Effects of a team-based assessment and intervention on patient safety culture in general practice: an open randomised controlled trial.

BACKGROUND: The measurement of safety culture in healthcare is generally regarded as a first step towards improvement. Based on a self-assessment of safety culture, the Frankfurt Patient Safety Matrix (FraTrix) aims to enable healthcare teams to improve safety culture in their organisations. In this study we assessed the effects of FraTrix on safety culture in general practice. METHODS: We conducted an open randomised controlled trial in 60 general practices. FraTrix was applied over a period of 9 months during three facilitated team sessions in intervention practices. At baseline and after 12 months, scores were allocated for safety culture as expressed in practice structure and processes (indicators), in safety climate and in patient safety incident reporting. The primary outcome was the indicator error management. RESULTS: During the team sessions, practice teams reflected on their safety culture and decided on about 10 actions per practice to improve it. After 12 months, no significant differences were found between intervention and control groups in terms of error management (competing probability=0.48, 95% CI 0.34 to 0.63, p=0.823), 11 further patient safety culture indicators and safety climate scales. Intervention practices showed better reporting of patient safety incidents, reflected in a higher number of incident reports (mean (SD) 4.85 (4.94) vs 3.10 (5.42), p=0.045) and incident reports of higher quality (scoring 2.27 (1.93) vs 1.49 (1.67), p=0.038) than control practices. CONCLUSIONS: Applied as a team-based instrument to assess safety culture, FraTrix did not lead to measurable improvements in error management. Comparable studies with more positive results had less robust study designs. In future research, validated combined methods to measure safety culture will be required. In addition, more attention should be paid to evaluation of process parameters. Implemented actions and incident reporting may be more appropriate target endpoints. TRIAL REGISTRATION: German Clinical Trials Register (Deutsches Register Klinischer Studien, DRKS) No. DRKS00000145.

Potential and requirements of IT for ambient assisted living technologies. Results of a Delphi study.

OBJECTIVES: Ambient Assisted Living (AAL) technologies are developed to enable elderly to live independently and safely. Innovative information technology (IT) can interconnect personal devices and offer suitable user interfaces. Often dedicated solutions are developed for particular projects. The aim of our research was to identify major IT challenges for AAL to enable generic and sustainable solutions. METHODS: Delphi Survey. An online questionnaire was sent to 1800 members of the German Innovation Partnership AAL. The first round was qualitative to collect statements. Statements were reduced to items by qualitative content analysis. Items were assessed in the following two rounds by a 5-point Likert-scale. Quantitative analyses for second and third round: descriptive statistics, factor analysis and ANOVA. RESPONDENTS: 81 in first, 173 in second and 70 in third round. All items got a rather high assessment. Medical issues were rated as having a very high potential. Items related to user-friendliness were regarded as most important requirements. Common requirements to all AAL-solutions are reliability, robustness, availability, data security, data privacy, legal issues, ethical requirements, easy configuration. The complete list of requirements can be used as framework for customizing future AAL projects. CONCLUSIONS: A wide variety of IT issues have been assessed important for AAL. The extensive list of requirements makes obvious that it is not efficient to develop dedicated solutions for individual projects but to provide generic methods and reusable components. Experiences and results from medical informatics research can be used to advance AAL solutions (e.g. eHealth and knowledge-based approaches).

Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Phase 2 (CALERIE Phase 2) screening and recruitment: methods and results.

The Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy Phase 2 (CALERIE) study is a systematic investigation of sustained 25% calorie restriction (CR) in non-obese humans. CALERIE is a multicenter (3 clinical sites, one coordinating center), parallel group, randomized controlled trial. Participants were recruited, screened, and randomized to the CR or control group with a 2:1 allocation. Inclusion criteria included ages 21-50 years for men and 21-47 years for women, and a body mass index (BMI) of 22.0 ≤ BMI < 28.0 kg/m(2). Exclusion criteria included abnormal laboratory markers, significant medical conditions, psychiatric/behavioral problems, and an inability to adhere to the rigors of the evaluation/intervention schedule. A multi-stage screening process (telephone screen and 3 in-clinic visits) was applied to identify eligible participants. Recruitment was effective and enrollment targets were met on time. 10,856 individuals contacted the clinical sites, of whom 9787 (90%) failed one or more eligibility criteria. Of the 1069 volunteers who started the in-clinic screening, 831 (78%) were either ineligible or dropped. 238 volunteers were enrolled (i.e., initiated the baseline evaluations), 220 were randomized, and 218 started the assigned intervention (2% from the first screening step). This study offered lessons for future multi-center trials engaging non-disease populations. Recruitment strategies must be tailored to specific sites. A multi-disciplinary screening process should be applied to address medical, physical, and psychological/behavioral suitability of participants. Finally, a multi-step screening process with simple criteria first, followed by more elaborate procedures has the potential to reduce the use of study resources.

Identifying factors associated with experiences of coronary heart disease patients receiving structured chronic care and counselling in European primary care.

BACKGROUND: Primary care for chronic illness varies across European healthcare systems. In patients suffering from coronary heart disease (CHD), factors associated with patients' experiences of receiving structured chronic care and counselling at the patient and practice level were investigated. METHODS: In an observational study comprising 140 general practices from five European countries (Austria, Germany, the Netherlands, Switzerland and the United Kingdom), 30 patients with Coronary Heart Disease (CHD) per practice were chosen at random to partake in this research. Patients were provided with a questionnaire and the Patient Assessment of Chronic Illness Care (PACIC-5A) - instrument. Practice characteristics were assessed through a practice questionnaire and face to face interviews. Data were aggregated to obtain two practice scores representing quality management and CHD care, respectively. A hierarchical multilevel analysis was performed to examine the impact of patient and practice characteristics on PACIC scores. RESULTS: The final sample included 1745 CHD-patients from 131 general practices with a mean age of 67.8 (SD 9.9) years. The overall PACIC score was 2.84 (95%CI: 2.79; 2.89) and the 5A score reflecting structured lifestyle counselling was 2.75 (95% CI: 2.69; 2.79). At the patient level, male gender, more frequent practice contact and fewer related or unrelated conditions were associated with higher PACIC scores. At the practice level, performance scores reflecting quality management (p = 0.013) and CHD care (p = 0.009) were associated with improved assessment of the structured chronic care and counselling received. CONCLUSIONS: Patients' perceived quality of care varies. However, good practice management and organisation of care were positively reflected in patients' assessments of receiving structured chronic illness care. This highlights the importance of integrating patient experiences into quality measurements to provide feedback to health care professionals.

Serum proteomic profiling in patients with drug-induced liver injury.

BACKGROUND: Idiosyncratic drug-induced liver injury (DILI) is a complex disorder that is difficult to predict, diagnose and treat. AIM: To describe the global serum proteome of patients with DILI and controls. METHODS: A label-free, mass spectrometry-based quantitative proteomic approach was used to explore protein expression in serum samples from 74 DILI patients (collected within 14 days of DILI onset) and 40 controls. A longitudinal analysis was conducted in a subset of 21 DILI patients with available 6-month follow-up serum samples. RESULTS: Comparison of DILI patients based on pattern, severity and causality assessment of liver injury revealed many differentially expressed priority 1 proteins among groups. Expression of fumarylacetoacetase was correlated with alanine aminotransferase (ALT; r = 0.237; P = 0.047), aspartate aminotransferase (AST; r = 0.389; P = 0.001) and alkaline phosphatase (r = -0.240; P = 0.043), and this was the only protein with significant differential expression when comparing patients with hepatocellular vs. cholestatic or mixed injury. In the longitudinal analysis, expression of 53 priority 1 proteins changed significantly from onset of DILI to 6-month follow-up, and nearly all proteins returned to expression levels comparable to control subjects. Ninety-two serum priority 1 proteins with significant differential expression were identified when comparing the DILI and control groups. Pattern analysis revealed proteins that are components of inflammation, immune system activation and several hepatotoxicity-specific pathways. Apolipoprotein E expression had the greatest power to differentiate DILI patients from controls (89% correct classification; AUROC = 0.97). CONCLUSION: This proteomic analysis identified differentially expressed proteins that are components of pathways previously implicated in the pathogenesis of idiosyncratic drug-induced liver injury.

Clinical research in epithelial ovarian cancer and patients' outcome.

We evaluated the relationship between the outcome of newly diagnosed ovarian cancer patients treated in 1123 German gynecology departments in 2001, and their participation in clinical trials through two German cooperative study groups. In addition, we evaluated other potential factors predicting outcome including hospital volume. The analysis was based on 476 patients from 165 hospitals and 3-year follow-up. Patients treated in study hospitals had a higher chance of receiving treatment according to national guidelines. This included a higher chance of receiving optimal staging in early stage disease and of receiving the recommended combination of surgical debulking and combination chemotherapy in advanced disease. On multivariable Cox model analysis, overall survival was significantly worse in patients treated in non-study hospitals.

Future research and methodological approaches.

This supplement has explored the evidence for benefits from the participation of healthcare institutions and their patients in clinical research. The questions have been clarified. There is some encouragement that research active healthcare institutions may deliver improved outcomes compared to less research-active or research-inactive institutions but there is a pressing need for further research. In this chapter we explore the methodological challenges to evaluating the impact of the process of clinical research on hospitals and other healthcare organizations. The postulated mechanisms by which benefits may be accrued are important drivers of the types of research needed and these are emphasized. Study designs are explored including formal randomized trials, the stepped wedge randomized design, approaches to the design and analysis of observational studies particularly to examine whether a temporal or spatial relationship exists between changes in research activity and patients' outcomes. It is acknowledged that in most future studies the data available will be cross-sectional and observational, and such studies are susceptible to many types of bias. The importance of identifying and addressing such biases in multivariate analysis is discussed and examples of successful studies are given.

Analysis of risk factors influencing the development of severe dizziness in patients with vestibular schwannomas in the immediate postoperative phase.

OBJECTIVE: Dizziness, a common postoperative symptom in patients with vestibular schwannomas (VSs) has a negative effect on the course of recovery, particularly in patients with severe symptoms. Reports on incidence and possible risk factors contributing to these symptoms are inconsistent and sometimes even contradictory. In order to establish a profile of patients at risk of severe symptoms in the immediate postoperative phase we retrospectively analyzed data of patients with unilateral VSs focusing on the incidence of severe dizziness and nausea during the immediate postoperative period and up to 1 year after surgery. METHODS: In a retrospective study data of 104 consecutive patients with VSs were analyzed. All patients underwent microsurgical tumor resection via a lateral-suboccipital approach. Factors that were assumed to affect the development of severe dizziness, such as age, gender, tumor size, tumor side, and cranial nerve function, were analyzed by means of univariate and multivariate logistic regression analyses. A three step grading system was used to describe symptoms of patients included in this study: 0=no symptoms of dizziness, 1=slight dizziness including light-headedness or feeling of disequilibrium and 2=severe dizziness with nausea including imbalance or insecurity when walking, requiring antiemetic treatment. RESULTS: Data of 92 patients, 41 men and 51 women, were available for analyses. Mean age of treated patients was 53 years (range 17-81). There was no predilection of side (52.2% right/47.8% left). Before surgery 39 patients (42.4%) were symptom free (grade 0), 13 patients (14.1%) had slight symptoms (grade 1) and 40 patients (43.5%) suffered from severe symptoms (grade 2). Immediately after surgery two patients (2.2%) where symptom free (grade 0), 19 patients (20.7%) had slight symptoms (grade 1) and 71 patients (77.2%) suffered from severe symptoms (grade 2). All patients with grade 2 symptoms required antiemetic treatment ranging between 1 and 10 days (mean 4 days). Logistic regression analyses showed young age, large tumor size (T3/T4), female gender, and severe preoperative symptoms to be main factors increasing the odds for patients to develop severe symptoms postoperatively. CONCLUSION: Patients at risk to develop severe symptoms should receive antiemetic treatment even before surgery. If in doubt about the actual risk for a specific patient with a large tumor (T3 or T4) available data suggests that patients will benefit if antiemetic treatment is started early, even before surgery.

Cerebral metastases in metastatic breast cancer: disease-specific risk factors and survival.

BACKGROUND: Survival of patients suffering from cerebral metastases (CM) is limited. Identification of patients with a high risk for CM is warranted to adjust follow-up care and to evaluate preventive strategies. PATIENTS AND METHODS: Exploratory analysis of disease-specific parameter in patients with metastatic breast cancer (MBC) treated between 1998 and 2008 using cumulative incidences and Fine and Grays' multivariable regression analyses. RESULTS: After a median follow-up of 4.0 years, 66 patients (10.5%) developed CM. The estimated probability for CM was 5%, 12% and 15% at 1, 5 and 10 years; in contrast, the probability of death without CM was 21%, 61% and 76%, respectively. A small tumor size, ER status, ductal histology, lung and lymph node metastases, human epidermal growth factor receptor 2 positive (HER2+) tumors, younger age and M0 were associated with CM in univariate analyses, the latter three being risk factors in the multivariable model. Survival was shortened in patient developing CM (24.0 months) compared with patients with no CM (33.6 months) in the course of MBC. CONCLUSION: Young patients, primary with non-metastatic disease and HER2+ tumors, have a high risk to develop CM in MBC. Survival of patients developing CM in the course of MBC is impaired compared with patients without CM.

Prognostic impact of additional extended surgical procedures in advanced-stage primary ovarian cancer.

BACKGROUND: Treatment of advanced-stage ovarian carcinoma includes radical cytoreductive surgery, which aims at removing all visible tumor tissue followed by platinum and paclitaxel chemotherapy. Complete tumor resection may require extended surgical procedures. This paper reports on the prognostic impact of extensive surgery and surgical morbidity in patients with advanced-stage ovarian carcinoma. METHODS: Patients with ovarian carcinoma [Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage IIIB-IV] undergoing primary surgery in our tertiary gynecologic oncology unit between 1997 and 2007 were eligible for this study. The impact of established prognostic factors and the interaction with extent of surgical procedures on survival were assessed. RESULTS: A total of 267 patients aged between 29 and 88 years (median 64 years) were eligible for this study. Overall survival time was improved in patients who underwent complete tumor resection [hazard ratio (HR) 3.61 (1.91-6.61), P < 0.001]. No significant survival difference was observed between completely operated patients in whom extended or standard surgical procedures were applied [HR 1.37 (0.70-2.69), P = 0.358], and severe surgical complications were found to be equally distributed between the two patient groups. CONCLUSIONS: Our results may encourage the application of extended surgical procedures in patients who would otherwise be rendered incompletely debulked after primary cytoreduction. We could demonstrate an impact of complete tumor resection on patient prognosis and this was not traded off for extensive additional surgical morbidity.

Pattern of care and impact of participation in clinical studies on the outcome in ovarian cancer.

The purpose of this study was to evaluate the pattern and quality of care for ovarian cancer in Germany and analyze prognostic factors with emphasis on characteristics of treating institutions, hospital volume, and participation in clinical trials. This study utilized national survey including patients with histologically proven invasive epithelial ovarian cancer diagnosed in the third quarter of 2001 including descriptive analysis of pattern of surgical care and systemic treatment in early (FIGO I-IIA) and advanced (FIGO IIB-IV) ovarian cancer and both univariate and multivariate analysis of prognostic factors. One third of all patients diagnosed in the third quarter of 2001 in Germany, 476 patients, were included. Standard care according to German guidelines was provided to only 35.5% of patients with early ovarian cancer. Recommended chemotherapy was given to 78% in advanced disease. Multivariate analysis showed advanced stage, poor performance status, comorbidity, ascites, and treatment in an institution not participating in cooperative studies to be associated with inferior survival. Non-participation was associated with an 82% increase of risk (HR = 1.82; 95% CI, 1.27-2.61; P= 0.001). Hospital volume did not affect treatment outcome. Adherence to treatment guidelines showed remarkable variety among German hospitals, indicating options and need for improvement. Selecting an institution that participates in cooperative trials might be an option for individual patients seizing the chance for better quality of care even when individual factors might hamper enrollment in a study.

[The Quality Assurance Program of the AGO Organkommission OVAR (QS-OVAR): Pattern of Care and Reality in Germany 2001]. / Das Qualitätssicherungsprogramm der AGO Organkommission OVAR (QS-OVAR): Versorgungsstruktur und Realität in Deutschland 2001.

PURPOSE: To evaluate pattern and quality of care for ovarian cancer in Germany and analyze adherence to treatment guidelines as well as prognostic factors for survival. METHODS: Nationwide survey including patients with histological proven invasive epithelial ovarian cancer diagnosed in the third quarter 2001 including descriptive analysis of pattern of surgical care and systemic treatment in early (FIGO I-IIA) and advanced (FIGO IIB-IV) ovarian cancer and both univariate and multivariate analysis of prognostic factors. RESULTS: 476, representing more than one third of all patients diagnosed in Q III 2001 in Germany were included. Standard care according to German guidelines was provided to only 35.5 % of patients with early ovarian cancer. Optimal debulking was reported for 61.4 % patients with FIGO stages IIB-IV. Recommended platinum-paclitaxel chemotherapy was given to 3 out of 4 patients in advanced disease. Multivariate analysis showed advanced stage, poor performance status, co-morbidity, ascites, postoperative tumor residuals, and less than standard care to be associated with inferior survival. CONCLUSIONS: Adherence to treatment guidelines showed remarkable variety among German hospitals indicating options and need for improvement.

[Impact of center characteristics on outcome in ovarian cancer in Germany]. / Welchen Einfluss haben Klinikmerkmale auf die Prognose beim Ovarialkarzinom in Deutschland?

PURPOSE: To evaluate the relationship between hospital characteristics and quality of care and outcome in ovarian cancer in Germany. METHODS: This 2nd national survey in patients with histologically proven epithelial ovarian cancer diagnosed in the 3 (rd) quarter 2001 analyzed pattern of care in early (FIGO I-II A) and advanced (FIGO II B-IV) disease. We performed univariate and multivariate analysis of the role of hospital characteristics, like hospital-volume, participation in cooperative clinical studies, and hospital category (university vs central clinic vs. two lower categories in Germany) as prognostic factor. RESULTS: 165 hospitals documented 476 patients (= about one third of all patients diagnosed in Germany within one quarter). Patients treated in study-centres received more frequently standard care and showed superior survival (multivariate analysis including biologic prognostic factors: HR 1.71; 95 % CI 1.2-2.5; p = 0.007). 2-year-survival was 72 % and 64 % in study-centres and hospitals not participating in studies, respectively. Neither hospital category nor hospital-volume showed any significant impact on survival. Only analysis of surrogate parameters like pattern of care in early ovarian cancer revealed advantages related to hospital category. Furthermore, analysis of some surgical details revealed advantages for high-volume centres and hospital category. CONCLUSION: Participation in clincal studies was the only transparent hospital characteristic with significant impact on prognosis of ovarian cancer. Study participation as criterion for quality of care should be included in counselling ovarian cancer patients and should help guiding selection of hospitals for primary therapy. All German hospitals with information about participation in cooperative clinical studies as well as in this quality assurance program are listed on the web.

Sample size calculations for controlled clinical trials using generalized estimating equations (GEE).

OBJECTIVES: Clinical trials with correlated response data based on generalized estimating equations (GEE) have become increasingly popular as they require smaller samples than classical methods that ignore the clustered nature of the data. We have recently derived the recommendation to use the independence estimating equations (IEE) as primary analysis in most controlled clinical trials instead of GEE with estimated correlations. Although several approaches for sample size and power calculation have been proposed, we have shown that most of these procedures are very specific and not as general as required for designing clinical trials. METHODS: We extended the previously developed SAS macro GEESIZE to overcome this restriction. Specifically, we have added the option of an independence working correlation matrix required for the IEE. Additionally, we have reformulated the hypotheses to allow for coding that includes an intercept term instead of the previously used analysis of variance coding. RESULTS: To demonstrate the validity of GEESIZE we investigate the calculated sample sizes for specific models where closed formulae are available. For illustration, we utilize GEESIZE for planning a new trial on the treatment of hypertension and thereby exemplify its flexibility. CONCLUSIONS: We show that our freely available macro is a very general and useful tool for sample size calculation purposes in clinical trials with correlated data.

A methodology for analysing a repeated measures and survival outcome simultaneously.

A considerable body of literature has arisen over the past 15 years for analysing univariate repeated measures data. It is rare in applied biomedical research, however, for interest to be restricted to a single outcome measure. In previous work, Rochon considered the case of bivariate repeated measures data in which each outcome is a discrete or continuous random variable. A GEE model was prescribed to relate each set of repeated measures to important explanatory variables. The 'seemingly unrelated regression' model was then applied to combine the pair of GEE models into an overall analysis framework. In this paper, we extend this approach to the case in which one endpoint is a repeated measures outcome but the second is a survival endpoint. Estimation and hypothesis testing issues are addressed and the methodology is illustrated with an example.

1,25-dihydroxyvitamin D3 synthetic analogs inhibit spontaneous metastases in a 1,2-dimethylhydrazine-induced colon carcinogenesis model.

In order to substantiate the role of vitamin D applicability for the prevention of colon cancer and its spontaneous metastases, the effect of 1,25-dihydroxyvitamin D3 and its synthetic analogs, 1, 25-dihydroxy-16,23Z-diene-26,27-hexafluoro-D3 (Ro 25-5317) and 1, 25-dihydroxy-16,23E-diene-26,27-hexafluoro-19-nor-D3 (Ro 25-9022), have been evaluated in a 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis model in Sprague-Dawley rats. In animals maintained on 2.75 nmol/kg 1,25-dihydroxyvitamin D3 diet no statistical difference was seen in tumor incidence when compared with control while in animals on 3.0 nmol/kg 1,25-dihydroxyvitamin D3 diet, the incidence of tumors was significantly lower. In animals maintained on 3.0 nmol/kg Ro 25-5317 diet also no statistical difference was seen in tumor incidence compared with control while in animals on 3. 5 nmol/kg Ro 25-5317 diet the incidence of tumors was significantly lower. The incidence of tumors in the group of animals maintained on 3.0 nmol/kg and 3.5 nmol/kg Ro 25-9022 was significantly lower, at 32.1% and 27.6% respectively, compared to control. In the two groups of animals maintained on the 1,25-dihydroxyvitamin D3 diet no significant difference in the incidence of metastasis was seen. In the group of animals maintained on 3.0 nmol/kg Ro 25-5317 diet only regional metastases were seen. However, no metastases developed in the rats on 3.5 nmol/kg Ro 25-5317 diet. After administration of 3.0 nmol/kg Ro 25-9022 diet, metastases developed in a significantly less number of animals while no metastases occurred in the rats maintained on the 3.5 nmol/kg Ro 25-9022 diet. The above studies will provide a scientific basis for the progression into further clinical trials in the treatment, and/or chemoprevention of human colorectal cancer.

Application of GEE procedures for sample size calculations in repeated measures experiments.

Derivation of the minimum sample size is an important consideration in an applied research effort. When the outcome is measured at a single time point, sample size procedures are well known and widely applied. The corresponding situation for longitudinal designs, however, is less well developed. In this paper, we adapt the generalized estimating equation (GEE) approach of Liang and Zeger to sample size calculations for discrete and continuous outcome variables. The non-central version of the Wald Chi 2 test is considered. We use the damped exponential family of correlation structures described in Muñoz et al. for the 'working' correlation matrix among the repeated measures. We present a table of minimum sample sizes for binary outcomes, and discuss extensions that account for unequal allocation, staggered entry and loss to follow-up.