with the test order randomized. Tested shock energy differed slightly between manufacturers because of differences in device programmability: first shock approximately 15 J below maximal output-if failed, second shock approximately 10 J below maximal output-if failed, third shock at maximal output. RESULTS: First shock success rate was 399/432 (92.4%). Comparing single and dual coil vectors, no differences were seen in first shock efficacy (91.7% vs. 93.1%, P = 0.629) or lowest tested succesfully stored energy (27.2 J vs. 27.1 J, P = 0.620). All successive internal shocks failed in 4/432 (0.9%) of inductions requiring external rescue shocks to restore circulation. Multivariate predictors of first shock failure were QRS duration (relative risk 0.81 per 10 ms, P = 0.001), amiodarone treatment (relative risk 3.30, P = 0.003), and body height (relative risk 1.70 per 10 cm, P = 0.019). CONCLUSIONS: Implant defibrillation testing of modern intravenous ICD systems demonstrates high shock efficacy with no difference between single and dual coil vectors.

Body Fat Percentage, Waist Circumference, and Obesity As Risk Factors for Rheumatoid Arthritis: A Danish Cohort Study.

OBJECTIVE: To investigate the relationship between bioimpedance-derived total body fat percentage, waist circumference, and body mass index (BMI) and the subsequent development of rheumatoid arthritis (RA). METHODS: A population-based prospective cohort study was conducted using 55,037 patients enrolled in the Danish Diet, Cancer, and Health cohort. Baseline data included anthropometric measures and lifestyle factors. Individuals who developed RA were identified through linkage with the Danish National Patient Registry. The relationships between bioimpedance-derived body fat percentage, waist circumference, and BMI and incident RA were assessed using Cox proportional hazards regression models, stratifying by sex. All analyses were performed for overall RA and the serologic subtypes seropositive and other RA. RESULTS: A total of 210 men (37.6% with seropositive RA) and 456 women (41.0% with seropositive RA) developed RA during a median follow-up of 20.1 years. In women, the overall RA risk was 10% higher for each 5% increment of total body fat (hazard ratio [HR] 1.10 [95% confidence interval (95% CI) 1.02-1.18]), 5% higher for each 5-cm increment of waist circumference (HR 1.05 [95% CI 1.01-1.10]), and nearly 50% higher in those whose BMI was in the obese range compared to normal range BMI (HR 1.46 [95% CI 1.12-1.90]). These positive associations were also found for patients with other RA. In men, there were no clear associations between body fat percentage, waist circumference, or BMI and RA. No significant associations were found for seropositive RA in women or men, possibly related to low sample size. CONCLUSION: In women, higher body fat percentage, higher waist circumference, and obesity were associated with a higher risk of RA.

Effects of Marine n-3 Polyunsaturated Fatty Acids on Heart Rate Variability and Heart Rate in Patients on Chronic Dialysis: A Randomized Controlled Trial.

Marine n-3 polyunsaturated fatty acids (PUFA) may improve autonomic dysfunction, as indicated by an increase in heart rate variability (HRV) and reduce the risk of sudden cardiac death. Hence, the aim of this study was to investigate the effects of marine n-3 PUFA on 24-h HRV in patients on chronic dialysis, who have a high risk of sudden cardiac death. Between June 2014 and March 2016, 112 patients on chronic dialysis from Denmark were allocated to a daily supplement of 2 g marine n-3 PUFA or control for three months in a randomized, double-blinded, controlled trial. A 48-h Holter monitoring was performed and mean 24-h HRV indices for the two days were available in 85 patients. The mean age was 62.3 years (SD: 14.3) and median dialysis vintage was 1.7 years (IQR: 0.5, 6.4). Within-group and between-group changes in outcome were evaluated by a paired and two sample t-test, respectively. Marine n-3 PUFA did not change the primary endpoint SDNN (SD of all RR-intervals) reflecting overall HRV, but other HRV indices increased and the mean RR-interval increased significantly, corresponding to a decrease in heart rate by 2.5 beats per minute (p = 0.04). In conclusion, marine n-3 PUFA did not change SDNN, but the mean heart rate was significantly reduced and changes in other HRV-indices were also observed, indicating an increase in vagal modulation that might be protective against malignant ventricular arrhythmias.

Reporting and Handling of Indeterminate Bone Scan Results in the Staging of Prostate Cancer: A Systematic Review.

Bone scintigraphy is key in imaging skeletal metastases in newly diagnosed prostate cancer. Unfortunately, a notable proportion of scans are not readily classified as positive or negative but deemed indeterminate. The extent of reporting of indeterminate bone scans and how such scans are handled in clinical trials are not known. A systematic review was conducted using electronic databases up to October 2016. The main outcome of interest was the reporting of indeterminate bone scans, analyses of how such scans were managed, and exploratory analyses of the association of study characteristics and the reporting of indeterminate bone scan results. Seventy-four eligible clinical trials were identified. The trials were mostly retrospective (85%), observational (95%), large trials (median 195 patients) from five continents published over four decades. The majority of studies had university affiliation (72%), and an author with imaging background (685). Forty-five studies (61%) reported an indeterminate option for the bone scan and 23 studies reported the proportion of indeterminate scans (median 11.4%). Most trials (44/45, 98%) reported how to handle indeterminate scans. Most trials (n = 39) used add-on supplementary imaging, follow-up bone scans, or both. Exploratory analyses showed a significant association of reporting of indeterminate results and number of patients in the study (p = 0.024) but failed to reach statistical significance with other variables tested. Indeterminate bone scan for staging of prostate cancer was insufficiently reported in clinical trials. In the case of indeterminate scans, most studies provided adequate measures to obtain the final status of the patients.

Single-coil and dual-coil defibrillator leads and association with clinical outcomes in a complete Danish nationwide ICD cohort.

BACKGROUND: The best choice of defibrillator lead in patients with routine implantable cardioverter-defibrillator (ICD) is not settled. Traditionally, most physicians prefer dual-coil leads but the use of single-coil leads is increasing. OBJECTIVE: The purpose of this study was to compare clinical outcomes in patients with single- and dual-coil leads. METHODS: All 4769 Danish patients 18 years or older with first-time ICD implants from 2007 to 2011 were included from the Danish Pacemaker and ICD Register. Defibrillator leads were 38.9% single-coil leads and 61.1% dual-coil leads. The primary end point was all-cause mortality. Secondary end points were lowest successful energy at implant defibrillation testing, first shock failure in spontaneous arrhythmias, structural lead failure, and lead extraction outcomes. RESULTS: Single-coil leads were associated with lower all-cause mortality with an adjusted hazard ratio of 0.85 (95% confidence interval 0.73-0.99; P = .04). This finding was robust in a supplementary propensity score-matched analysis. However, dual-coil leads were used in patients with slightly higher preimplant morbidity, making residual confounding by indication the most likely explanation for the observed association between lead type and mortality. The lowest successful defibrillation energy was higher using single-coil leads (23.2 ± 4.3 J vs 22.1 ± 3.9 J; P < .001). No significant differences were observed for other secondary end points showing high shock efficacies and low rates of lead failures and extraction complications. CONCLUSION: Shock efficacy is high for modern ICD systems. The choice between single-coil and dual-coil defibrillator leads is unlikely to have a clinically significant impact on patient outcomes in routine ICD implants.

Short look-back periods in pharmacoepidemiologic studies of new users of antibiotics and asthma medications introduce severe misclassification.

PURPOSE: The aim of this study was to quantify the effect of the look back period on the misclassification of new users of antibiotics and asthma medications. METHODS: We included all children born in Denmark from 1995 through 2006 and all prescriptions of antibiotics and asthma medication from 1995 through 2011. The study period was 2007 through 2011. True new users redeemed their first prescription in the study period whereas prior users redeemed their first prescription before the study period. Look-back periods ranged from 30 days up to 12 years prior to the study period, and we defined new users as those without a prescription in the look-back period. The relative misclassification (RM) was estimated as the number of defined new users divided by the number of true new users. RESULTS: For antibiotics, the RM decreased from 4.75 for look-back periods of 30 days to 2.36 for 2 years and 1.33 for 5 years. For asthma medication, the RM decreased from 2.53 for look-back periods of 30 days to 1.48 for 2 years and 1.20 for 5 years. Older age, male gender, and absence of treatment-related diagnoses were associated with higher RM. CONCLUSIONS: Studies applying the new user design are strongly dependent on the available information on prescriptions. For drug classes with intermittent use such as asthma medications, even a 2-year look-back period produced severe misclassification. Excluding children with a prior treatment-related diagnosis can reduce the level of misclassification.

Psychiatric diagnoses and psychoactive medication use among nonsurgical critically ill patients receiving mechanical ventilation.

IMPORTANCE: The relationship between critical illness and psychiatric illness is unclear. OBJECTIVE: To assess psychiatric diagnoses and medication prescriptions before and after critical illness. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study in Denmark of critically ill patients in 2006-2008 with follow-up through 2009, and 2 matched comparison cohorts from hospitalized patients and from the general population. EXPOSURES: Critical illness defined as intensive care unit admission with mechanical ventilation. MAIN OUTCOMES AND MEASURES: Adjusted prevalence ratios (PRs) of psychiatrist-diagnosed psychiatric illnesses and prescriptions for psychoactive medications in the 5 years before critical illness. For patients with no psychiatric history, quarterly cumulative incidence (risk) and adjusted hazard ratios (HRs) for diagnoses and medications in the following year, using Cox regression. RESULTS: Among 24,179 critically ill patients, 6.2% had 1 or more psychiatric diagnoses in the prior 5 years vs 5.4% for hospitalized patients (adjusted PR, 1.31; 95% CI, 1.22-1.42; P<.001) and 2.4% for the general population (adjusted PR, 2.57; 95% CI, 2.41-2.73; P<.001). Five-year preadmission psychoactive prescription rates were similar to hospitalized patients: 48.7% vs 48.8% (adjusted PR, 0.97; 95% CI, 0.95-0.99; P<.001) but were higher than the general population (33.2%; adjusted PR, 1.40; 95% CI, 1.38-1.42; P<.001). Among the 9912 critical illness survivors with no psychiatric history, the absolute risk of new psychiatric diagnoses was low but higher than hospitalized patients: 0.5% vs 0.2% over the first 3 months (adjusted HR, 3.42; 95% CI, 1.96-5.99; P <.001), and the general population cohort (0.02%; adjusted HR, 21.77; 95% CI, 9.23-51.36; P<.001). Risk of new psychoactive medication prescriptions was also increased in the first 3 months: 12.7% vs 5.0% for the hospital cohort (adjusted HR, 2.45; 95% CI, 2.19-2.74; P<.001) and 0.7% for the general population (adjusted HR, 21.09; 95% CI, 17.92-24.82; P<.001). These differences had largely resolved by 9 to 12 months after discharge. CONCLUSIONS AND RELEVANCE: Prior psychiatric diagnoses are more common in critically ill patients than in hospital and general population cohorts. Among survivors of critical illness, new psychiatric diagnoses and psychoactive medication use is increased in the months after discharge. Our data suggest both a possible role of psychiatric disease in predisposing patients to critical illness and an increased but transient risk of new psychiatric diagnoses and treatment after critical illness.

Hospitalization with acute exacerbation of chronic obstructive pulmonary disease and associated health resource utilization: a population-based Danish cohort study.

OBJECTIVE: Health resource utilization (HRU) and outcomes associated with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) are not well described. Therefore, a population-based cohort study was conducted to characterize patients hospitalized with AECOPD with regard to HRU, mortality, recurrence, and predictors of readmission with AECOPD. METHODS: Using Danish healthcare databases, this study identified COPD patients with at least one AECOPD hospitalization between 2005-2009 in Northern Denmark. Hospitalized AECOPD patients' HRU, in-hospital mortality, 30-day, 60-day, 90-day, and 180-day post-discharge mortality and recurrence risk, and predictors of readmission with AECOPD in the year following study inclusion were characterized. RESULTS: This study observed 6612 AECOPD hospitalizations among 3176 prevalent COPD patients. Among all AECOPD hospitalizations, median length of stay was 6 days (interquartile range [IQR] 3-9 days); 5 days (IQR 3-9) among those without ICU stay and 11 days (IQR 7-20) among the 8.6% admitted to the ICU. Mechanical ventilation was provided to 193 (2.9%) and non-invasive ventilation to 479 (7.2%) admitted patients. In-hospital mortality was 5.6%. Post-discharge mortality was 4.2%, 7.8%, 10.5%, and 17.4% at 30, 60, 90, and 180 days, respectively. Mortality and readmission risk increased with each AECOPD hospitalization experienced in the first year of follow-up. Readmission at least twice in the first year of follow-up was observed among 286 (9.0%) COPD patients and was related to increasing age, male gender, obesity, asthma, osteoporosis, depression, myocardial infarction, diabetes I and II, any malignancy, and hospitalization with AECOPD or COPD in the prior year. LIMITATIONS: The study included only hospitalized AECOPD patients among prevalent COPD patients. Furthermore, information was lacking on clinical variables. CONCLUSION: These findings indicate that AECOPD hospitalizations are associated with substantial mortality and risk of recurrence.

Type 2 diabetes and 1-year mortality in intensive care unit patients.

BACKGROUND: Data on the prognostic impact of diabetes and diabetic complications in intensive care unit (ICU) patients are limited and inconsistent. We, therefore, examined mortality in ICU patients with type 2 diabetes with and without pre-existing heart and kidney diseases compared with nondiabetic patients. DESIGN: We conducted this population-based cohort study in Northern Denmark during 2005-2011. We included all ICU patients aged 40 years or older from the 17 ICUs in the area and identified type 2 diabetes by either a filled prescription for an antidiabetic drug, a previous diagnosis of diabetes, or an elevated glycosylated haemoglobin level. Diabetic patients were disaggregated according to pre-existing diagnoses of heart disease (myocardial infarction or heart failure) and kidney disease. We estimated 1-year mortality by the Kaplan-Meier method and hazard ratios of death (HRs) during follow-up using Cox regression, controlling for confounding factors and stratified by relevant subgroups. RESULTS: Among 45 018 ICU patients, 7219 (16·0%) had type 2 diabetes. Overall, 1-year mortality was 36·0% in ICU patients with type 2 diabetes, rising to 54·6% in patients with pre-existing heart and kidney diseases, compared with 29·1% in nondiabetic patients. Comparing diabetic with nondiabetic patients, the adjusted 0- to 30-day HR was 1·20 (95% confidence interval (CI): 1·13-1·26) and 1·19 (95% CI: 1·10-1·28) during the 31- to 365-day follow-up period. Pre-existing kidney disease further increased the impact of diabetes, while heart disease alone had no such effect. CONCLUSIONS: ICU patients with type 2 diabetes had higher 1-year mortality compared with nondiabetic ICU patients, particularly those with pre-existing kidney disease.

Three-year mortality among alcoholic patients after intensive care: a population-based cohort study.

INTRODUCTION: Alcoholic patients comprise a large proportion of patients in intensive care units (ICUs). However, data are limited on the impact of alcoholism on mortality after intensive care. METHODS: We conducted a cohort study among 16,848 first-time ICU patients between 2001 and 2007 to examine 30-day and 3-year mortality among alcoholic patients. Alcoholic patients with and without complications of alcohol misuse (for example, alcoholic liver disease) were identified from previous hospital contacts for alcoholism-related conditions or redemption of a prescription for alcohol deterrents. Data on medication use, demographics, hospital diagnoses, and comorbidity were obtained from medical databases. We computed 30-day and 3-year mortality and mortality rate ratios (MRRs) by using Cox regression analysis, controlling for covariates. RESULTS: In total, 1,229 (7.3%) ICU patients were current alcoholics. Among alcoholic patients without complications of alcoholism (n=785, 4.7% of the cohort), 30-day mortality was 15.9% compared with 19.7% among nonalcoholic patients. Compared with nonalcoholic patients, the adjusted 30-day MRR was 1.04 (95% confidence interval (CI), 0.87 to 1.25). Three-year mortality was 36.2% compared with 40.9% among nonalcoholic patients, corresponding to an adjusted 3-year MRR of 1.16 (95% CI, 1.03 to 1.31). For alcoholic patients with complications (n=444, 2.6% of the cohort), 30-day mortality was 33.6%, and 3-year mortality was 64.5%, corresponding to adjusted MRRs, with nonalcoholics as the comparator, of 1.64 (95% CI, 1.38 to 1.95) and 1.67 (95% CI, 1.48 to 1.90), respectively. CONCLUSIONS: Alcoholic ICU patients with chronic complications of alcoholism have substantially increased 30-day and 3-year mortality. In contrast, alcoholics without complications have no increased 30-day and only slightly increased 3- year mortality.

Concomitant use of clopidogrel and statins and risk of major adverse cardiovascular events following coronary stent implantation.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • The CYP3A4 inhibition by lipophilic statins may attenuate the effectiveness of clopidogrel. • No studies have measured drug exposure in a time-varying manner that detects discontinuation and restart of clopidogrel and statin therapy, allowing clinical quantification of the interaction effect. WHAT THIS STUDY ADDS: • Clopidogrel and CYP3A4-metabolizing statin use were each associated with a substantially reduced rate of major adverse cardiovascular events within 12 months after coronary stent implantation. • Although we observed an interaction between use of clopidogrel and statins, statin use vs. non-use was not associated with an increased rate of major adverse cardiovascular events in patients using clopidogrel after coronary stent implantation. AIMS: To examine whether CYP3A4-metabolizing statin use modified the association between clopidogrel use and major adverse cardiovascular events (MACE) after coronary stent implantation, using time-varying drug exposure ascertainment. METHODS: We conducted this population-based cohort study in Western Denmark (population: 3 million) using medical databases. We identified all 13 001 patients with coronary stent implantation between 2002 and 2005 and their comorbidities. During 12 months of follow-up, we tracked the use of clopidogrel and CYP3A4-metabolizing statins and the rate of MACE. We used Cox regression to compute hazard ratios (HRs) controlling for potential confounders. RESULTS: The rate of MACE per 1000 person years was 104 for concomitant clopidogrel and statin use, 130 for clopidogrel without statin use, 108 for statin without clopidogrel use and 446 for no use of either drug. The adjusted HR comparing clopidogrel use with non-use was 0.68 (95% confidence interval (CI) 0.58, 0.79) among statin users and 0.34 (95% CI 0.29, 0.40) among statin non-users, yielding an interaction effect (i.e. relative rate increase) of 1.97 (95% CI 1.59, 2.44). The adjusted HR for MACE comparing statin use with non-use was 0.97 (95% CI 0.83, 1.13) among clopidogrel users and 0.49 (95% CI 0.42, 0.57) among clopidogrel non-users. CONCLUSIONS: Clopidogrel and CYP3A4-metabolizing statin use were each associated with a substantially reduced rate of MACE within 12 months after coronary stent implantation. Although we observed an interaction between use of clopidogrel and statins, statin use vs. non-use was not associated with an increased rate of MACE in patients using clopidogrel after coronary stent implantation.

Use of clopidogrel and calcium channel blockers and risk of major adverse cardiovascular events.

BACKGROUND: The CYP3A4 inhibition by calcium channel blockers (CCBs) may attenuate the effectiveness of clopidogrel. Using time-varying drug exposure ascertainment, we examined whether CCB use modified the association between clopidogrel use and major adverse cardiovascular events (MACE) after coronary stent implantation. DESIGN: We conducted this population-based cohort study in western Denmark (population 3 million) using medical databases. We identified all 13,001 patients with coronary stent implantation between 2002 and 2005 and their comorbidities. During 12-month follow-up, we tracked the use of clopidogrel and CCBs and the rate of MACE (composite of myocardial infarction, ischaemic stroke, stent thrombosis, target lesion revascularization, or cardiac death). We used Cox regression to compute hazard ratios, controlling for potential confounders. RESULTS: Overall, the 12-month risk for MACE was 14·5%. The rate was 130 per 1000 person years for concomitant clopidogrel and CCB use, 106 for clopidogrel without CCB use, 213 for CCB without clopidogrel use, and 248 for no use of either drug. The adjusted hazard ratio for MACE comparing clopidogrel use with nonuse was 0·52 [95% confidence interval (CI): 0·42-0·64] for CCB users and 0·48 (95% CI: 0·42-0·54) for nonusers, yielding an interaction effect, i.e. relative rate increase, of 1·09 (95% CI: 0·86-1·38). The adjusted hazard ratio for MACE comparing CCB use with nonuse was 1·06 (95% CI: 0·89-1·25) among clopidogrel users. CONCLUSIONS: Concomitant use of CCBs as a class did not modify the protective effect of clopidogrel and was not associated with increased cardiovascular risk among patients using clopidogrel after coronary stent implantation.

Hospitalization rates and survival associated with COPD: a nationwide Danish cohort study.

We examined rates of first hospitalization for COPD, rates of 5-year mortality among patients hospitalized for COPD, and comparisons of mortality between COPD patients and a matched cohort free of COPD. We computed standardized rates of first COPD hospitalization. Using Cox regression, we compared 180- and 181-day to 5-year mortality among COPD patients with the comparison cohort. We used medical databases in Denmark (population 5.4 million) from 1997 to 2006. We included patients 40 years or older with first hospitalization for COPD (64,499) and an age- and gender-matched comparison cohort of persons without COPD hospitalization (322,495). We examined the incidence of COPD hospitalization and risks and rates of mortality in the 5 years after hospitalization. Standardized rates of first hospitalization for COPD declined from 276 per 100,000 person-years in 1999 to 231 per 100,000 person-years in 2006. Within 180 days of hospitalization, 16% of COPD patients and 2.4% of persons in the matched cohort died (adjusted hazard ratio = 7.00, 95% CI = 6.79-7.22). Between 181 days and 5 years, 46% of COPD patients who survived the first 180 days and 19% of persons in the comparison cohort died (adjusted hazard ratio = 2.91, 95% CI = 2.86-2.95). COPD and comorbid diseases interacted to increase mortality in the first 180 days, but not thereafter. COPD continues to be a major public health problem causing substantial mortality in the 5 years after hospitalization, particularly in the first 180 days and in patients with comorbid diseases.

Change from oral antidiabetic therapy to insulin and risk of urinary tract infections in Type 2 diabetic patients: a population-based prescription study.

BACKGROUND: Diabetes is a risk factor for urinary tract infections (UTI), but the impact of insulin treatment and glycaemic control on UTI risk is not clear. METHODS: We determined the risk of antibiotic-treated UTI episodes in a population-based cohort of 2737 Type 2 diabetic patients who switched from oral antidiabetic drug (OAD) to insulin therapy. Each patient was observed for 365 days before and after the switch date, excluding a 120-day time window around this date. Episodes of UTI were defined as filled prescriptions for a UTI-specific antibiotic. We used conditional logistic regression to estimate the relative risk (odds ratio) of having one or more UTIs in the insulin vs. OAD period overall and stratified by glycaemic change. RESULTS: After the switch to insulin, 53% of all patients experienced a decrease in individual mean hemoglobin A1c (median decrease=1.5%, interquartile range 0.9%-2.3%). Episodes of treated UTIs occurred in 446 (16.3%) Type 2 diabetic patients in the insulin period and 437 (16.0%) in the OAD period (relative risk 1.04, 95% CI 0.86-1.26). Stratified analyses showed no consistent association between levels of glycaemic improvement and decreased UTI risk during insulin treatment. CONCLUSIONS: Among patients with Type 2 diabetes, no evidence was found that switch to insulin therapy with or without tightened glycaemic control decreased their high annual risk of antibiotic-treated UTI episodes.