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Influenced by the growing share of Renewable Energies, higher flexibility and increased efficiency of fossil power plants as well as improved cost efficiency in production of turbine components are evident market trends. Daily cycling in turbine operations leads to advanced requirements for robust design especially of rotating parts. Low pressure (LP) steam turbine end-stage blades with larger exhaust areas are one lever to increase the efficiency of the turbine by reduction of exhaust losses and also to realize cost-efficient single flow exhaust applications. Consequently, blade steels with improved mechanical properties are required. The results of the development of a new high-strength precipitation-hardening steel for LP end-stage blade application with significantly enhanced material properties are reported. The paper covers the testing strategy applied and information on crucial material parameters like improved low cycle and high cycle fatigue behavior while keeping good stress corrosion cracking resistance and corrosion fatigue properties. Furthermore, first manufacturing experiences and validation results from a full-scale component test rig are presented.

Background Pemetrexed in combination with cisplatin (Pem/Cis) is the only approved chemotherapeutic regimen for malignant pleural mesothelioma (MPM). At the time of launch, limited safety information was available. The purpose of this postmarketing all-case registry study was to investigate the safety and effectiveness of pemetrexed in patients with MPM. Methods From January 2007 to May 2008, MPM patients to be treated with pemetrexed in Japan were registered to this study to monitor its safety and effectiveness. Supply of pemetrexed was restricted to institutions with experienced medical oncologists based on predetermined criteria. Results Of 953 patients registered, data from 903 patients were eligible for analysis. Most patients were male, with median age of 65 years and 68.5% had a history of asbestos exposure. More than 90% of patients received the first cycle of Pem/Cis treatment; median number of treatment cycles was 4.0. Treatment-associated death was reported in 0.8% of patients. The incidence of Interstitial lung disease (ILD) associated with Pem/Cis during the observation period was 0.9%. The frequency of ILD in patients with pre-existing asbestosis was higher than that in patients without it. For tumor response, the overall response rate was 25.0% (95% confidence interval (CI): 22.2–28.0%). The six-month survival rate estimated by the Kaplan–Meier method was 75.9%. Conclusions This large scale all case registry study appeared to have enrolled a major portion of Japanese MPM patients. Treatment with pemetrexed was generally well tolerated and showed safety and effectiveness comparable to prior clinical trials.

Routine surveillance of spontaneous reporting data and subsequent disproportionality analyses have indicated that the use of vancomycin might be associated with an increased risk of hepatic events.To conduct a meta-analysis of published randomized controlled clinical trials (RCTs) to better understand if the use of vancomycin is potentially associated with an increased risk of hepatic events.A comprehensive search and review of published clinical studies indexed in MEDLINE, PubMed, International Pharmaceutical Abstracts and the Cochrane Library from 1950 to June 2010 was conducted.The inclusion criteria consisted of (i) published RCTs comparing vancomycin with/without other additional treatments to other comparators; and (ii) studies that reported hepatic events.The data related to any hepatic events reported in RCTs were extracted and examined. The quality of selected studies was assessed based on the Jadad scale. The effect size was presented as a risk ratio (RR) with a 95% CI and number needed to harm. The pooled RRs were calculated by using both fixed-effects and random-effects models. The impact of publication bias was assessed by funnel plot and the Egger's test.A total of 20 RCTs, including 7419 patients, met the study inclusion criteria and were selected. An increased incidence of hepatic events, specifically elevated serum aminotransferase levels, was observed in patients receiving vancomycin, when compared with other comparators (pooled RR=1.95; 95% CI 1.62, 2.36; p0.001), but the majority of the events were mild to moderate in nature. No evidence is currently available suggesting that the use of vancomcycin confers a risk of progressive or severe drug-induced liver injury.Continuous monitoring of hepatic events on a routine basis among patients with the use of vancomycin is suggested.

OBJECTIVE To assess the maintenance of efficacy of duloxetine beyond 3 months, using data from several long-term, open-label studies, as the efficacy of duloxetine 40-mg twice daily for treating women with stress urinary incontinence (SUI) for up to 3 months has been established in several randomized, placebo-controlled clinical trials. PATIENTS AND METHODS Data from 1424 patients (Cohort A) enrolled in three 12-week, placebo-controlled clinical trials and their uncontrolled, open-label extensions, and in one uncontrolled, open-label study, were used to assess long-term continuation rates and continued efficacy based on responses to the validated Patient Global Impression of Improvement (PGI-I) scale for up to 30 months. Data from another 2758 patients (Cohort B) enrolled in an additional placebo-controlled study and its open-label extension were used to assess PGI-I ratings, reductions in incontinence episode frequency (IEF) recorded on urinary diaries, and the relationship between PGI-I ratings and reductions in IEF for up to 72 weeks. RESULTS In Cohort A, the duloxetine continuation rate at 1 year was 42.5%. At 12, 24 and 30 months, most (83%, 83% and 88%, respectively) patients in Cohort A who continued treatment rated their incontinence in one of the three ‘better since starting treatment’ PGI-I categories. Both the median IEF reductions (50–77%) and the PGI-I ‘better’ ratings (70–88% of patients) remained fairly consistent over 72 weeks in Cohort B. Finally, IEF reductions increased with increasing PGI-I ratings (≈46% for ‘a little better’, 75% for ‘much better’ and 95% for ‘very much better’) over the first year of treatment. CONCLUSION The benefits of duloxetine were maintained in patients who continued treatment for up to 30 months. However, these favourable results need to be interpreted cautiously, as many patients discontinued treatment and those with better responses are more likely to continue taking medication.

Databases held by regulatory agencies and by pharmaceutical companies may be used to detect safety signals. We compared the utility of a company safety database with those from two large regulatory authority databases in assessing potential safety signals in order to understand how the different sources may be used. Proportional reporting ratios (PRRs) were calculated from the company database for historical events that had led to changes in prescribing information (PI) and were compared to PRRs calculated in external databases (the US Food and Drug Administration Freedom of Information database and the UK Adverse Drug Reactions On-line Information Tracking database). For most events there was agreement between all of the databases. For some selected historical events we have shown that if a company database is large enough and a wide range of therapeutic areas is covered then there is insignificant difference between PRRs calculated from the company database and larger external databases.

The Fe–Al–Nb phase diagram including isothermal sections at 1000, 1150, and 1300 °C as well as the liquidus surface and corresponding reaction scheme was studied experimentally by a combination of scanning electron microscopy (SEM), electron probe microanalysis (EPMA), X-ray diffraction (XRD), and differential thermal analysis (DTA). No genuinely ternary intermetallic phase exists in the system, but the two Fe–Nb phases NbFe2 (C14-type Laves phase) and Fe7Nb6 (μ phase) have extended homogeneity ranges in the ternary system, where large amounts of Fe can be substituted by Al in both cases. The solubility of the third element was studied for all binary phases and the effect on the lattice parameters is discussed. From analysis of the as-cast microstructures and DTA experiments, the liquidus surface including all invariant reactions as well as the occurring solid state reactions were established. Three ternary eutectics, one eutectoid, and two peritectic reactions were found, and the list of invariant points is completed by seven U-type reactions.

To assess the impact of duloxetine dose escalation on tolerability and efficacy, 516 women with stress urinary incontinence were randomized to receive placebo or duloxetine in one of three regimens: 40 mg BID for 8 weeks, 40 mg QD for 2 weeks escalating to 40 mg BID for 6 weeks or 20 mg BID for 2 weeks escalating to 40 mg BID for 6 weeks. A non-inferiority analysis confirmed that the 20 mg BID starting dose was significantly better than the other two duloxetine regimens for nausea reduction (16.5% vs 25.2% and 29.4%). There were also significant differences in the discontinuation rates (7.5% vs 11.8% and 16.2%). The efficacy after 4 weeks was significantly better with duloxetine than with placebo. Starting duloxetine at 20 mg BID for 2 weeks before increasing to 40 mg BID significantly improved tolerability but did not impact duloxetine efficacy after all the subjects had been on 40 mg BID for at least 2 weeks.

Objective To describe the characteristics of women seeking treatment for symptoms of urinary incontinence (UI) in European countries. Design Prospective urinary incontinence research (PURE) was a 6-month, observational, pan-European study, primarily aimed at determining the direct costs of urinary incontinence treatment. The secondary objectives of PURE were to describe the impact of UI on health-related quality of life (HRQoL) in treatment seeking patients and to illustrate the treatment patterns for UI in Europe. Setting One thousand and Fifty-five physicians from 14 European countries, including general practitioners (GPs), gynaecologists, urologists and geriatricians, observed women seeking treatment for their UI and recorded data at the first observation and then prospectively at 3 and 6 months after the first observation during the normal course of therapy. Subjects Women of at least 18 years of age who had experienced urinary leakage in the 12 months prior to enrolment in the study, who were seeking treatment or under treatment for UI and who presented within the normal course of UI care were included in the 6 months study. The first observation characteristics of the patients are described here. Methods Demographic characteristics, as well as disease and treatment status at first observation were explored using descriptive summary statistics to gain an understanding of the population studied. Results In total, 9487 women took part in PURE, with the largest patient groups from Germany, Spain and the UK/Ireland. The majority of women were post-menopausal and had a mean age of 60.7 years, were not current smokers and tended to be overweight (BMI > 25.0). Overall, mixed UI symptoms were more common than SUI and UUI, as defined by clinical opinion (SUI 38%, MUI 42% and UUI 18%), and by a two-item questionnaire, the S/UIQ (SUI 29%, MUI 58% and UUI 13%). Around half of the patients (48%) suffered from their symptoms for less than 2 years before consulting a physician; 28% delayed seeking treatment for 3–5 years, with 13% waiting for 6–10 years and the remaining 11% waiting for 11 or more years. Conclusions Some of the described patients’ characteristics may provide important information to clinicians to enable them to take a more active approach to case-finding, which will ultimately benefit the incontinent patient.

Objectives: To assess the proportion of women who consult their doctor about urinary incontinence (UI), and explore factors associated with help-seeking in France, Germany, Spain and the UK. Methods: A representative sample of 29,500 women received a 13 item postal questionnaire to identify those with UI. A randomly selected sub-sample of 2953 women with UI received a more detailed follow-up questionnaire. Results: There was a response rate of 58% in the initial survey and 53% in the second. Thirty-one percent of all women had consulted a doctor about their UI symptoms with more women consulting in France and Germany than in the UK and Spain. A number of factors relating to general health care, UI and women's attitudes were found to be associated with help-seeking after adjusting for women's age, UI duration and frequency, and ‘bothersomeness' of UI; factors traditionally associated with help-seeking. After adjusting for these factors, willingness to take long-term medication and having spoken to others about UI were found to be strong predictors of help-seeking in all four countries.

Objective To compare continuous combined hormone replacement therapy (ccHRT) and raloxifene with respect to compliance and quality of life, which were predefined secondary endpoints of a large, prospective study designed to investigate the uterine effects of both treatments. Design Double-blind, randomised controlled trial of six-month duration. Setting One hundred and twenty-nine gynaecology hospital departments, clinics or practices specialised in women's healthcare, located in Europe, South Africa and Israel. Population Healthy postmenopausal women (n= 1008). Main outcome measures Changes in quality of life using the Women's Health Questionnaire (WHQ) and compliance using a compliance questionnaire and pill count. Adverse event and early discontinuation rates and satisfaction with treatment using a visual analogue scale (VAS). Results Women taking raloxifene reported greater satisfaction with their treatment as assessed on the VAS (P= 0.004),and a lower proportion, as compared with ccHRT, reported being worried by the treatment (9.6%vs 20.2%, P < 0.01). Women taking ccHRT reported greater deterioration in scores from the WHQ for depressed mood and menstrual symptoms than those taking raloxifene (P < 0.01). For memory, vasomotor symptoms and sexual behaviour, the ccHRT group reported significantly greater mean improvements (P < 0.05). Over half (58.8%) of those taking raloxifene noticed no effect, 37.7% felt better and 3.4% felt worse as measured using the compliance questionnaire. Fifty percent of the women taking ccHRT felt better, 37.8% noticed no effect but over 10% felt worse. More women on raloxifene (94.6%) than on ccHRT (85.9%) reported that they were taking their double-blinded medication regularly (P < 0.01). Conclusions A lower rate of adverse event-related discontinuations, the lack of negative effects on quality of life and a smaller proportion of women being worried by the drug treatment were associated with higher treatment satisfaction and better compliance in postmenopausal women taking ccHRT or raloxifene.

A review of the literature revealed that recently published phase diagrams of the Fe-Nb system show considerable discrepancies regarding phase equilibria with the melt and the homogeneity ranges of the intermetallic phases, specifically of the Laves phase Fe2Nb. Therefore the system has been reinvestigated by metallography, electron probe microanalysis (EPMA), and differential thermal analysis (DTA). Temperatures of invariant reactions were determined and the homogeneity ranges of the two intermetallic phases, Fe2Nb Laves phase and Fe7Nb6 μ phase, which both exist within a wide composition range, were established.

Large, defect-free single-phase samples of the hexagonal C14 NbFe2 and Nb(Fe,Al)2, and the cubic C15 NbCo2 Laves phases have been produced by a modified levitation melting technique. The compressive strength of NbFe2 and NbCo2 has been determined in dependence on the Nb content, that of Nb(Fe,Al)2 in dependence on the Al content. The binary phases did not show either a maximum (defect softening) or minimum (defect hardening) in strength when the Nb content was varied. Instead, for both phases an increase of the compressive strength with increasing Nb content is observed.

To evaluate short- and long-term safety and efficacy of duloxetine in women with predominant stress urinary incontinence (SUI).The study was a 6-week, double-blind, randomised, parallel, placebo-controlled study followed by an uncontrolled open-label extension (OLE) run in 342 study centres in 16 European countries. Women with predominant SUI were randomly assigned to placebo (n = 1380) or duloxetine 40 mg twice daily (n = 1378) for 6 weeks. Completers of the acute phase were enrolled in the OLE, which had a minimum duration of 6 weeks and ended, based on the approval status of duloxetine in the participating country.The primary outcome measure was the change in incontinence episode frequency (IEF) over 6 weeks. Secondary outcome measures were the long-term maintenance of effect on IEF and Patient Global Impression of Improvement (PGI-I), the short- and long-term impact on quality of life using the King's Health Questionnaire (KHQ), and the long-term safety of duloxetine.After 6 weeks, the decrease in weekly IEF was significantly greater with duloxetine treatment compared to placebo (-50.0 vs. -29.9%; p0.001). The percentage of responders (defined asor =50% decrease in IEF) was significantly higher with duloxetine treatment than with placebo (50.6 vs. 31.2%; p0.001). Duloxetine treatment was associated with improvements in weekly pad use (-31.4%), PGI-I ratings (63.6%), and KHQ score (-6.25) compared to placebo (-12.5%, 48.5% and -3.13, respectively, all p0.001). Treatment-emergent adverse events were significantly more common during duloxetine treatment (48.3%) than placebo (33.3%), (p0.001). Of the 2290 patients continuing into the OLE, 1165 (42.2%) completed the available duration, and 592 (21.5%) discontinued because of an adverse event (percentages relative to total randomised patients). Long-term efficacy in the OLE was assessed over a 72-week period and was maintained over that time. However, the results should be interpreted within the context that better responding patients are more likely to remain on duloxetine, while patients responding poorly are more likely to discontinue over time.Duloxetine seems to be an efficacious treatment with an acceptable safety profile for women with SUI. Achieved improvement is maintained over the longer term in those women who remain on therapy.

Single-phase Fe-Nb and Co-Nb Laves phase alloys were produced by arc melting and levitation melting. By casting the levitation melted alloys in a preheated mould and subsequent slow cooling to room temperature, solid rods of 15 mm in diameter and about 100 mm length of the brittle Laves phases were obtained. Within the extended homogeneity ranges of the NbFe2 and NbCo2 Laves phases, the Vickers hardness was measured in dependence on composition. The results show that the hardness has a maximum at the stoichiometric composition in both systems, indicating defect softening. Nanoindentation measurements on a Co-Nb diffusion couple confirm the dependence of the hardness on composition. In addition, these measurements indicate that the crystal structure of the Laves phase polytype – cubic or hexagonal – seems to have no effect on the hardness. Indentation fracture toughness KIC-IF data for the different polytypes of the Laves phases were evaluated from the Palmquist cracks originating from the edges of the Vickers indentations.

Introduction: The Bradford Hill criteria are a widely used, useful tool for the assessment of biomedical causation. We have examined their application to pharmacovigilance using the example of cisapride-induced QTc interval prolongation/arrhythmia. Methods: A literature search was conducted using MEDLINE, EMBASE, Reactions Weekly and regulatory websites to identify evidence for the association between cisapride and QTc interval prolongation/arrhythmia that had been published in the English language. Two hundred and five publications were identified as being potentially suitable for the study. After excluding irrelevant articles, studies on high-risk populations and review articles, 70 publications were assessed using the Bradford Hill criteria. These included 24 case reports, case series or spontaneous report summaries; eight epidemiological studies; 22 clinical studies; and 16 experimental (in vivo and in vitro) publications. Results: The most compelling evidence for an association between cisapride use and QTc interval prolongation/arrhythmia came from case/spontaneous reports and biological plausibility. Considering the rare incidence of serious cardiac events, these criteria formed the basis for the strength of the association. The number of reports from different populations showed consistency. Specificity was supported by clinical and cardiographic characterisation of the events. There were temporal relationships between the events and the initiation of cisapride treatment, increases in the dosage and the receipt of interacting medications. The relationships between the adverse events and the latter two factors exhibited biological gradients. Experimental evidence could be found from biological models, as well as reports of positive dechallenge and/or rechallenge found in individual patients. Cisapride was found to bind the human ether-a-go-go-related gene (HERG) potassium channel, which provides a plausible mechanism for QTc interval prolongation/arrhythmia. Other QTc interval-prolonging/arrhythmic drugs that also bind to HERG provided an analogy for cisapride causing QTc interval prolongation/arrhythmia via this mechanism. The evidence provided by clinical studies was inconsistent, and epidemiological studies failed to demonstrate an association. Nevertheless, this did not prevent the assessment of causation. Discussion: This study showed how different types of evidence found in pharmacovigilance can be evaluated using the Bradford Hill criteria. Further work is required to examine how the criteria can be applied to different types of adverse events and how they may be applied to pharmacovigilance.

OBJECTIVE To determine the prevalence, type and treatment behaviour of women with urinary incontinence in four European countries. SUBJECTS AND METHODS Data were collected using a postal survey which was sent to 29 500 community-dwelling women aged ≥ 18 years in France, Germany, Spain and the UK. Subjects were asked about the type of urinary incontinence they had experienced and their treatment behaviour. RESULTS Of the women who responded, 35% reported involuntary loss of urine in the preceding 30 days; stress urinary incontinence was the most prevalent type. The lowest prevalence was in Spain (23%), while the prevalence was 44%, 41% and 42% for France, Germany and the UK, respectively. About a quarter of women with urinary incontinence in Spain (24%) and the UK (25%) had consulted a doctor about it; in France (33%) and Germany (40%) the percentages were higher. Overall

The potential hematotoxic effects of antipsychotic drugs are well known and may limit the use of some effective therapies. Although some previous studies have suggested that patients with schizophrenia may have altered "normal" values, only limited data were available. It is now believed that biological values do not usually follow a normal distribution; therefore, reference ranges are frequently used when interpreting laboratory tests in clinical practice and in research. However, it may be important to use disease-specific hematologic reference ranges when evaluating laboratory test results for patients with schizophrenia. In this study, data taken from patients with schizophrenia prior to treatment in previous phase II and phase III pharmaceutical studies were analyzed to produce reference ranges for a variety of hematologic parameters. An increased variability was shown in the reference ranges for all white blood cell indices between patients with schizophrenia and the population without schizophrenia. Certain reference values also showed heterogeneity for gender, age, and racial descent. This study suggests that abnormal hematologic findings in patients with schizophrenia should be assessed in the context of a valid reference range. This information will be of value to psychiatrists, laboratory scientists, and other physicians who encounter hematologic problems in patients with schizophrenia, as well as in the assessment of the adverse effects of new therapeutic agents.