Noninvasive Diagnosis of Acute Rejection in Renal Transplant Patients Using Mass Spectrometric Analysis of Urine Samples: A Multicenter Diagnostic Phase III Trial.

Timely recognition and treatment of acute kidney graft rejection is important to prevent premature graft failure. A predefined urinary marker set for acute T cell-mediated rejection (TCMR) containing 14 peptides was tested for this purpose in a multicenter in-place validation study. Methods: Three hundred twenty-nine prospectively collected and 306 archived urine samples from 11 transplant centers in Germany, France, and Belgium were examined. Samples were taken immediately before a biopsy, performed for graft dysfunction within the first transplant year. Primary outcomes were sensitivity and specificity of the marker set for the diagnosis of biopsy-proven acute TCMR, with prespecified thresholds of 83% for sensitivity and 70% for specificity. Results: Eighty-two patients (13%) had acute TCMR grade I-III. In relation to the biopsy diagnosis of TCMR, the sensitivity of the urine test was 0.66 (95% confidence interval, 0.56-0.76) and the specificity 0.47 (95% confidence interval, 0.43-0.51), with an area under the curve (AUC) of 0.60. The different TCMR grades I-III were not reflected by the marker set, and borderline TCMR was not specifically detected. Secondary independent masked assessment of biopsies consented by 2 pathologists revealed an interobserver kappa value of 0.49 for diagnosing TCMR, compared with the local center's diagnosis. Using this consensus diagnosis, the AUC of the urine test was 0.63 (sensitivity 0.73, specificity 0.45). Post hoc optimization of the marker set improved the diagnostic performance in the study cohort (AUC 0.67) and in an independent patient cohort (AUC 0.69). Conclusions: This study illustrates the difficulty of proteomics-based diagnosis of TCMR and highlights the need for rigorous independent in-place validation and optimization of diagnostic biomarkers.

Randomized Comparison of Pazopanib and Doxorubicin as First-Line Treatment in Patients With Metastatic Soft Tissue Sarcoma Age 60 Years or Older: Results of a German Intergroup Study.

PURPOSE: Doxorubicin is a standard of care in patients with advanced, inoperable soft tissue sarcoma (STS). We tested whether pazopanib has efficacy comparable to that of doxorubicin in elderly patients with STS and offers superior tolerability for hematologic toxicity. PATIENTS AND METHODS: Patients age 60 years or older without previous systemic treatment for progressive advanced or metastatic STS who had Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate organ function were included. Treatment consisted of pazopanib 800 mg once per day or doxorubicin 75 mg/m2 once every 3 weeks (≤ 6 cycles) after being randomly assigned in a 2:1 ratio. Noninferiority was assumed for progression-free survival (PFS), if the upper limit of the 95% CI for the hazard ratio (HR) was less than 1.8. Neutropenia and febrile neutropenia were key secondary end points. The European Organisation for Research and Treatment of Cancer (30-item) Quality of Life Questionnaire and geriatric assessment were used to measure patient-reported outcomes. Cox regression analysis and Kaplan-Meier curves were used for analysis. RESULTS: Pazopanib and doxorubicin were given to 81 and 39 patients, respectively. The median age was 71 years (range, 60-88 years). PFS was noninferior (HR, 1.00; 95% CI, 0.65 to 1.53) and the incidence of grade 4 neutropenia and febrile neutropenia favored pazopanib. Objective response rates for pazopanib and doxorubicin were 12.3% and 15.4%, respectively. Overall survival did not differ significantly between arms (HR, 1.08; 95% CI, 0.68 to 1.72; P = .735). Geriatric assessment revealed 2 or more comorbidities in 15.8% of the patients and impairment of activities of daily living in 28.3% of patients. CONCLUSION: Pazopanib was noninferior to doxorubicin, rendering pazopanib a putative therapeutic option in the first-line treatment of STS in patients age 60 years or older. The distinct adverse event profile may be used to counsel patients and tailor therapy to individual needs.

Comparison of MRI and VQ-SPECT as a Screening Test for Patients With Suspected CTEPH: CHANGE-MRI Study Design and Rationale.

The diagnostic strategy for chronic thromboembolic pulmonary hypertension (CTEPH) is composed of two components required for a diagnosis of CTEPH: the presence of chronic pulmonary embolism and an elevated pulmonary artery pressure. The current guidelines require that ventilation-perfusion single-photon emission computed tomography (VQ-SPECT) is used for the first step diagnosis of chronic pulmonary embolism. However, VQ-SPECT exposes patients to ionizing radiation in a radiation sensitive population. The prospective, multicenter, comparative phase III diagnostic trial CTEPH diagnosis Europe - MRI (CHANGE-MRI, ClinicalTrials.gov identifier NCT02791282) aims to demonstrate whether functional lung MRI can serve as an equal rights alternative to VQ-SPECT in a diagnostic strategy for patients with suspected CTEPH. Positive findings are verified with catheter pulmonary angiography or computed tomography pulmonary angiography (gold standard). For comparing the imaging methods, a co-primary endpoint is used. (i) the proportion of patients with positive MRI in the group of patients who have a positive SPECT and gold standard diagnosis for chronic pulmonary embolism and (ii) the proportion of patients with positive MRI in the group of patients with negative SPECT and gold standard. The CHANGE-MRI trial will also investigate the performance of functional lung MRI without i.v. contrast agent as an index test and identify cardiac, hemodynamic, and pulmonary MRI-derived parameters to estimate pulmonary artery pressures and predict 6-12 month survival. Ultimately, this study will provide the necessary evidence for the discussion about changes in the recommendations on the diagnostic approach to CTEPH.

Short term results of dynamic splinting for hallux valgus - A prospective randomized study.

Background Hallux valgus is a common diagnosis in orthopedics. Only a few studies have analyzed the effects of conservative therapy. Therefore, the current study analyzed the effect of a dynamic hallux valgus splint. Methods Seventy patients were included in this prospective randomized trial. Patients with a hallux valgus were treated using a dynamic splint or underwent no treatment. Clinical and radiological parameters were evaluated. Results We found no significant changes in hallux valgus angle, intermetatarsal I-II angle, AOFAS score, FAOS or SF-36 score between the groups. However, a significant between-group difference was found for pain during walking and running and in the FAOS subscale for pain and pain at rest at follow-up. Conclusions Wearing a dynamic hallux valgus splint does provide some pain relief in patients with a symptomatic hallux valgus, but showed no effect on hallux valgus position. Level of evidence: 1.

Keratinized mucosa width is associated with severity of peri-implant mucositis. A cross-sectional study.

OBJECTIVES: This is a cross-sectional study designed with the aim to assess associations between the width of keratinized tissue and peri-implant mucositis. MATERIALS AND METHODS: Two hundred and thirty one dental implants in 52 patients were evaluated. The width of keratinized mucosa (KM), plaque index (mPI), gingival index (mGI), bleeding on probing index (BoP), and the probing depth (PD) were measured clinically. Reduced KM was defined as a width of KM below 2 mm and 1 mm, respectively. In the primary analysis, data were analyzed on the implant level with the help of a generalized estimating equations (GEE) model. In sensitivity analyses, an adjusted linear mixed model was performed. RESULTS: Forty four implants in 12 patients had less than 2 mm KM, and 187 implants in 40 patients had ≥ 2 mm KM. In the non-adjusted analysis on the implant level, reduced keratinized tissue width was significantly associated with peri-implant mucositis (OR 3.3, 95%-CI (1.3-8.0), p = 0.009) and severity of disease (mean difference 2.5, 95%-CI (0.8-4.2) p = 0.004). In sensitivity analyses, reduced keratinized tissue showed a significant association with severity of disease (OR 1.7, 95%-confidence interval = 0.1-34, p = 0.040). CONCLUSION: A reduced width of keratinized tissue around dental implants is a risk indicator for severity of peri-implant mucositis. The overall tendency of the results indicates that a sufficient amount of KM may contribute to reduce risk for and severity of peri-implant mucositis.

Complications of CT-guided lung biopsy with a non-coaxial semi-automated 18 gauge biopsy system: Frequency, severity and risk factors.

OBJECTIVES: To evaluate frequency and severity of complications after CT-guided lung biopsy using the Society of Interventional Radiology (SIR) classification, and to assess risk factors for overall and major complications. MATERIALS AND METHODS: 311 consecutive biopsies with a non-coaxial semi-automated 18 gauge biopsy system were retrospectively evaluated. Complications after biopsy were classified into minor SIR1-2 and major SIR3-6. Studied risk factors for complications were patient-related (age, sex and underlying emphysema), lesion-related (size, location, morphologic characteristic, depth from the pleura and histopathology), and technique-related (patient position during procedure, thoracic wall thickness at needle path, procedure time length and number of procedural CT images, number of pleural passes, fissure penetration and needle-to-blood vessel angle). Data were analyzed using logistic and ordinal regression. RESULTS: Complications were pneumothorax and pulmonary hemorrhage. The complications were minor SIR1-2 in 142 patients (45.6%), and major SIR3-4 in 25 patients (8%). SIR5-6 complications were not present. Emphysema, smaller deeply located lesion, increased puncture time length and number of procedural CT images, multiple pleural passes and fissure puncture were significant risk factors for complication severity in univariate analysis. Emphysema (OR = 8.8, p<0.001), lesion depth from the pleura (OR = 1.9 per cm, p<0.001), and fissure puncture (OR = 9.4, p = 0.01) were the independent factors for major complications in a multiple logistic regression model. No statistical difference of complication rates between the radiologists performing biopsies was observed. CONCLUSIONS: Knowledge about risk factors influencing complication severity is important for planning and performing CT-guided lung biopsies.

Risk factors for death in kidney transplant patients: analysis from a large protocol biopsy registry.

BACKGROUND: Identification and quantification of the relevant factors for death can improve patients' individual risk assessment and decision-making. We used a well-documented patient cohort (n = 892) in a renal transplant programme with protocol biopsies to establish multivariable Cox models for risk assessment at 3 and 12 months post-transplantation. METHODS: Patients transplanted between 2000 and 2007 were observed up to 11 years (total observation 5227 patient-years; median 5.9 years). Loss to follow-up was negligible (n = 15). A total of 2251 protocol biopsies and 1214 biopsies for cause were performed. All rejections and clinical borderline rejections in protocol biopsies were treated. RESULTS: Overall 10-year patient survival was 78%, with inferior survival of patients with graft loss and superior survival of patients with living-donor transplantation. Eight factors were common in the models at 3 and 12 months, including age, pre-transplant heart failure and a score of cardiovascular disease and type 2 diabetes, post-transplant urinary tract infection, treatment of rejection, new-onset heart failure, coronary events and malignancies. Additional variables of the model at 3 months included deceased donor transplantation, transplant lymphocele, BK virus nephropathy and severe infections. Graft function and graft loss were significant factors of the model at 12 months. Internal validation and validation with a separate cohort of patients (n = 349) demonstrated good discrimination of the models. CONCLUSIONS: The identified factors indicate the important areas that need special attention in the pre- and post-transplant care of renal transplant patients. On the basis of these models, we provide nomograms as a tool to weigh individual risks that may contribute to decreased survival.

Left ventricular volume and wall stress are linked to lung function impairment in COPD.

BACKGROUND: Cardiovascular comorbidities are common in chronic obstructive pulmonary disease (COPD). We examined the association between airflow limitation, hyperinflation and the left ventricle (LV). METHODS: Patients from the COPD cohort COSYCONET underwent evaluations including forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), effective airway resistance (Reff), intrathoracic gas volume (ITGV), and echocardiographic LV end-diastolic volume (LVEDV), stroke volume (LVSV), end-systolic volume (LVESV), and end-diastolic and end-systolic LV wall stress. Data from Visit 1 (baseline) and Visit 3 (18 months later) were used. In addition to comparisons of both visits, multivariate regression analysis was conducted, followed by structural equation modelling (SEM) with latent variables "Lung" and "Left heart". RESULTS: A total of 641 participants were included in this analysis. From Visit 1 to Visit 3, there were significant declines in FEV1 and FEV1/FVC, and increases in Reff, ITGV and LV end-diastolic wall stress, and a borderline significant decrease in LV mass. There were significant correlations of: FEV1% predicted with LVEDV and LVSV; Reff with LVSV; and ITGV with LV mass and LV end-diastolic wall stress. The SEM fitted the data of both visits well (comparative fit index: 0.978, 0.962), with strong correlation between "Lung" and "Left heart". CONCLUSIONS: We demonstrated a relationship between lung function impairment and LV wall stress in patients with COPD. This supports the hypothesis that LV impairment in COPD could be initiated or promoted, at least partly, by mechanical factors exerted by the lung disorder.

The contribution of symptoms and comorbidities to the economic impact of COPD: an analysis of the German COSYCONET cohort.

Background: Although patients with COPD often have various comorbidities and symptoms, limited data are available on the contribution of these aspects to health care costs. This study analyzes the association of frequent comorbidities and common symptoms with the annual direct and indirect costs of patients with COPD. Methods: Self-reported information on 33 potential comorbidities and symptoms (dyspnea, cough, and sputum) of 2,139 participants from the baseline examination of the German COPD cohort COSYCONET was used. Direct and indirect costs were calculated based on self-reported health care utilization, work absence, and retirement. The association of comorbidities, symptoms, and COPD stage with annual direct/indirect costs was assessed by generalized linear regression models. Additional models analyzed possible interactions between COPD stage, the number of comorbidities, and dyspnea. Results: Unadjusted mean annual direct costs were €7,263 per patient. Other than COPD stage, a high level of dyspnea showed the strongest driving effect on direct costs (+33%). Among the comorbidities, osteoporosis (+38%), psychiatric disorders (+36%), heart disease (+25%), cancer (+24%), and sleep apnea (+21%) were associated with the largest increase in direct costs (p<0.01). A sub-additive interaction between advanced COPD stage and a high number of comorbidities reduced the independent cost-driving effects of these factors. For indirect costs, besides dyspnea (+34%), only psychiatric disorders (+32%) and age (+62% per 10 years) were identified as significant drivers of costs (p<0.04). In the subsequent interaction analysis, a high number of comorbidities was found to be a more crucial factor for increased indirect costs than single comorbidities. Conclusion: Detailed knowledge about comorbidities in COPD is useful not only for clinical purposes but also to identify relevant cost factors and their interactions and to establish a ranking of major cost drivers. This could help in focusing therapeutic efforts on both clinically and economically important comorbidities in COPD.

Redefining Cut-Points for High Symptom Burden of the Global Initiative for Chronic Obstructive Lung Disease Classification in 18,577 Patients With Chronic Obstructive Pulmonary Disease.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) can be classified into groups A/C or B/D based on symptom intensity. Different threshold values for symptom questionnaires can result in misclassification and, in turn, different treatment recommendations. The primary aim was to find the best fitting cut-points for Global initiative for chronic Obstructive Lung Disease (GOLD) symptom measures, with an modified Medical Research Council dyspnea grade of 2 or higher as point of reference. METHODS: After a computerized search, data from 41 cohorts and whose authors agreed to provide data were pooled. COPD studies were eligible for analyses if they included, at least age, sex, postbronchodilator spirometry, modified Medical Research Council, and COPD Assessment Test (CAT) total scores. MAIN OUTCOMES: Receiver operating characteristic curves and the Youden index were used to determine the best calibration threshold for CAT, COPD Clinical Questionnaire, and St. Georges Respiratory Questionnaire total scores. Following, GOLD A/B/C/D frequencies were calculated based on current cut-points and the newly derived cut-points. FINDINGS: A total of 18,577 patients with COPD [72.0% male; mean age: 66.3 years (standard deviation 9.6)] were analyzed. Most patients had a moderate or severe degree of airflow limitation (GOLD spirometric grade 1, 10.9%; grade 2, 46.6%; grade 3, 32.4%; and grade 4, 10.3%). The best calibration threshold for CAT total score was 18 points, for COPD Clinical Questionnaire total score 1.9 points, and for St. Georges Respiratory Questionnaire total score 46.0 points. CONCLUSIONS: The application of these new cut-points would reclassify about one-third of the patients with COPD and, thus, would impact on individual disease management. Further validation in prospective studies of these new values are needed.

Cardiovascular risk in patients with alpha-1-antitrypsin deficiency.

BACKGROUND: Alpha-1-antitrypsin deficiency (AATD) is a rare inherited condition caused by mutations of the SERPINA1 gene that is associated with the development of a COPD like lung disease. The comorbidities in patients with AATD-related lung diseases are not well defined. The aim of this study was to analyze the clinical phenotype of AATD patients within the German COPD cohort study COSYCONET ("COPD and SYstemic consequences-COmorbidities NETwork") cohort focusing on the distribution of comorbidities. METHOD AND RESULTS: The data from 2645 COSYCONET patients, including 139 AATD patients (110 with and 29 without augmentation therapy), were analyzed by descriptive statistics and regression analyses. We found significantly lower prevalence of cardiovascular comorbidities in AATD patients as compared to non-AATD COPD patients. After correction for age, pack years, body mass index, and sex, the differences were still significant for coronary artery disease (p = 0.002) and the prevalence of peripheral artery disease as determined by an ankle-brachial-index <= 0.9 (p = 0.035). Also the distribution of other comorbidities such as bronchiectasis differed between AATD and non-deficient COPD. CONCLUSION: AATD is associated with a lower prevalence of cardiovascular disease, the underlying mechanisms need further investigation.

Combatting pain after orthopedic/trauma surgery- perioperative oral extended-release tapentadol vs. extended-release oxycodone/naloxone.

BACKGROUND: High post-operative pain scores after "minor" orthopedic/trauma surgery are in part attributed to inadequate prescription of opioid analgesics. Novel concepts aiming to achieve sufficient analgesia while minimizing opioid-related side effects by avoiding fluctuating plasma levels are based on perioperative oral administration of extended-release opioids beginning with the first dose pre-operatively. This is the first study to evaluate analgesic efficacy and side effect rates of extended-release tapentadol compared to oxycodone/naloxone following orthopedic/trauma surgery. METHODS: This randomized, observer-blinded, active-controlled prospective clinical trial had 2 co-primary endpoints: (1) Analgesic efficacy: Mean pain level on a numeric rating scale (NRS) from 0 to 10 during exercise over 5 days. (2) Safety: Side effect sum score of the following events: Nausea, vomiting, constipation, sedation, vertigo, somnolence. The study was powered to detect superiority of tapentadol for at least one endpoint pending statistical proof of non-inferiority for both endpoints in a first step. RESULTS: Two hundred sixty-six trauma patients were randomized to receive either tapentadol (n = 133) or oxycodone/naloxone (n = 133). Analgesic efficacy: Mean (±SD) daily pain levels in the first five post-operative days were 2.8 ± 1.3 in both groups. Mean maximum pain intensity during exercise in the first 24 h after surgery was 3.8 ± 1.9 (tapentadol) and 3.8 ± 2.1 (oxycodone/naloxone). Statistically tapentadol was non-inferior but not superior to oxycodone/naloxone. SAFETY: Vomiting on day 1 occurred in 11%, constipation in 35% of the tapentadol patients and in 16% and 30% of the oxycodone/naloxone patients (p = 0.60 and 0.33), respectively. The incidence of sedation/ vertigo was <10%, that of somnolence <2% in both groups (p > 0.3, respectively). The sum score of side effect events was 51% in the tapentadol vs. 49% in the oxycodone/naloxone group; risk difference 3% [95% CI, -8 to 14%]; p = 0.6). Non-inferiority of tapentadol could not be concluded as the pre-defined non-inferiority margin was exceeded. CONCLUSIONS: With both concepts, mean maximum pain intensity during exercise within the first 24 h after orthopedic/trauma surgery was reduced to a score of <4. This analgesic efficacy came at the cost of mainly gastro-intestinal side effects. Thus, we now use a prophylaxis against nausea and vomiting and pre-emptive laxatives as part of these concepts. TRIAL REGISTRATION: https://eudract.ema.europa.eu (EudraCT- Nr. 2011-003238-15 ); October 24th, 2012.

Costs and health-related quality of life in Alpha-1-Antitrypsin Deficient COPD patients.

BACKGROUND: Alpha-1-Antitrypsin Deficiency (AATD) is an economically unexplored genetic disease. METHODS: Direct and indirect costs (based on self-reported information on healthcare utilization) and health-related quality of life (HRQL, as assessed by SGRQ, CAT, and EQ-5D-3 L) were compared between 131 AATD patients (106 with, 25 without augmentation therapy (AT)) and 2,049 COPD patients without AATD participating in the COSYCONET COPD cohort. The medication costs of AT were excluded from all analyses to reveal differences associated with morbidity profiles. The association of AATD (with/without AT) with costs or HRQL was examined using generalized linear regression modelling (GLM) adjusting for age, sex, GOLD grade, BMI, smoking status, education and comorbidities. RESULTS: Adjusted mean direct annual costs were €6,099 in AATD patients without AT, €7,117 in AATD patients with AT (excluding costs for AT), and €7,460 in COPD patients without AATD. AATD with AT was significantly associated with higher outpatient (+273%) but lower inpatient (-35%) and medication costs (-10%, disregarding AT) compared with COPD patients without AATD. There were no significant differences between groups regarding indirect costs and HRQL. CONCLUSION: Apart from AT costs, AATD patients tended to have lower, though not significant, overall costs and similar HRQL compared to COPD patients without AATD. AT was not associated with lower costs or higher HRQL. TRIAL REGISTRATION: NCT01245933.

Peripheral Artery Disease and Its Clinical Relevance in Patients with Chronic Obstructive Pulmonary Disease in the COPD and Systemic Consequences-Comorbidities Network Study.

RATIONALE: Knowledge about the prevalence of objectively assessed peripheral artery disease (PAD) and its clinical relevance in patients with chronic obstructive pulmonary disease (COPD) is scarce. OBJECTIVES: We aimed to: (1) assess the prevalence of PAD in COPD compared with distinct control groups; and (2) study the association between PAD and functional capacity as well as health status. METHODS: The ankle-brachial index was used to diagnose PAD (ankle-brachial index ≤ 0.9). The 6-minute-walk distance, health status (St. George's Respiratory Questionnaire), COPD Assessment Test, and EuroQol-5-Dimensions were assessed in patients enrolled in the German COPD and Systemic Consequences-Comorbidities Network cohort study. Control groups were derived from the Study of Health in Pomerania. MEASUREMENTS AND MAIN RESULTS: A total of 2,088 patients with COPD (61.1% male; mean [SD] age, 65.3 [8.2] years, GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages I-IV: 9.4, 42.5, 37.5, and 10.5%, respectively) were included, of which 184 patients (8.8%; GOLD stage I-IV: 5.1, 7.4, 11.1, and 9.5%, respectively, vs. 5.9% in patients with GOLD stage 0 in the COPD and Systemic Consequences-Comorbidities Network) had PAD. In the Study of Health in Pomerania, PAD ranged from 1.8 to 4.2%. Patients with COPD with PAD had a significantly shorter 6-minute-walk distance (356 [108] vs. 422 [103] m, P < 0.001) and worse health status (St. George's Respiratory Questionnaire: 49.7 [20.1] vs. 42.7 [20.0] points, P < 0.001; COPD Assessment Test: 19.6 [7.4] vs. 17.9 [7.4] points, P = 0.004; EuroQol-5-Dimensions visual analog scale: 51.2 [19.0] vs. 57.2 [19.6], P < 0.001). Differences remained significant after correction for several confounders. CONCLUSIONS: In a large cohort of patients with COPD, 8.8% were diagnosed with PAD, which is higher than the prevalence in control subjects without COPD. PAD was associated with a clinically relevant reduction in functional capacity and health status.

Short- and long-term effects of the use of RAAS blockers immediately after renal transplantation.

BACKGROUND: The efficacy and safety of renin angiotensin aldosterone system blockers (RAASB's) if introduced immediately after renal transplantation have not been extensively investigated. METHODS: The medical charts of 142 kidney transplant recipients who received a RAASB in the early postoperative period and of 114 matched controls were analyzed. The RAASB was given primarily for blood pressure control. RESULTS: 117 patients continued to receive and 50 controls remained continuously free of the RAASB in the first year. The RAASB was added on average at postoperative day 8 and the mean duration of follow-up was 5.4 years. Systolic, blood pressure at treatment initiation was increased in the RAASB group (150 ± 17 vs. 141 ± 16, p < 0.001). At discharge from hospital and during follow-up blood pressure was similar in both groups, without differences in GFR, potassium and proteinuria. The endpoints "graft failure" and "graft failure or death from any cause" were significantly better in patients treated with RAASB's (p = 0.03 and p = 0.04, respectively). The treatment effects in the RAASB group persisted even after adjustment for demographic parameters, immunological risk factors, peritransplant risk factors, duration of dialysis prior to transplantation and medical comorbidities. CONCLUSIONS: Thus, RAASB's can be used effectively and safely to treat hypertension in the early postoperative period after kidney transplantation and are renoprotective in the long term.

ACEMg-mediated hearing preservation in cochlear implant patients receiving different electrode lengths (PROHEARING): study protocol for a randomized controlled trial.

BACKGROUND: The indications for a cochlear implant (CI) have been extended to include patients with some residual hearing. Shorter and thinner atraumatic electrodes have been designed to preserve the residual hearing in the implanted ear. However, the insertion of the electrode array into the cochlea, with potential mechanical trauma and the presence of this foreign body inside the cochlea, may lead to free radical formation and reduced blood perfusion of the cochlea which can result in the loss of residual hearing. METHODS/DESIGN: In this single-center, randomized, placebo-controlled, double-blind phase II clinical trial the effect of free radical scavengers and a vasodilator on the residual hearing of 140 CI patients will be evaluated. The formulation is composed of ß-carotene (vitamin A), ascorbic acid (vitamin C), dl-α-tocopherol acetate (vitamin E) and the vasodilator magnesium (Mg), or ACEMg. Medication is administered twice daily per os for approximately 3 months. The primary measure is based upon the reduction in postoperative low-frequency air-conducted pure-tone thresholds compared to preoperative thresholds in ACEMg-treated patients compared to those of a placebo group. Additionally, the effect of different electrode lengths (20, 24 and 28 mm) is analyzed. Study visits are scheduled 2 days before surgery, at first fitting, which is the adjustment and start of stimulation via CI 4 weeks after surgery and 3, 6, 9 and 12 months after first fitting. The primary endpoint is the air-conduction hearing loss at 500 Hz 3 months after first fitting. Additionally, speech recognition tests, hearing aid benefit in the implanted ear and electrophysiological measurements of implant function are assessed. Since this is a blinded clinical trial and recruitment is still ongoing, data continue to accrue and we cannot yet analyze the outcome of the ACEMg treatment. DISCUSSION: There is an unfulfilled need for new strategies to preserve acoustic hearing in CI patients. This study will provide first-in-man data on ACEMg-mediated protection of residual hearing in CI patients. Performing all surgeries and patient follow-up at one study site improves consistency in diagnosis and therapy and less variability in surgery, audiological test techniques and fitting. This approach will allow investigation of the influence of ACEMg on residual hearing in CI patients. TRIAL REGISTRATION: The German Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) application number 4039192, was registered on 6 December 2013 with protocol amendment version 3.0 from 19 August 2014. EudraCT number: 2012-005002-22 .

The ONLINE-TICS Study Protocol: A Randomized Observer-Blind Clinical Trial to Demonstrate the Efficacy and Safety of Internet-Delivered Behavioral Treatment for Adults with Chronic Tic Disorders.

BACKGROUND: In recent years, behavioral therapy with comprehensive behavioral intervention for tics (CBIT) has been recognized as an effective and safe treatment in patients with Gilles de la Tourette syndrome. In Germany, however, dissemination of CBIT is restricted due to a considerable lack of well-trained therapists. The aim of this study is to overcome this deficiency by creating a new and sophisticated Internet-delivered CBIT (iCBIT) program. With this study, we want to demonstrate that iCBIT is superior to Internet-delivered psychoeducation and comparable to face-to-face CBIT. METHOD AND ANALYSIS: This is a multicenter, prospective, randomized, controlled, observer-blind clinical trial, which will be conducted at five sites in Germany (ONLINE-TICS). Over the course of 2 years, 160 adult patients with chronic tic disorders will be assigned to one of three treatment arms: iCBIT (n = 72), online psychoeducation (n = 72), or face-to-face CBIT (n = 16). All treatments will consist of eighty therapy sessions over a period of 10 weeks and will follow the well-established CBIT manual by Woods and colleagues. The primary outcome measure will be the change in Yale Global Tic Severity Scale (YGTSS) at 1-week posttreatment. Secondary outcome measures include YGTSS change at 3 and 6 months, video- and self-ratings of tics as well as scales for psychiatric comorbidities assessed at each visit. The primary analysis will compare iCBIT to online psychoeducation using a mixed linear model with the YGTSS change as dependent variable. Secondary analyses will look at the comparison between iCBIT and face-to-face CBIT in a non-inferiority analysis. DISCUSSION: If iCBIT proves to be effective, it would be a considerable contribution to close the wide gap in treatment providers for tic disorders not only in Germany but also in several other countries, since this Internet-delivered therapy does not require the supervision of a therapist. In addition, iCBIT would be a cost-effective and readily available treatment alternative that guarantees high quality standard of CBIT. ETHICS AND DISSEMINATION: All institutional review boards approve the protocol. All participants will provide informed consent. There are no conflicts of interest. After study completion, the results will be published. STUDY REGISTRATION: ClinicalTrials.gov Identifier: NCT02413216.

Relative impact of COPD and comorbidities on generic health-related quality of life: a pooled analysis of the COSYCONET patient cohort and control subjects from the KORA and SHIP studies.

BACKGROUND: Health-related quality of life (HRQL) is an important patient-reported outcome measure used to describe the burden of chronic obstructive pulmonary disease (COPD) which is often accompanied by comorbid conditions. METHODS: Data from 2275 participants in the COPD cohort COSYCONET and from 4505 lung-healthy control subjects from the population-based KORA and SHIP studies were pooled. Main outcomes were the five dimensions of the generic EQ-5D-3 L questionnaire and two EQ-5D index scores using a tariff based on valuations from the general population and an experience-based tariff. The association of COPD in GOLD grades 1-4 and of several comorbid conditions with the EQ-5D index scores was quantified by multiple linear regression models while adjusting for age, sex, education, body mass index (BMI), and smoking status. RESULTS: For all dimensions of the EQ-5D, the proportion of participants reporting problems was higher in the COPD group than in control subjects. COPD was associated with significant reductions in the EQ-5D index scores (-0.05 points for COPD grades 1/2, -0.09 for COPD grade 3, -0.18 for COPD grade 4 according to the preference-based utility tariff, all p < 0.0001). Adjusted mean index scores were 0.89 in control subjects and 0.85, 0.84, 0.81, and 0.72 in COPD grades 1-4 according to the preference-based utility tariff and 0.76, 0.71, 0.68, 0.64, and 0.58 for control subjects and COPD grades 1-4 for the experience-based tariff respectively. Comorbidities had additive negative effects on the index scores; the effect sizes for comorbidities were comparable to or smaller than the effects of COPD grade 3. No statistically significant interactions between COPD and comorbidities were observed. Score differences between COPD patients and control subjects were most pronounced in younger age groups. CONCLUSIONS: Compared with control subjects, the considerable reduction of HRQL in patients with COPD was mainly due to respiratory limitations, but observed comorbidities added linearly to this effect. Younger COPD patients showed a greater loss of HRQL and may therefore be in specific need of comprehensive disease management. TRIAL REGISTRATION: NCT01245933.

A phase II trial comparing pazopanib with doxorubicin as first-line treatment in elderly patients with metastatic or advanced soft tissue sarcoma (EPAZ): study protocol for a randomized controlled trial.

BACKGROUND: Anthracycline-based treatment remains the backbone of chemotherapy for nonresectable soft tissue sarcomas (STS). More than 30 % of patients with STS are aged 60 years or older, limiting the choice of treatment to single-agent approaches for this elderly population. Hematological toxicity is frequent during doxorubicin monotherapy, grade 4 neutropenia is reported in 34 %, with a febrile neutropenia rate of 9 % in STS. We assume that comorbidities in the elderly population may limit tolerability of doxorubicin, and novel agents may improve tolerability and health-related quality of life while maintaining efficacy. We therefore investigated whether the tyrosine kinase inhibitor pazopanib exerts such a clinical benefit in elderly patients with STS (pazopanib for elderly [the EPAZ study]). METHODS/DESIGN: This study is a randomized, controlled, open-label, multicenter, phase II noninferiority trial in which pazopanib 800 mg once daily is being compared six cycles of intravenous doxorubicin 75 mg/m(2) as first-line treatment in elderly patients (≥60 years) with metastatic or advanced STS. A total of 120 patients will be randomized 1:2 to receive doxorubicin or pazopanib, stratified by Eastern Cooperative Oncology Group performance status (0-1 vs. 2) and liposarcoma histology (yes vs. no). The primary endpoint is progression-free survival based on local tumor assessment according to Response Evaluation Criteria in Solid Tumors criteria. Secondary endpoints include grade 4 neutropenia and febrile neutropenia in hierarchical order, as well as overall survival, objective response rate, health-related quality of life, and geriatric assessments. DISCUSSION: Pazopanib is associated with promising tolerability according to previous studies and may offer a significant clinical advantage in first-line treatment of STS compared with doxorubicin. The elderly population seems especially appealing for such an approach, since these patients are not suitable for aggressive combination therapy. The EPAZ study will confirm whether pazopanib may be an alternative to toxic chemotherapy for elderly patients with STS. TRIAL REGISTRATION: ClinicalTrials.gov NCT01861951 ; registered on 11 April 2013. EudraCT 2011-004168-30; registered on 4 June 2012.

Assessing health-related quality of life in COPD: comparing generic and disease-specific instruments with focus on comorbidities.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) influences different aspects of patient's health-related quality of life (HRQL). While disease-specific HRQL instruments focus on symptoms and functional impairments, generic instruments cover a broader view on health. This study compares the generic EQ-5D-3 L and two disease-specific questionnaires (St.-George's Respiratory Questionnaire (SGRQ-C), COPD Assessment Test (CAT)) in a comprehensive spectrum of COPD disease grades with particular attention on comorbidities and assesses the discriminative abilities of these instruments. METHODS: Using data from the baseline visit of the German COPD cohort COSYCONET, mean HRQL scores in different COPD grades were compared by linear regression models adjusting for age, sex, education, smoking status, BMI, and low vs. high number of comorbidities or a list of several self-reported comorbid conditions. Discriminative abilities of HRQL instruments to differentiate between COPD grades were assessed by standardized mean differences. RESULTS: In 2,291 subjects in COPD GOLD grades 1-4 EQ-5D-3 L utility, EQ-5D VAS, SGRQ, and CAT were found able to discriminate between COPD grades, with some limitations for the EQ-5D utility in mild disease. Both generic and disease-specific HRQL instruments reflected the burden of comorbid conditions. The SGRQ showed the best discrimination between COPD grades and was less influenced by comorbidities, while EQ-5D utility put a higher weight on comorbid conditions. For all instruments, psychiatric disorders and peripheral artery disease showed the strongest negative associations with HRQL. CONCLUSION: All HRQL instruments considered reflect considerable impairment of HRQL in COPD patients, worsening with increasing COPD grade and number of comorbidities. Findings may support clinical assessment, choice of HRQL instrument in future studies, and parameterization of decision-analytic models.