Intersession reliability of lower limb muscle strength assessments in adults with obesity eligible for bariatric surgery.

BACKGROUND: The aim of this study was to examine the test-retest reliability in lower limb muscle strength and rate of torque development (RTD) using isokinetic dynamometry in adults with obesity, with a body mass index (BMI) ≥ 35 kg/m2. METHOD: Thirty-two adults with a BMI of 43.8 ± 6.6 kg/m2 eligible for bariatric surgery were enroled in the study. Isokinetic and isometric knee extensor (KE) and flexor (KF) strength were assessed in an isokinetic dynamometer (Biodex 4) during three test sessions separated by 3-7 days. RESULTS: There were no statistical differences in peak KE and KF torque for any test modalities between sessions. Intraclass correlation (ICC) was 0.91-0.94 between sessions 1 and 2 and 0.94-0.97 between sessions 2 and 3. Standard error of measurement (SEM%) and coefficient of variation (CV) ranged across test sessions from 4.3% to 7.3%. KE RTD showed high test-retest reliability following familiarization, with ICC, CV and SEM% values ranging from 0.84 to 0.90, 13.3%-20.3% and 14.6%-24.9%, respectively. CONCLUSION: Maximal lower limb muscle strength measured by isokinetic dynamometry showed excellent test-retest reliability manifested by small measurement errors and low CV. Reliability was slightly improved by including a familiarization session. KE RTD but not KF RTD demonstrated high test-retest reliability following familiarization. The present data indicate that isokinetic dynamometry can be used to detect even small changes in lower limb muscle strength in adults with obesity.

Cochlear Implantation in Sporadic Intralabyrinthine Schwannomas with Single-Sided Deafness: Implications for Binaural Hearing.

BACKGROUND AND OBJECTIVE: Intralabyrinthine schwannomas (ILSs) may have detrimental effects on ipsilateral hearing, commonly leading to single-sided deafness (SSD). Cochlear implantation in patients with ILSs is an option to partly restore ipsilateral hearing; however, the available literature fails to account for the binaural hearing benefits of a cochlear implant (CI) for ILSs. METHODS: We prospectively evaluated SSD patients with sporadic ILS undergoing cochlear implantation with simultaneous tumor resection (n = 10) or with tumor observation (n = 1). Patients completed the Speech, Spatial and Qualities Questionnaire (SSQ12) and the Nijmegen Cochlear Implant Questionnaire (NCIQ) pre- and postoperatively, as well as the Bern Benefit in Single-Sided Deafness (BBSSD) questionnaire postoperatively. Patients were also tested postoperatively with and without their CI to measure the effect on localization ability and binaural summation, squelch, and head shadow. RESULTS: Evaluation was completed for nine and six patients (subjective and objective data, respectively). The CI significantly improved the speech reception threshold (SRT) in the head shadow condition where the target signal was presented to the CI side and the noise to the front (SCIN0). On the other hand, the SRTs in the colocated condition (S0N0) and the condition where the target signal was presented to the front and the noise to the CI side (S0NCI) were unaffected by the CI. The mean localization error decreased significantly from 102° to 61° (p = 0.0031) with the addition of a CI. The scores from SSQ12 demonstrated nonsignificant changes. For NCIQ, the self-esteem and the social interaction domains increased significantly but insignificantly for the remaining domains. The BBSSD responses ranged from +0.5 to +3.5 points. CONCLUSION: After implantation, patients achieved significantly better scores across some of the patient-reported and objective parameters. In addition to reporting on a number of ILS cases where implantation was performed, the study is the first of its kind to document patient-reported and objective binaural hearing improvement after cochlear implantation in patients with ILS and, thereby, lends support to the active management of ILS.

Microcirculatory Function in Nonhypertrophic and Hypertrophic Myocardium in Patients With Aortic Valve Stenosis.

Background Left ventricular hypertrophy (LVH) has often been supposed to be associated with abnormal myocardial blood flow and resistance. The aim of this study was to evaluate and quantify the physiological and pathological changes in myocardial blood flow and microcirculatory resistance in patients with and without LVH attributable to severe aortic stenosis. Methods and Results Absolute coronary blood flow and microvascular resistance were measured using a novel technique with continuous thermodilution and infusion of saline. In addition, myocardial mass was assessed with cardiac magnetic resonance imaging. Fifty-three patients with aortic valve stenosis were enrolled in the study. In 32 patients with LVH, hyperemic blood flow per gram of tissue was significantly decreased compared with 21 patients without LVH (1.26±0.48 versus 1.66±0.65 mL·min-1·g-1; P=0.018), whereas minimal resistance indexed for left ventricular mass was significantly increased in patients with LVH (63 [47-82] versus 43 [35-63] Wood Units·kg; P=0.014). Conclusions Patients with LVH attributable to severe aortic stenosis had lower hyperemic blood flow per gram of myocardium and higher minimal myocardial resistance compared with patients without LVH.

The Collagen Receptor uPARAP in Malignant Mesothelioma: A Potential Diagnostic Marker and Therapeutic Target.

Malignant mesothelioma (MM) is a highly aggressive cancer with limited therapeutic options. We have previously shown that the endocytic collagen receptor, uPARAP, is upregulated in certain cancers and can be therapeutically targeted. Public RNA expression data display uPARAP overexpression in MM. Thus, to evaluate its potential use in diagnostics and therapy, we quantified uPARAP expression by immunohistochemical H-score in formalin-fixed paraffin-embedded bioptic/surgical human tissue samples and tissue microarrays. We detected pronounced upregulation of uPARAP in the three main MM subtypes compared to non-malignant reactive mesothelial proliferations, with higher expression in sarcomatoid and biphasic than in epithelioid MM. The upregulation appeared to be independent of patients' asbestos exposure and unaffected after chemotherapy. Using immunoblotting, we demonstrated high expression of uPARAP in MM cell lines and no expression in a non-malignant mesothelial cell line. Moreover, we showed the specific internalization of an anti-uPARAP monoclonal antibody by the MM cell lines using flow cytometry-based assays and confocal microscopy. Finally, we demonstrated the sensitivity of these cells towards sub-nanomolar concentrations of an antibody-drug conjugate formed with the uPARAP-directed antibody and a potent cytotoxin that led to efficient, uPARAP-specific eradication of the MM cells. Further studies on patient cohorts and functional preclinical models will fully reveal whether uPARAP could be exploited in diagnostics and therapeutic targeting of MM.

Initiation of and persistence with P2Y12 inhibitors in patients with myocardial infarction according to revascularization strategy: a nationwide study.

BACKGROUND: We aimed to analyse initiation of and persistence with P2Y12 inhibitors after first-time myocardial infarction (MI). METHODS AND RESULTS: Using Danish nationwide registries, we identified patients ≥30 years with first-time MI during 1 January 2005-30 June 2016 and subsequent prescriptions of P2Y12 inhibitors. Independent factors related to initiation of and persistence with P2Y12 inhibitors were analysed by multivariable logistic regression and a Cox proportional hazards model. Patients were stratified by revascularization strategy: percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), or medical therapy alone (MTA). Overall, 79 597 MI patients were included with 39 172 undergoing PCI, 2619 CABG, and 16 640 MTA, showing initiation of P2Y12 inhibitors of 93.4%, 49.0%, and 51.5%, respectively. Congestive heart failure, cerebrovascular disease, cardiac dysrhythmias, renal failure, previous bleeding, and oral anticoagulants were associated with less initiation of P2Y12 inhibitors. Female sex was associated with less initiation of P2Y12 inhibitors following MTA. MTA, coronary angiography, cerebrovascular disease, diabetes with complications, previous bleeding, antidiabetics, and ticagrelor as P2Y12 inhibitor were associated with non-persistence, whereas female sex, advanced age, and concomitant pharmacotherapy with angiotensin-converting enzyme inhibitors, beta-blockers, statins, oral anticoagulants, and aspirin were associated with high persistence. CONCLUSION: Initiation of P2Y12 inhibitors in PCI-treated MI patients was high in contrast to those treated with CABG or MTA and patients with certain comorbidities. Further studies on the benefit-risk ratio of P2Y12 inhibitors in CABG-treated or MTA-treated patients and patients with comorbidities after first-time MI are warranted, as is focus on persistence among patients receiving MTA, patients with comorbidities, and users of ticagrelor.

Depressive symptoms among patients with COPD according to smoking status: a Danish nationwide case-control study of 21 184 patients.

INTRODUCTION: Depressive symptoms appear more often among patients with COPD and are associated with reduced disease control and increased mortality. Both smoking and COPD increase the risk of depressive symptoms. Whether smoking cessation among COPD patients affects the occurrence of depressive symptoms is unknown. We hypothesised that smoking cessation in patients with COPD leads to reduced use of antidepressants and fewer admissions to psychiatric hospitals with depression, anxiety or bipolar disorder. METHODS: We conducted a nationwide retrospective case-control study, in patients from The Danish Register for COPD with spirometry-verified COPD, age ≥40 years, a history of smoking and absence of cancer. Consistent smokers were matched 1:1 with ex-smokers using a propensity score model. Prescription fillings of antidepressants and risk of admissions to psychiatric hospitals with either depression, anxiety or bipolar disorder both descriptively was assessed by Cox proportional hazard models. RESULTS: We included 21 184 patients. A total of 2011 consistent smokers collected antidepressant prescriptions compared with 1821 ex-smokers. Consistent smoking was associated with increased risk of filling prescription on antidepressants (HR 1.4, 95% CI 1.3-1.5, p<0.0001) and with increased risk of psychiatric hospital admission with either depression, anxiety or bipolar disorder (HR 2.0, 95% CI 1.6-2.5). The associations persisted after adjustment for former use of antidepressants. CONCLUSION: Consistent smoking among COPD patients was associated with increased use of antidepressants and admissions to psychiatric hospitals with either depression, anxiety or bipolar disorder, compared to smoking cessation.

Antithrombotic treatment and major adverse cardiac events after bleeding in patients with myocardial infarction: a retrospective analysis of nationwide registry data.

AIMS: The aim of this study was to describe the use of antithrombotic therapy following a bleeding event among patients with myocardial infarction (MI), and the associated risk of major adverse cardiac events (MACE). METHODS AND RESULTS: Using Danish nationwide registries, patients hospitalized with a bleeding event within 1 year after MI were identified. Antithrombotic treatment with aspirin, clopidogrel, and/or vitamin K antagonists (VKA) was determined at the bleeding and at Day 90 and 180 post-bleed. Based on guidelines, patients were stratified into four groups: expected, reduced, discontinued, or intensified treatment. Risk of MACE (ischaemic stroke, MI, or death) within the first year was assessed by Cox proportional hazard models. A total of 3324 patients with a bleeding after MI were included. At Day 90 post-bleed, 1052 (31.7%) received expected antithrombotic treatment, 1301 (39.2%) reduced, 164 (4.9%) intensified, and 807 (24.3%) no treatment. Major adverse cardiac events occurred in 637 (19.2%) patients. With dual antiplatelet therapy as reference, adjusted hazard ratios for MACE were: aspirin 1.81 (1.06-3.09), clopidogrel 1.08 (0.64-1.82), VKA 1.08 (0.47-2.48), VKA + aspirin 1.97 (0.95-4.07), VKA + clopidogrel 0.26 (0.03-1.91), triple 1.73 (0.50-5.95), and no treatment 1.93 (1.11-3.36). CONCLUSION: The majority of MI patients reduced or discontinued their antithrombotic therapy post-bleed. Patients in monotherapy with aspirin or no treatment post-bleed had a higher risk of MACE Further studies of optimal antithrombotic treatments after a bleed are needed.

Short- and long-term cause of death in patients undergoing isolated coronary artery bypass grafting: A nationwide cohort study.

OBJECTIVES: Knowledge of the association between time and causes of death after coronary artery bypass grafting is sparse. We examined short- and long-term mortality and cause of death in patients undergoing coronary artery bypass grafting. METHODS: With the use of Danish nationwide registries, we identified all patients undergoing isolated coronary artery bypass grafting from 1998 to 2014. Cause of death was classified as cardiovascular or noncardiovascular according to death certificates. Landmark analyses of the cumulative incidences of cardiovascular and noncardiovascular mortality after 1, 3, and 5 years after coronary artery bypass grafting were performed. Multivariable cause-specific Cox regression models were used to evaluate changes over time in the risk of all-cause, cardiovascular, and noncardiovascular mortality after 1 and 7 years after coronary artery bypass grafting, respectively. RESULTS: Among 37,495 included patients, 12,230 (32.6%) died during a median follow-up of 7.4 years. Causes of death were classified as cardiovascular in 6459 patients (52.8%) and noncardiovascular in 5771 patients (47.2%). Within the first year, the incidence of cardiovascular death was higher compared with noncardiovascular death (3.9% vs 1.1%, P < .001). The cumulative incidences of cardiovascular and noncardiovascular were deaths similar in the periods 1 to 3 years (2.3% vs 2.6%, P = .004), 3 to 5 years (3.1% vs 3.2%, P = .75), and 5 to 7 years postsurgery (3.7% vs 4.0%, P = .07). The crude rates and adjusted risks of short- and long-term all-cause and cardiovascular mortality decreased during the study period despite an increase in age and burden of comorbidities. CONCLUSIONS: In patients undergoing coronary artery bypass grafting, cardiovascular causes were responsible for the majority of deaths within the first year. Deaths due to noncardiovascular causes gained importance over time elapsed since coronary artery bypass grafting.

Relation of Bleeding Events to Mortality in Patients With ST-Segment Elevation Myocardial Infarction Treated by Percutaneous Coronary Intervention (a DANAMI-3 Substudy).

Bleeding events in relation to treatment of ST-segment elevation myocardial infarction (STEMI) have previously been associated with mortality. In this study, we investigated the incidence and prognosis of, and variables associated with serious bleedings within 30 days after primary percutaneous coronary intervention in patients from The Third Danish Study of Optimal Acute Treatment of Patients with ST-Segment Elevation Myocardial Infarction (DANAMI-3) (n = 2,217). Hospital charts were read within 30 days postadmission to assess bleeding events using thrombolysis in myocardial infarction (TIMI) and Bleeding Academic Research Consortium criteria. TIMI minor/major bleeding (TMMB) occurred in 59 patients (2.7%). Variables associated with TMMB were female gender (hazard ratio [HR] 3.9, 95% confidence interval [CI] 2.2 to 6.7, p <0.0001), symptom-to-catheterization time >3 hours (HR 1.9, 95% CI 1.1 to 3.3, p = 0.02), use of glycoprotein IIb/IIIa inhibitor (HR 2.1, 95% CI 1.2 to 3.7, p = 0.01), and increasing S-creatinine (HR 1.1, 95% CI 1.0 to 1.2, p = 0.001). Undergoing 2 in-hospital procedures were not associated with increased risk of TMMB. TMMB was strongly associated with 30-day mortality in multivariable analysis (HR 4.8, 95% CI 2.2 to 10.4, p <0.0001) but not with mortality days 31 to 365. When excluding fatal bleedings from the analysis, a TMMB was no longer associated with 30-day mortality. In conclusion, we found that in a contemporary STEMI-population, the incidence of 30-day TMMB was low. A TMMB was strongly associated with 30-day mortality but not with mortality days 31 to 365. If patients survived a serious bleeding, their short- and long-term prognoses were not affected.

Second generation drug-eluting stents versus bare-metal stents for percutaneous coronary intervention of the proximal left anterior descending artery: An analysis of the BASKET-PROVE I and II trials.

OBJECTIVES: To compare mid-term outcomes between patients undergoing proximal left anterior descending artery (LAD) percutaneous coronary intervention (PCI) with second generation drug-eluting stent (DES) or bare-metal stent (BMS). BACKGROUND: PCI with BMS and first-generation DES have shown to be safe options for the treatment of proximal LAD stenosis, however associated with considerable reintervention rates. Overall, second-generation DES has proven to be superior to BMS and first-generation DES, nevertheless, its effect for proximal LAD PCI has not previously been reported. METHODS: We analyzed 2-year outcomes of 1,100 patients from the BASKET-PROVE I and II trials, referred for proximal LAD PCI with second generation DES (n = 680) or BMS (n = 420). RESULTS: The cumulative 2-year incidence of major adverse cardiac events (MACE, composite of cardiac death, myocardial infarction (MI) and target vessel revascularization (TVR)) was lower in second generation DES than in BMS treated patients (7.3% vs. 12.3%; HR 0.57, 95% CI 0.39/0.85), mainly driven by a reduced rate of TVR (3.7% vs. 10.0%; HR 0.35, CI 0.21/0.58). No difference was found in cardiac death (1.9% vs. 1.9%; HR 1.01, CI 0.42/2.44) and MI (4.4% vs. 4.7%; HR 0.93, CI 0.53/1.64). The benefit of DES use seemed to be more prominent in female patients with a reduction in MACE (P for interaction = 0.025). CONCLUSIONS: In patients with proximal LAD stenosis, treatment with second-generation DES was associated with reduced 2-year rates of adverse cardiac events and TVR compared to BMS, with reintervention rates similar to those earlier reported from bypass surgery.

Frequency of Cardiac Death and Stent Thrombosis in Patients With Chronic Obstructive Pulmonary Disease Undergoing Percutaneous Coronary Intervention (from the BASKET-PROVE I and II Trials).

Chronic obstructive pulmonary disease (COPD) is associated with long-term all-cause death after percutaneous coronary intervention with bare-metal stents. Regarding other outcomes, previous studies have shown conflicting results and the impact of drug-eluting stent (DES) in this population is not well known. We analyzed 4,605 patients who underwent percutaneous coronary intervention with bare-metal stents (33.1%) or DES (66.9%) from the Basel Stent Kosten-Effektivitats Trial-Prospective Validation Examination trials I and II. COPD patients (n = 283, 6.1%), were older and had more frequently a smoking or cardiovascular event history. At 2-year follow-up, cumulative event rates for patients with versus without COPD were the following: major adverse cardiac events (MACE: composite of cardiac death, nonfatal myocardial infarction, and target vessel revascularization): 15.2% versus 8.1% (p <0.001); all-cause death: 11.7% versus 2.4% (p <0.001); cardiac death: 5.7% versus 1.2% (p <0.001); myocardial infarction: 3.5% versus 1.9% (p = 0.045); definite/probable/possible stent thrombosis: 2.5% versus 0.9% (p = 0.01); and major bleeding: 4.2% versus 2.1% (p = 0.014). After adjusting for confounders including smoking status, COPD remained an independent predictor for MACE (hazard ratio [HR] 1.80, 95% confidence interval [CI] 1.31 to 2.49), all-cause death (HR 3.62, 95% CI 2.41 to 5.45), cardiac death (HR 3.12, 95% CI 1.74 to 5.60), and stent thrombosis (HR 2.39, 95% CI 1.03 to 5.54). We did not find evidence of an interaction between COPD and DES implantation (p for interaction = 0.29) for MACE. In conclusion, COPD is associated with increased 2-year rates of all-cause death, cardiac death, and stent thrombosis after stent implantation. DES use appears to be beneficial also in patients with COPD.

Use of diagnostic coronary angiography in women and men presenting with acute myocardial infarction: a matched cohort study.

BACKGROUND: Based on evident sex-related differences in the invasive management of patients presenting with acute myocardial infarction (AMI), we sought to identify predictors of diagnostic coronary angiography (DCA) and to investigate reasons for opting out an invasive strategy in women and men. METHODS: The study was designed as a matched cohort study. We randomly selected 250 female cases from a source population of 4000 patients hospitalized with a first AMI in a geographically confined region of Denmark from January 2010 to November 2011. Each case was matched to a male control on age and availability of cardiac invasive facilities at the index hospital. We systematically reviewed medical records for risk factors, comorbid conditions, clinical presentation, and receipt of DCA. Clinical justifications, as stated by the treating physician, were noted for the subset of patients who did not receive a DCA. RESULTS: Overall, 187 women and 198 men received DCA within 60 days (75 % vs. 79 %, hazard ratio: 0.82 [0.67-1.00], p = 0.047).In the subset of patients who did not receive a DCA (n = 114), clinical justifications for opting out an invasive strategy was not documented for 21 patients (18.4 %). Type 2 myocardial infarction was noted in 11 patients (women versus men; 14.5 % vs. 3.8 %, p = 0.06) and identified as a potential confounder of the sex-DCA relationship. Receipt of DCA was predicted by traditional risk factors for ischaemic heart disease (family history of cardiovascular disease, hypercholesterolemia, and smoking) and clinical presentation (chest pain, ST-segment elevations). Although prevalent in both women and men, the presence of relative contraindications did not prohibit the use of DCA. CONCLUSION: In this matched cohort of patients with a first AMI, women and men had different clinical presentations despite similar age. However, no differences in the distribution of relative contraindications for DCA were found between the sexes. Type 2 MI posed a potentiel confounder for the sex-related differences in the use of DCA. Importantly,clinical justification for opting out an invasive strategy was not documented in almost one fifth of patients not receiving a DCA.

Clinical epidemiological studies of women undergoing surgery for urogynaecological disorders.

UNLABELLED: This PhD thesis was performed during my employment at the Center for Clinical Epidemiology, Odense University Hospital and University of Southern Denmark, 2010-2013. It comprises an overview and four papers, two published in international peer-reviewed scientific journals, one under review, and one in draft. INTRODUCTION: Urinary incontinence (UI) and pelvic organ prolapse (POP) are prevalent disorders among women worldwide, affecting their psychological and social wellbeing, with reductions in quality of life. Treatment options are conservative (e.g. pelvic floor exercises, weight loss, and bladder training), pharmacological, and surgical. Surgery has especially for UI undergone an improvement during the last decades with development of minimally-invasive sub-urethral sling procedures, and the number of surgeries has increased in Denmark and other countries. AIMS: In a population of Danish women undergoing surgery for UI or POP, we aimed: to describe the establishment of the Danish Urogynaecological Database (DugaBase), and to evaluate the completeness and the validity of surgery registration in the DugaBase; to study patient reported outcome measures in Danish women undergoing urogynaecological surgery; to study the use of symptom-relieving drugs before and after surgery for UI; to study the use of antibiotics for urinary tract infection (UTI) before and after surgery for UI METHODS: Study I The completeness of DugaBase was assessed by comparing procedure codes in the DugaBase to iodes registered in the National Patient Registry, 2006-2010. The study also included review of medical journals from 200 women (computed randomly from DugaBase), representing 22 departments in Denmark. Information on selected variables was compared to registered data in the DugaBase. DATA SOURCES: the National Patient Registry, the DugaBase, and medical records. Study II was based on a national cohort of women undergoing surgery for UI and POP registered in the DugaBase, 2006-2011. Clinical data and data from patient questionnaires were retrieved. DATA SOURCES: the DugaBase. Study III+IV were cohort studies based on national register data and prescription data. A total of 2,151 women with a first time surgical procedure for UI within 1996-2010 were included. The data were supplemented with registry information on redeemed prescriptions on symptom-relieving drugs/antibiotics for UTI/oestrogen, comorbidity, and educational level and income. DATA SOURCES: the Danish National Patient Registry, Odense University Pharmacoepidemiologic Database, and the Register for Education Statistics, and the Register of Family Income. RESULTS: Study I: A total of 16,509 procedures were registered in the DugaBase by 31 December 2010. The database completeness has increased from 38.2% to 93.2% during the years. According to the validation, all 200 medical records were retrieved. The overall percentage agreement between medical records and the DugaBase was at least 90% for selected key variables: procedure code, date, hospital department, use of antibiotics, prior surgery, height, weight, parity, and smoking. Study II: In the study period, 20,629 urogynaecological procedures were performed in Denmark and reported to the DugaBase. For approximately one third of these women, the patient questionnaires on severity of symptoms and quality of life were completed both pre- and postoperatively, and thus included. After both UI and POP surgery, more than 80% had improved symptoms and showed a significant improvement in quality of life. Study III: A total of 2,151 women with a primary UI procedure were included. Of these, 358 (16.6%) were exposed to symptom-relieving drugs preoperatively, and 1,793 (83.4%) were not. Preoperative usage of symptom-relieving drugs was the strongest risk factor of postoperative use, both within 0-60 days OR (adjusted) = 33.0 (95% confidence interval (CI) 20.0-54.7)) and 61-365 days OR (adjusted) = 7.2 (95% CI 5.4-9.6)). Adjusted for age, procedure type, calendar year, comorbidity, preoperative use of oestrogen, educational level, and personal annual income. Only a minority of preoperative non-users started using symptom-relieving drugs postoperatively. Study IV: The same study population as in study III. Of the 2,151 women, 496 (23.1%) were antibiotic users prior to surgery, and 1,655 (76.9%) were non-users. Preoperative usages of antibiotics for UTI was a strong risk factor of postoperative use of the same antibiotics, both within 0-60 days OR (adjusted) = 2.6 (95% CI 2.9-3.5), and within 61-356 days OR (adjusted) = 4.5 (95% CI 3.5-5.7)). Adjusted for age, procedure type, calendar year, comorbidity, preoperative use of oestrogen, educational level, and personal annual income. Comorbidity and procedure types were found to be significant risk factors as well, although less important than preoperative antibiotic use. CONCLUSIONS: Due to a high completeness and data of high validity the DugaBase offers a unique possibility for continuing quality assessment of urogynaecological surgery in Denmark, as well as for future research. Surgeries for UI and POP performed in Danish women were effective in alleviating symptoms of UI and POP and improvement in quality of life based on patient reported outcome measures. Our pharmacoepidemiological studies showed that preoperative use of symptom-relieving drugs and antibiotics for UTI were strong risk factors of postoperative usage of the same drugs.

Dysphagia screening and intensified oral hygiene reduce pneumonia after stroke.

OBJECTIVES: Dysphagia occurs in approximately 51%-78% of patients with acute stroke. The incidence of pneumonia caused by aspiration in dysphagic patients increases both mortality and the need for hospitalization. The aim of this study was to investigate whether the incidence of aspiration pneumonia could be reduced in such patients by an early screening for dysphagia and intensified oral hygiene. MATERIAL AND METHODS: In this controlled trial, 146 hospitalized acute stroke patients with moderate or severe dysphagia were included in three groups: an intervention group (n = 58), one internal control group (n = 58, retrospectively selected from same clinic), and one external control group (n = 30) from a comparable stroke unit in a neighboring hospital. The intervention consisted of early screening with a clinical method of dysphagia screening, the Gugging Swallowing Screen, and intensified oral hygiene. RESULTS: The incidence of x-ray verified pneumonia was 4 of 58 (7%) in the intervention group compared with 16 of 58 (28%) in the internal control group (p < .01) and with 8 of 30 (27%) in the external control group (p < .05). CONCLUSIONS: Early and systematic dysphagia screening by the Gugging Swallowing Screen method and intensified oral hygiene reduced the incidence of x-ray verified pneumonia.

Risk of cancer in patients using glucose-lowering agents: a nationwide cohort study of 3.6 million people.

OBJECTIVES: To study the association between exposures to glucose-lowering therapy and risk of cancer using the nationwide administrative registers in Denmark. DESIGN: Nationwide cohort study. SETTING: All hospitals in Denmark. PARTICIPANTS: All individuals aged ≥35 years in 1998-2009 who were naive to glucose-lowering treatment and had no history of cancer. Primary measures outcomes: first cancer diagnosis between 1998 and 2009. The RR of cancer as dependent on exposure to individual glucose-lowering agents was assessed by multivariable Poisson regression models. RESULTS: Of 159 894 patients that initiated treatment with glucose-lowering agents, 12 789 developed cancer, incidence rate 17.4/1000 person-years. Of the remaining 3 447 904 individuals not using glucose-lowering agents, 293 878 developed cancer, incidence rate 7.9/1000 person-years. Use of different types of glucose-lowering agents including human insulin, insulin analogues, as well as sulfonylureas were associated with a quantitatively similar and significantly increased RR of cancer of 1.2-1.3 compared with unexposed individuals after multivariable adjustment. For the majority of agents, the authors identified the highest RR of cancer during the first 30 treatment days with a subsequent decline of risk approaching the cancer risk of the background population only 6-12 months after initiation of treatments. CONCLUSIONS: Use of most glucose-lowering agents including sulfonylureas was associated with a comparable increased risk of cancer shortly after initiation of treatment and subsequently a decline to the risk of the background population. This suggests that the relation is not causal.

Significance of the invasive strategy after acute myocardial infarction on prognosis and secondary preventive medication: a nationwide study of 6364 women and 11,915 men.

OBJECTIVE: To describe gender-specific long-term outcome and initiation of secondary preventive medication among patients with acute myocardial infarction (AMI). DESIGN: Observational cohort study. SETTING: Nationwide registries. PATIENTS: We included 18,279 patients: 6364 women (35%) and 11,915 men (65%), admitted with AMI (median age, 67 years; range, 30-90 years) surviving for at least 2 months. INTERVENTIONS: According to sex, patients were stratified by invasive treatment strategy: (1) revascularized; (2) examined with coronary angiography (CAG) but not revascularized; and (3) not examined with CAG. MAIN OUTCOME MEASURES: All-cause mortality and readmission with AMI. Initiation of secondary preventive medication. RESULTS: Of 18,279 patients with a first AMI who survived 2 months, 1857 women (29%) and 1756 men (15%) were not examined with CAG (P<.001), 1295 women (20%) and 1563 men (13%) were examined but not revascularized (P<.001), and 3212 women (51%) and 8596 men (72%) were revascularized (P<.001). Not being examined with CAG after AMI was associated with a three-fold increase in risk of death and, importantly, a 50% increase in the risk of a recurrent AMI compared with patients who were revascularized. Among patients who were revascularized, 85-92% initiated recommended secondary preventive medication compared to 46-71% in patients not examined with CAG (P<.001). Initiation of secondary preventive medication was higher in men (81-84%) than in women (73-79%; P<.001), which could be ascribed to the differences in invasive strategy. CONCLUSIONS: In both sexes, those who were not examined had a highly increased risk of both recurrent AMI and death. Moreover, initiation of secondary preventive medication was closely related to the choice of invasive strategy disfavoring the women.

Spontaneous cytotoxic T-Cell reactivity against indoleamine 2,3-dioxygenase-2.

Several lines of data have suggested a possible link between the indoleamine 2,3-dioxygenase (IDO)-like protein IDO2 and cancer. First, IDO2 expression has been described in human tumors, including renal, gastric, colon, and pancreatic tumors. Second, the apparent selective inhibition of IDO2 by the D stereoisomer of the IDO blocker 1-methyl-tryptophan (1MT), which tends to be more active than the L-isomer in a variety of biological assays for IDO function, suggests that IDO2 may be important to sustain immune escape and growth of tumors. Especially, D-1MT heightens chemotherapeutic efficacy in mouse models of cancer in a nontoxic fashion. Here, we describe the immunogenicity of IDO2 by showing the presence of spontaneous cytotoxic T-cell reactivity against IDO2 in peripheral blood of both healthy donors and cancer patients. Furthermore, we show that these IDO2-specific T cells are cytotoxic effector cells that recognize and kill tumor cells. Our data suggest that IDO2 might be a useful target for anticancer immunotherapeutic strategies.

Efficacy of post-operative clopidogrel treatment in patients revascularized with coronary artery bypass grafting after myocardial infarction.

OBJECTIVES: The objective of this study was to examine the clinical efficacy of clopidogrel treatment on death and recurrent myocardial infarction (MI) among MI patients revascularized by coronary artery bypass graft surgery (CABG). BACKGROUND: The benefit from post-operative clopidogrel in CABG-treated MI patients is largely unknown. METHODS: All patients admitted with first-time MI between 2002 and 2006, treated with CABG within 180 days after admission, were identified by nationwide administrative registers. Clopidogrel treatment was determined by claimed prescriptions after discharge from surgery. Risk of death or recurrent MI, and of a combined end point of the 2, were assessed by cumulative incidence and Cox proportional hazards model. A propensity score-matched subgroup analysis was done. RESULTS: We included 3,545 patients, and of these, 957 (27.0%) were treated with clopidogrel after CABG. Mean follow-up was 466 ± 144 days. Among patients treated with clopidogrel, 39 (4.1%) died or experienced a recurrent MI, whereas that occurred in 203 (7.8%) patients without clopidogrel (log-rank p = 0.0003). Hazard ratio was 0.59 (95% confidence interval [CI]: 0.42 to 0.85) for patients treated with clopidogrel, with no-clopidogrel as reference. By propensity score, of 945 patients with or without clopidogrel treatment who were matched, death or recurrent MI occurred in 38 (4.0%) patients with clopidogrel and 57 (6.0%) without clopidogrel (log-rank p = 0.05). Corresponding hazard ratio was 0.67 (95% CI: 0.44 to 1.00) for clopidogrel users, with no-clopidogrel as reference. CONCLUSIONS: Among MI patients revascularized by CABG, only 27% received clopidogrel after discharge. Clopidogrel-treated patients had a lower risk of the combined end point of death or recurrent MI. Focus on discharge clopidogrel treatment of these patients should be made.

Identification of a cyclin B1-derived CTL epitope eliciting spontaneous responses in both cancer patients and healthy donors.

With the aim to identify cyclin B1-derived peptides with high affinity for HLA-A2, we used three in silico prediction algorithms to screen the protein sequence for possible HLA-A2 binders. One peptide scored highest in all three algorithms, and the high HLA-A2-binding affinity of this peptide was verified in an HLA stabilization assay. By stimulation with peptide-loaded dendritic cells a CTL clone was established, which was able to kill two breast cancer cell lines in an HLA-A2-dependent and peptide-specific manner, demonstrating presentation of the peptide on the surface of cancer cells. Furthermore, blood from cancer patients and healthy donors was screened for spontaneous T-cell reactivity against the peptide in IFN-γ ELISPOT assays. Patients with breast cancer, malignant melanoma, or renal cell carcinoma hosted powerful and high-frequency T-cell responses against the peptide. In addition, when blood from healthy donors was tested, similar responses were observed. Ultimately, serum from cancer patients and healthy donors was analyzed for anti-cyclin B1 antibodies. Humoral responses against cyclin B1 were frequently detected in both cancer patients and healthy donors. In conclusion, a high-affinity cyclin B1-derived HLA-A2-restricted CTL epitope was identified, which was presented on the cell surface of cancer cells, and elicited spontaneous T-cell responses in cancer patients and healthy donors.

Indoleamine 2,3-dioxygenase specific, cytotoxic T cells as immune regulators.

Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme that is implicated in suppressing T-cell immunity in normal and pathologic settings. Here, we describe that spontaneous cytotoxic T-cell reactivity against IDO exists not only in patients with cancer but also in healthy persons. We show that the presence of such IDO-specific CD8(+) T cells boosted T-cell immunity against viral or tumor-associated antigens by eliminating IDO(+) suppressive cells. This had profound effects on the balance between interleukin-17 (IL-17)-producing CD4(+) T cells and regulatory T cells. Furthermore, this caused an increase in the production of the proinflammatory cytokines IL-6 and tumor necrosis factor-α while decreasing the IL-10 production. Finally, the addition of IDO-inducing agents (ie, the TLR9 ligand cytosine-phosphate-guanosine, soluble cytotoxic T lymphocyte-associated antigen 4, or interferon γ) induced IDO-specific T cells among peripheral blood mononuclear cells from patients with cancer as well as healthy donors. In the clinical setting, IDO may serve as an important and widely applicable target for immunotherapeutic strategies in which IDO plays a significant regulatory role. We describe for the first time effector T cells with a general regulatory function that may play a vital role for the mounting or maintaining of an effective adaptive immune response. We suggest terming such effector T cells "supporter T cells."