Relationship between ICD implantation volume and treatment parameters of patients receiving an ICD with remote monitoring.

BACKGROUND: Both highly specialized heart centres and less specialized hospitals care for patients with implantable ICDs/CRT-Ds with remote monitoring. OBJECTIVE: To investigate potential differences in patient treatment according to centre's ICD implantation volume. METHODS: Based on their 2012 ICD/CRT-D implantation volume, centres enrolled in the NORDIC ICD trial in Germany were assigned to one of three groups: high- (HV, n= 345), medium- (MV, n= 340) or low-volume (LV, n= 189). RESULTS: The HV-centres had a significant higher CRT-D proportion (41.7%; LV: 36.5%; MV: 23.2%; P𝑔𝑙𝑜𝑏𝑎𝑙< 0.001), significant shorter median procedure duration (49 min; MV: 58 min; LV: 60 min; P𝑔𝑙𝑜𝑏𝑎𝑙< 0.001) but significant longer median hospital stay (4 days; MV and LV: 3 days; P𝑔𝑙𝑜𝑏𝑎𝑙< 0.001) compared to MV- and LV-centres. The X-ray exposure was shorter in MV/HV-centres (MV: 3.4 min; HV: 3.6 min; LV: 5.5 min; P𝑔𝑙𝑜𝑏𝑎𝑙< 0.001). Only 3.5% (LV: 2.6%; HV: 3.5%; MV: 4.1%) patients received at least one delivered inappropriate shock and 2.5% (HV: 2.0%; LV: 2.6%; MV: 2.9%) patients had withheld inappropriate ICD shocks without subsequent inappropriate shock delivery within 24.5 months of median follow-up. CONCLUSION: Implantation volume-dependent differences were observed in the device selection, procedure duration and x-ray exposure duration. Remote monitoring in combination with adequate response pattern prevented imminent inappropriate shocks in all three groups.

Systematic comparison of approaches to analyze clustered competing risks data.

BACKGROUND: In many clinical trials the study interest lies in the comparison of a treatment to a control group regarding a time to event endpoint like time to myocardial infarction, time to relapse, or time to a specific cause of death. Thereby, an event can occur before the primary event of interest that alters the risk for or prohibits observing the latter, i.e. a competing event. Furthermore, multi-center studies are often conducted. Hence, a cluster structure might be observed. However, commonly only the aspect of competing events or the aspect of the cluster structure is modelled within primary analysis, although both are given within the study design. Methods to adequately analyze data in such a design were recently described but were not systematically compared yet. METHODS: Within this work we provide a systematic comparison of four approaches for the analysis of competing events where a cluster structure is present based on a real life data set and a simulation study. The considered methods are the commonly applied cause-specific Cox proportional hazards model with a frailty, the Fine and Gray model for considering competing risks, and extensions of the latter model by Katsahian et al. and Zhou et al. RESULTS: Based on our simulation results, the model by Katsahian et al. showed the best performance in bias, square root of mean squared error, and power in nearly all scenarios. In contrast to the other three models this approach allows both unbiased effect estimation and prognosis. CONCLUSION: The provided comparison and simulations help to guide applied researchers to choose an adequate method for the analysis of competing events where a cluster structure is present. Based on our simulation results the approach by Katsahian et al. can be recommended.

Stop of proton-pump inhibitor treatment in patients with liver cirrhosis (STOPPIT): study protocol for a prospective, multicentre, controlled, randomized, double-blind trial.

BACKGROUND: Proton-pump inhibitors (PPI) are liberally prescribed in patients with liver cirrhosis. Observational studies link PPI therapy in cirrhotic patients with an increased risk for infectious complications, hepatic encephalopathy and an increased risk for hospitalization and mortality. However, patients with liver cirrhosis are also considered to be at risk for peptic ulcer bleeding. The STOPPIT trial evaluates if discontinuation of a pre-existing PPI treatment delays a composite endpoint of re-hospitalization and/or death in patients (recently) hospitalized with liver cirrhosis compared to patients on continued PPI medication. METHODS: The STOPPIT-trial is a prospective, multicentre, randomized, double-blinded, placebo-controlled, parallel-group trial. In total, 476 patients with complicated liver cirrhosis who already receive long-term PPI therapy without evidence-based indication are 1:1 randomized to receive either esomeprazole 20 mg (control group) or placebo (intervention group) for 360 days. Patients with an indication for PPI therapy (such as a recent diagnosis of peptic ulcers, severe reflux esophagitis, severe hemorrhagic gastritis, recent endoscopic therapy for oesophageal varices) are excluded. The primary composite endpoint is the time-to re-hospitalization and/or death. Secondary endpoints include rates of re-hospitalization, mortality, occurrence of infections, hepatic decompensation and acute-on-chronic liver failure. The safety endpoint is defined as manifestation of an evidence-based indication for PPI re-therapy. The impact of PPI continuation or discontinuation on the intestinal microbiota will be studied. The recruitment will take place at 18 study sites throughout Germany. Recruitment has started in April 2021. DISCUSSION: The STOPPIT trial is the first clinical trial to study the effects of PPI withdrawal on relevant outcome variables in patients with complicated liver cirrhosis. If the hypothesis that PPI withdrawal improves clinical outcomes of cirrhosis patients is confirmed, this would argue for a strong restriction of the currently liberal prescription practice of PPIs in this population. If, on the other hand, the trial demonstrates an increased risk of gastrointestinal bleeding events in patients after PPI withdrawal, this could create a rationale for a more liberal, prophylactic PPI treatment in patients with liver cirrhosis. TRIAL REGISTRATION: EU clinical trials register EudraCT 2019-005008-16 (registered December 27, 2019). CLINICALTRIALS: gov NCT04448028 (registered June 25, 2020). German Clinical Trials Register DRKS00021290 (registered March 10, 2021).

Heat stress reveals a specialized variant of the pachytene checkpoint in meiosis of Arabidopsis thaliana.

Plant growth and fertility strongly depend on environmental conditions such as temperature. Remarkably, temperature also influences meiotic recombination and thus, the current climate change will affect the genetic make-up of plants. To better understand the effects of temperature on meiosis, we followed male meiocytes in Arabidopsis thaliana by live cell imaging under three temperature regimes: at 21°C; at heat shock conditions of 30°C and 34°C; after an acclimatization phase of 1 week at 30°C. This work led to a cytological framework of meiotic progression at elevated temperature. We determined that an increase from 21°C to 30°C speeds up meiosis with specific phases being more amenable to heat than others. An acclimatization phase often moderated this effect. A sudden increase to 34°C promoted a faster progression of early prophase compared to 21°C. However, the phase in which cross-overs mature was prolonged at 34°C. Since mutants involved in the recombination pathway largely did not show the extension of this phase at 34°C, we conclude that the delay is recombination-dependent. Further analysis also revealed the involvement of the ATAXIA TELANGIECTASIA MUTATED kinase in this prolongation, indicating the existence of a pachytene checkpoint in plants, yet in a specialized form.

Prognostic markers of all-cause mortality in patients with atrial fibrillation: data from the prospective long-term registry of the German Atrial Fibrillation NETwork (AFNET).

AIMS: Atrial fibrillation (AF) is associated with a high risk of cardiovascular and non-cardiovascular death, even on anticoagulation. It is controversial, which conditions-including concomitant diseases and AF itself-contribute to this mortality. To further clarify these questions, major determinants of long-term mortality and their contribution to death were quantified in an unselected cohort of AF patients. METHODS AND RESULTS: We established a large nationwide registry comprising 8833 AF-patients with a median follow-up of 6.5 years (45 345 patient-years) and central adjudication of adverse events. Baseline characteristics of the patients were evaluated as predictors of mortality using Cox regression and C-indices for determination of predictive power. Annualized mortality was highest in the first year (6.2%) and remained high thereafter (5.2% in men and 5.5% in women). Thirty-eight percent of all deaths were cardiovascular, mainly due to heart failure or sudden death. Sex-specific age was the strongest predictor of mortality, followed by concomitant cardiovascular and non-cardiovascular conditions. These factors accounted for 25% of the total mortality beyond age and sex and for 84% of the mortality differences between AF types. Thus, the electrical phenotype of the disease at baseline contributed only marginally to prediction of mortality. CONCLUSION: Mortality is high in AF patients and arises primarily from heart failure, peripheral artery disease, chronic obstructive lung disease, chronic kidney disease, and diabetes mellitus, which, therefore, should be targeted to lower mortality. Parameters related to the electrical manifestation of AF did not have an independent impact on long-term mortality in our representative cohort.

Biperiden and mepazine effectively inhibit MALT1 activity and tumor growth in pancreatic cancer.

MALT1 is a key mediator of NF-κB signaling and a main driver of B-cell lymphomas. Remarkably, MALT1 is expressed in the majority of pancreatic ductal adenocarcinomas (PDACs) as well, but absent from normal exocrine pancreatic tissue. Following, MALT1 shows off to be a specific target in cancer cells of PDAC without affecting regular pancreatic cells. Therefore, we studied the impact of pharmacological MALT1 inhibition in pancreatic cancer and showed promising effects on tumor progression. Mepazine (Mep), a phenothiazine derivative, is a known potent MALT1 inhibitor. Newly, we described that biperiden (Bip) is a potent MALT1 inhibitor with even less pharmacological side effects. Thus, Bip is a promising drug leading to reduced proliferation and increased apoptosis in PDAC cells in vitro and in vivo. By compromising MALT1 activity, nuclear translocation of c-Rel is prevented. c-Rel is critical for NF-κB-dependent inhibition of apoptosis. Hence, off-label use of Bip or Mep represents a promising new therapeutic approach to PDAC treatment. Regularly, the Anticholinergicum Bip is used to treat neurological side effects of Phenothiazines, like extrapyramidal symptoms.

Nurse-work instability and incidence of sick leave - results of a prospective study of nurses aged over 40.

BACKGROUND: The Nurse Work Instability Scale (Nurse-WIS) is an occupation-specific instrument that ascertains "work instability," the interval before restricted work ability or prolonged sick leave occurs. The objective of the study was to assess if nurses with a high risk baseline-score in the Nurse-WIS take longer periods of sick leave due to musculoskeletal diseases and/or psychological impairments than other nurses. METHODS: A total of 4500 nurses randomly selected from one of the largest health insurance funds in Germany (DAK-Gesundheit) were invited by letter to participate in the study. The participants answered a questionnaire at baseline and gave consent to a transfer of data concerning sick leave during the twelve months following completion of the questionnaire from the health insurance to the study centre. Sensitivity, specificity and positive and negative predictive values (PPV and NPV) for long-term sick leave were calculated. In order to analyze the association between the Nurse-WIS and sick leave during follow-up, a multiple ordinal logistic model (proportional odds model) was applied. RESULTS: A total of 1592 nurses took part in the study (response 35.6%). No loss of follow-up occurred. The number of nurses with a high score (20-28 points) in the Nurse-WIS was 628 (39.4%), and 639 (40.1%) had taken sick leave due to musculoskeletal diseases or psychological impairment during the follow-up period. The odds ratio for sick leave in nurses with a high Nurse-WIS score was 3.42 (95%CI 2.54-4.60). Sensitivity for long-term sick leave (< 42 days) was 64.1%, specificity 63.4%, PPV 17.0% and NPP 93.8%. CONCLUSION: The German version of the Nurse-WIS predicts long-term sick leave, but the PPV is rather low. Combining questionnaire data with secondary data from a health insurer was feasible. Therefore further studies employing this combination of data are advisable.

Adaptive servo-ventilation to treat central sleep apnea in heart failure with reduced ejection fraction: the Bad Oeynhausen prospective ASV registry.

BACKGROUND: Central sleep apnea (CSA) is highly prevalent in heart failure patients with reduced left ventricular ejection fraction (HF-REF). The Bad Oeynhausen Adaptive Servo-ventilation (ASV) registry (NCT01657188) was designed to investigate whether treatment of CSA with ASV improved survival in HF-REF patients; the effects of ASV on symptoms and cardiopulmonary performance were also investigated. METHODS AND RESULTS: From January 2004 to October 2013, the registry prospectively enrolled HF-REF patients [NYHA class ≥ II, left ventricular ejection fraction (LVEF) ≤ 45%] with moderate to severe predominant CSA [apnea-hypopnea index (AHI) ≥ 15/h]. ASV-treated patients were followed up at 3, 6, 12 and 24 months, including natriuretic peptide concentrations, blood gas analyses, echocardiography, 6-min walk distance (6MWD), and cardiopulmonary exercise (CPX) testing. 550 patients were included [age 67.7 ± 10 years, 90% male, 52% in NYHA class ≥ III, LVEF 29.9 ± 8%, AHI 35.4 ± 13.6/h, and time with nocturnal oxygen saturation < 90% (T < 90%) 58 ± 73 min]; ASV was prescribed to 224 patients. Over a median follow-up of 6.6 years, 109 (48.7%) ASV-treated patients and 191 (58.6%) controls died (adjusted Cox modelling hazard ratio of 0.95, 95% confidence interval 0.68-1.24; p = 0.740); older age, lower LVEF, impaired renal function, low sodium concentration, and nocturnal hypoxemia were significant predictors of mortality. Patient reported NYHA functional class improved in the ASV group, but LVEF, CPX, 6MWD, natriuretic peptides and blood gases remained unchanged. CONCLUSIONS: Long-term ASV treatment of predominant CSA in HF-REF patients included in our registry had no statistically significant effect on survival. ASV improved HF symptoms, but had no significant effects on exercise capacity, LVEF, natriuretic peptide concentrations or blood gases during follow-up as compared to control patients.

Shock efficacy of single and dual coil electrodes-new insights from the NORDIC ICD Trial.

Aims: Dual coil (DC) electrodes are preferred to single coil (SC) electrodes because of an assumed higher shock efficacy. However, DC-electrodes may be associated with an increased difficulty and risk of lead extraction. We aimed to compare SC- and DC-electrodes with respect to the first shock efficacy (FSE) after implantable cardioverter defibrillator (ICD) implantation. Methods and results: One thousand and seventy-seven patients of the NORDIC ICD trial were randomly assigned to first time ICD implantation with or without defibrillation (DF) testing. The electrode configuration was determined before randomization. One thousand and sixty-seven patients eventually received an ICD, 516 (48.4%) with a SC- and 551 (51.6%) with a DC-electrode. DC-electrodes were preferentially selected in older patients, renal failure, atrial fibrillation, dual chamber, Cardiac Resynchronization Therapy (CRT) devices, angiotensin-converting-enzyme (ACE) inhibitors/angiotensin (AT) receptor blockers and without Sotalol. However, the preference of the investigational site was dominant over clinical parameters. The DF energy at the final electrode position was higher in SC-electrodes (adjusted difference +1.15 J; P = 0.005; only patients tested). Less patients with DC-electrodes required intra-operative system reconfiguration (adjusted difference -3.9; P = 0.046; only patients tested). Using mixed logistic regression, the FSE was 92.6% in SC- and 97.8% in DC-electrodes (adjusted odds ratio 4.3 (95% confidence interval [1.9, 9.8]; P < 0.001)). Conclusion: Dual coil-electrode selection mainly depends on the preference of the investigational site and seems to be preferred in older patients, renal failure, atrial fibrillation, dual chamber, and CRT devices. Patients with DC-electrodes required less intraoperative system reconfigurations. Dual coil-electrodes provided a substantially higher FSE during follow-up. Mortality rates were not significantly different in patients with DC- and SC-electrodes.

Voxel based analysis of recurrence dynamics in intracranial aneurysms after coiling.

BACKGROUND: Understanding aneurysm growth is critical for the appropriate follow-up of patients after coil embolization and the need for retreatment. The purpose of the study was to stratify the growth dynamics of aneurysm recurrences after coiling by volumetric analysis and to determine predictive factors for aneurysm recurrences. METHODS: Source images of follow-up three-dimensional time of flight MR angiography (ToF-MRA) scans were compared with the first post-interventional ToF-MRA scan and analyzed for residual flow after co-registration using ANALYZE-software. In the event of incomplete occlusion, the residual volume was segmented and calculated. Growth dynamic was determined for each aneurysm after embolization. RESULTS: We analyzed 326 patients with 345 aneurysms from two centers. Each case had at least two ToF-MRA examinations after endovascular therapy. The mean observation interval was 59 months. Volumetric analysis of 1139 follow-up MRAs revealed that 218/345 aneurysms (63.2%) showed complete occlusion on initial follow-up imaging, and of these 95.0% remained stable. A steady increase in intra-aneurysmal flow was observed in 83/345 (24.1%). Less frequent observations were a steep increase (21/345; 6.1%) and a decrease (27/345; 7.8%). Independent predictors of increasing residual flow were greatest aneurysm diameter, total coil length, and incomplete occlusion. CONCLUSIONS: Volumetric analysis of registered three-dimensional ToF-MRA follow-up datasets allows the detection of different growth patterns with high precision, avoids the low inter-rater reliability, and represents a promising approach for future studies that include analysis of more complex predictors of residual flow. In cases of aneurysm recurrence after coiling, the major pattern seems to be a steady increase in intra-aneurysmal flow over several months.

DECADE-pilot: decision aid, action planning, and follow-up support for patients to reduce the 10-year risk of cardiovascular diseases-a protocol of a randomized controlled pilot trial.

BACKGROUND: A healthy lifestyle can reduce cardiovascular risk (CVR) and prevent premature death. Usually most patients at increased CVR have difficulties implementing the necessary health behavior changes, such as smoking cessation, increasing of physical activity, healthy diet, stress reduction, etc. In this pilot study, a new intervention (DECADE) that includes a cardiovascular risk calculation, evidence-based decision aids, action planning, and follow-up support for patients to reduce their 10-year risk of cardiovascular diseases will be tested in primary care. The objectives of this trial are to test (1) the feasibility of the study design in preparation for the main trail including (2) the usability and acceptance of DECADE, and (3) initial data to ascertain that changes can be observed in these patients. METHODS: This randomized controlled pilot trial will generate initial data on the potential effects of DECADE on patients' self-evaluated activity and behavior change as well as on clinical outcomes such as blood pressure, cholesterol, body mass index (BMI), HbA1C, and CVR score. In the qualitative part of the study, we will analyze data collected in semi-structured interviews with participating general practitioners (GP) and in patient questionnaires. DISCUSSION: The outcomes of this pilot study will indicate whether DECADE is a promising intervention in the domain of patient-centered prevention of cardiovascular diseases (CVD) and whether a larger multi-center randomized controlled trial is feasible. TRIAL REGISTRATION: German Clinical Trials Register (DRKS), DRKS00010584.

Improving the Prognostic Ability through Better Use of Standard Clinical Data - The Nottingham Prognostic Index as an Example.

BACKGROUND: Prognostic factors and prognostic models play a key role in medical research and patient management. The Nottingham Prognostic Index (NPI) is a well-established prognostic classification scheme for patients with breast cancer. In a very simple way, it combines the information from tumor size, lymph node stage and tumor grade. For the resulting index cutpoints are proposed to classify it into three to six groups with different prognosis. As not all prognostic information from the three and other standard factors is used, we will consider improvement of the prognostic ability using suitable analysis approaches. METHODS AND FINDINGS: Reanalyzing overall survival data of 1560 patients from a clinical database by using multivariable fractional polynomials and further modern statistical methods we illustrate suitable multivariable modelling and methods to derive and assess the prognostic ability of an index. Using a REMARK type profile we summarize relevant steps of the analysis. Adding the information from hormonal receptor status and using the full information from the three NPI components, specifically concerning the number of positive lymph nodes, an extended NPI with improved prognostic ability is derived. CONCLUSIONS: The prognostic ability of even one of the best established prognostic index in medicine can be improved by using suitable statistical methodology to extract the full information from standard clinical data. This extended version of the NPI can serve as a benchmark to assess the added value of new information, ranging from a new single clinical marker to a derived index from omics data. An established benchmark would also help to harmonize the statistical analyses of such studies and protect against the propagation of many false promises concerning the prognostic value of new measurements. Statistical methods used are generally available and can be used for similar analyses in other diseases.

Enhanced Effective Connectivity Between Primary Motor Cortex and Intraparietal Sulcus in Well-Recovered Stroke Patients.

BACKGROUND AND PURPOSE: Ischemic strokes with motor deficits lead to widespread changes in neural activity and interregional coupling between primary and secondary motor areas. Compared with frontal circuits, the knowledge is still limited to what extent parietal cortices and their interactions with frontal motor areas undergo plastic changes and might contribute to residual motor functioning after stroke. METHODS: Fifteen well-recovered patients were evaluated 3 months after stroke by means of functional magnetic resonance imaging while performing visually guided hand grips with their paretic hand. Dynamic causal modeling was used to investigate task-related effective connectivity between ipsilesional posterior parietal regions along the intraparietal sulcus and frontal key motor areas, such as the primary motor cortex, the ventral premotor cortex, and the supplementary motor area. RESULTS: Compared with healthy controls of similar age and sex, we observed significantly enhanced reciprocal facilitatory connectivity between the primary motor cortex and the anterior intraparietal sulcus of the ipsilesional hemisphere. Beyond that and as a fingerprint of excellent recovery, the coupling pattern of the parietofrontal network was near-normal. An association between coupling parameters and clinical scores was not detected. CONCLUSIONS: The present analysis further adds to the understanding of the parietofrontal network of the ipsilesional hemisphere as a prominent circuit involved in plastic changes after stroke.

Nocturnal hypoxaemia is associated with increased mortality in stable heart failure patients.

AIM: This study investigated the prognostic value of sleep-disordered breathing (SDB) in a large cohort of patients with heart failure with reduced left ventricular function (HF-REF), with focus on the role of nocturnal hypoxaemia. METHODS: This single-centre prospective cohort study enrolled patients with chronic stable HF-REF (NYHA ≥II) receiving guideline-based treatment. Unattended in-hospital polygraphy was performed to determine the apnoea-hypopnoea index (AHI). Pulse oximetry was used to determine hypoxaemic burden [time with oxygen saturation <90% (T90)], and all-cause mortality was recorded. RESULTS: Complete data were available for 963 of 1249 patients. At baseline, 58% of patients had moderate-to-severe SDB. The median follow-up was 7.35 years; 480 of 963 (49.8%) patients died. Mortality rate (per 100 person-years) was 8.1 [95% confidence interval (CI) 7.0-9.4] in patients with no or mild SDB, but 12.2 (95% CI 10.9-13.7) in moderate-to-severe SDB. Apnoea-hypopnoea index was significantly associated with time to death from any cause in a simple Cox model [hazard ratio (HR) 1.011, P < 0.001], but was no longer significant after adjustment for confounding factors (HR 1.005, P = 0.085). T90 was significantly (P < 0.001) associated with time to death from any cause even after adjustment for confounding factors. The risk of death increased by 16.1% (95% CI 8.6-24.2) per hour of T90. Five-year survival probabilities for patients in T90 quartiles 1, 2, 3, and 4 were 70, 63, 60, and 50%, respectively. CONCLUSION: Hypoxaemic burden was a robust and independent predictor of all-cause mortality in chronic stable HF-REF patients. Whether or not targeting nocturnal hypoxaemia is associated with beneficial effects on mortality in HF-REF patients remains to be determined.

On stability issues in deriving multivariable regression models.

In many areas of science where empirical data are analyzed, a task is often to identify important variables with influence on an outcome. Most often this is done by using a variable selection strategy in the context of a multivariable regression model. Using a study on ozone effects in children (n = 496, 24 covariates), we will discuss aspects relevant for deriving a suitable model. With an emphasis on model stability, we will explore and illustrate differences between predictive models and explanatory models, the key role of stopping criteria, and the value of bootstrap resampling (with and without replacement). Bootstrap resampling will be used to assess variable selection stability, to derive a predictor that incorporates model uncertainty, check for influential points, and visualize the variable selection process. For the latter two tasks we adapt and extend recent approaches, such as stability paths, to serve our purposes. Based on earlier experiences and on results from the example, we will argue for simpler models and that predictions are usually very similar, irrespective of the selection method used. Important differences exist for the corresponding variances, and the model uncertainty concept helps to protect against serious underestimation of the variance of a predictor-derived data dependently. Results of stability investigations illustrate severe difficulties in the task of deriving a suitable explanatory model. It seems possible to identify a small number of variables with an important and probably true influence on the outcome, but too often several variables are included whose selection may be a result of chance or may depend on a small number of observations.

Treatment of primary breast cancer at the surgical unit of the Charité 1984-1998.

BACKGROUND: We have analyzed the patient population of one clinic (Charité) over a period of 15 years. Besides the changes in the technical facilities and therapeutical guidelines during these years, this period also reflects the changes in the health system attributable to the reunification of East and West Germany. Until now only few analyses for breast cancer patients from the German speaking area have been reported. PATIENTS AND METHODS: All 2,062 patients undergoing surgical treatment for breast cancer between 1984 and 1998 were documented and followed up until 2007. The analysis included 1,560 patients with a primary breast cancer who fulfilled certain inclusion criteria. The treatment strategies applied to this population are presented in 3 time periods (1984-1990, 1991-1993, and 1994-1998). The effects of prognostic factors on overall survival were investigated using univariate analyses. RESULTS: The percentage of pT1 tumors changed from 50.7% in the first period to 63.1% in the third period. The percentage of node-negative patients hardly changed with time (on average 61.6%). However, the percentage of patients with less than 10 assessed nodes decreased from 48.4% to 6.7% and 2.5% for the 3 periods, respectively. Therapeutic strategies changed drastically. Survival rate increased substantially, most likely due to improved therapeutic strategies, but also for other reasons not considered in the analysis.

Shared decision-making in antihypertensive therapy: a cluster randomised controlled trial.

BACKGROUND: Hypertension is one of the key factors causing cardiovascular diseases. A substantial proportion of treated hypertensive patients do not reach recommended target blood pressure values. Shared decision making (SDM) is to enhance the active role of patients. As until now there exists little information on the effects of SDM training in antihypertensive therapy, we tested the effect of an SDM training programme for general practitioners (GPs). Our hypotheses are that this SDM training (1) enhances the participation of patients and (2) leads to an enhanced decrease in blood pressure (BP) values, compared to patients receiving usual care without prior SDM training for GPs. METHODS: The study was conducted as a cluster randomised controlled trial (cRCT) with GP practices in Southwest Germany. Each GP practice included patients with treated but uncontrolled hypertension and/or with relevant comorbidity. After baseline assessment (T0) GP practices were randomly allocated into an intervention and a control arm. GPs of the intervention group took part in the SDM training. GPs of the control group treated their patients as usual. The intervention was blinded to the patients. Primary endpoints on patient level were (1) change of patients' perceived participation (SDM-Q-9) and (2) change of systolic BP (24h-mean). Secondary endpoints were changes of (1) diastolic BP (24h-mean), (2) patients' knowledge about hypertension, (3) adherence (MARS-D), and (4) cardiovascular risk score (CVR). RESULTS: In total 1357 patients from 36 general practices were screened for blood pressure control by ambulatory blood pressure monitoring (ABPM). Thereof 1120 patients remained in the study because of uncontrolled (but treated) hypertension and/or a relevant comorbidity. At T0 the intervention group involved 17 GP practices with 552 patients and the control group 19 GP practices with 568 patients. The effectiveness analysis could not demonstrate a significant or relevant effect of the SDM training on any of the endpoints. CONCLUSION: The study hypothesis that the SDM training enhanced patients' perceived participation and lowered their BP could not be confirmed. Further research is needed to examine the impact of patient participation on the treatment of hypertension in primary care. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00000125.

Implementation of shared decision making by physician training to optimise hypertension treatment. Study protocol of a cluster-RCT.

BACKGROUND: Hypertension is one of the key factors causing cardiovascular diseases which make up the most frequent cause of death in industrialised nations. However about 60% of hypertensive patients in Germany treated with antihypertensives do not reach the recommended target blood pressure. The involvement of patients in medical decision making fulfils not only an ethical imperative but, furthermore, has the potential of higher treatment success. One concept to enhance the active role of patients is shared decision making. Until now there exists little information on the effects of shared decision making trainings for general practitioners on patient participation and on lowering blood pressure in hypertensive patients. METHODS/DESIGN: In a cluster-randomised controlled trial 1800 patients receiving antihypertensives will be screened with 24 h ambulatory blood pressure monitoring in their general practitioners' practices. Only patients who have not reached their blood pressure target (approximately 1200) will remain in the study (T1 - T3). General practitioners of the intervention group will take part in a shared decision making-training after baseline assessment (T0). General practitioners of the control group will treat their patients as usual. Primary endpoints are change of systolic blood pressure and change of patients' perceived participation. Secondary endpoints are changes of diastolic blood pressure, knowledge, medical adherence and cardiovascular risk. Data analysis will be performed with mixed effects models. DISCUSSION: The hypothesis underlying this study is that shared decision making, realised by a shared decision making training for general practitioners, activates patients, facilitates patients' empowerment and contributes to a better hypertension control. This study is the first one that tests this hypothesis with a (cluster-) randomised trial and a large sample size.

Comparison of procedures to assess non-linear and time-varying effects in multivariable models for survival data.

The focus of many medical applications is to model the impact of several factors on time to an event. A standard approach for such analyses is the Cox proportional hazards model. It assumes that the factors act linearly on the log hazard function (linearity assumption) and that their effects are constant over time (proportional hazards (PH) assumption). Variable selection is often required to specify a more parsimonious model aiming to include only variables with an influence on the outcome. As follow-up increases the effect of a variable often gets weaker, which means that it varies in time. However, spurious time-varying effects may also be introduced by mismodelling other parts of the multivariable model, such as omission of an important covariate or an incorrect functional form of a continuous covariate. These issues interact. To check whether the effect of a variable varies in time several tests for non-PH have been proposed. However, they are not sufficient to derive a model, as appropriate modelling of the shape of time-varying effects is required. In three examples we will compare five recently published strategies to assess whether and how the effects of covariates from a multivariable model vary in time. For practical use we will give some recommendations.