Prevalence of Back Pain among German Ophthalmologists.

INTRODUCTION: The aim of this study was to evaluate the prevalence of back pain among German ophthalmologists, to investigate the relationship towards age, gender, various profession-related factors, to correlate localization of pain to subspecialties, and to explore individual therapeutic and coping strategies. METHODS: In this prospective, cross-sectional survey, a 9-item questionnaire was sent via mail to all members of the German professional association of ophthalmologists "Berufsverband der Augenärzte Deutschlands e.V. (BVA)." Responses were analyzed according to a pre-specified analysis plan. RESULTS: From a total of 5,954 members contacted, 1,861 copies (31%) were received back, of which 1,807 (30%) were suitable for analysis. 913 (51%) participants were female and 876 (48%) were male, with a median age of 50 years (interquartile range: 44; 57). 1,464 ophthalmologists (81%) reported current back problems, considerably more than had been reported in the general population or in other medical specialties. Older age, female gender, and higher number of professional years appeared to be risk factors for developing back pain. Overall, neck pain was the leading symptom in 951 attendees (65%) but differed between ophthalmologists who primarily performed conservative treatment (cervical spine) and those who performed surgery (mainly lumbar spine). 1,037 participants (71%) link their complaints to their occupational activity. Exercising and back training were reported as common strategies for prevention and coping with the problem. Recommendations for improvement were mainly ergonomic optimization of the working place. CONCLUSIONS: The prevalence of back pain complaints in German ophthalmologists is high. Neck pain (65%) was the leading localization, followed by low back pain (53%) and shoulder (38%) problems, which might emphasize a special back pain complaint profile in ophthalmologists. Low back pain seems to be more common in ophthalmologists with surgical specialization than in those with mainly medical tasks. The high prevalence of back pain in ophthalmologists should be communicated with employers, the industry, and professional societies to develop and implement a strategy to prevent occupational-related musculoskeletal disorders and preserve the ability to work and the quality of life.

Efficacy and safety of a fixed bimonthly ranibizumab treatment regimen in eyes with neovascular age-related macular degeneration: results from the RABIMO trial.

PURPOSE: To evaluate prospectively the efficacy and safety of a fixed bimonthly ranibizumab treatment regimen (RABIMO) in eyes with neovascular age-related macular degeneration (nAMD) and to compare these results with a pro re nata (PRN) treatment scheme. METHODS: This was a 12-month, phase IV, single center, randomised, non-inferiority study. Following three initial monthly injections, patients were randomised to receive either ranibizumab bimonthly (RABIMO group) or ranibizumab PRN (PRN group) (n = 20 each). Main outcome measures were best-corrected visual acuity (BCVA), central retinal thickness (CRT), number of injections, and adverse events (AEs). RESULTS: BCVA [median (interquartile range, IQR)] increased significantly in both groups after 12 months [RABIMO group +8.5 (14); PRN group +6.5 (16) ETDRS letters] when compared to baseline (p < 0.0001; p = 0.0085). At month 12, the RABIMO treatment regimen was non-inferior to the PRN scheme (∆BCVA = 3.5 ETDRS letters; p < 0.0001). CRT was significantly reduced in both groups after the 12-month study period (p < 0.0001 each), with no significant difference between groups (p = 0.6772). Number of overall injections [median (IQR)] was 8 (0) in the RABIMO versus 4 (5) in the PRN group (p = 0.0037). Three patients in the RABIMO group received one additional unscheduled injection. We observed no significant differences between groups in the number of patients with reported SAEs/AEs (RABIMO group n = 6/15; PRN group n = 7/13) (p = 0.7357/p = 0.4902). CONCLUSIONS: We found no evidence of significant functional or anatomical differences between the RABIMO and PRN treatment regimens. However, the RABIMO group's number of injections was twice as high as the PRN group's (protocol-driven). In light of potential side effects, the fixed bimonthly treatment regimen might not be advisable for routine clinical care, but it might be a worthwhile treatment option if monthly monitoring is not possible. Eudra-CT number: 2009-017324-11.

Do different vaginal tapes need different suburethral incisions? The one-half rule.

AIM: Despite a wide array of vaginal tapes to treat stress urinary incontinence (SUI), evidence suggesting that both patient characteristics and tape positioning influence outcomes, and differing tape insertion pathways (retropubic vs. transobturator), it remains unclear if the same incision location is effective for all tapes. The aim of the study was to compare outcomes using two different surgical incision locations when inserting a transobturator vaginal tape (TOT) to treat SUI. METHODS: We compared patient characteristics, tape positioning, and surgical outcomes in 123 women undergoing a TOT procedure who were randomly assigned to have the surgical incision begin at 1/3 of the sonographically-measured urethral length (similar to the traditional retropubic approach) or 1/2 of the urethral length. RESULTS: It was feasible to place the tape according to intention in 99.2% of the study cohort. The overall cure rate was higher when the incision site began at 1/2 the urethral length (83.6%) than 1/3 (62.9%) (P = 0.01). In the subgroup analyses, only patients with normal urethral mobility had significantly different cure rates (85.7% vs. 55.2%, P = 0.02). No significant differences in cure rates were observed between the other mobility categories of the study groups-hypermobility was consistently associated with high cure rates and hypomobility with low cure rates. CONCLUSIONS: When surgically treating SUI with a TOT, incision at the mid-urethra using the 1/2 rule is recommended as it leads to better outcomes for most patients, particularly those with normal urethral mobility.

Rituximab after lymphoma-directed conditioning and allogeneic stem-cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial.

BACKGROUND: Allogeneic stem-cell transplantation has had limited success for patients with refractory and relapsed aggressive B-cell or T-cell lymphoma. We investigated the effect of adding rituximab to standard prophylaxis for graft-versus-host disease after transplantation and estimated overall survival when using a lymphoma-directed myeloablative conditioning regimen. METHODS: We did this randomised, open-label, phase 2 study at seven German transplantation centres. We enrolled patients with aggressive B-cell or T-cell lymphoma and primary refractory disease, early relapse (<12 months after first-line treatment), or relapse after autologous transplantation. Conditioning with fludarabine (125 mg/m(2)), busulfan (12 mg/kg oral or 9·6 mg/kg intravenous), and cyclophosphamide (120 mg/kg) was followed by allogeneic stem-cell transplantation. Patients were randomly assigned (1:1) to receive rituximab (375 mg/m(2) on days 21, 28, 35, 42, 175, 182, 189, and 196) or not. Allocation was done with a centralised computer-generated procedure; patients were stratified by histological subtype (B-cell vs T-cell lymphoma) and donor match (HLA-identical vs non-identical). Neither investigators nor patients were masked to allocation. The primary endpoints were the incidence of acute graft-versus-host disease grade 2-4 in each treatment group and overall survival at 1 year in both groups combined. All analyses were done for the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00785330. FINDINGS: Between June 16, 2004, and March 24, 2009, we screened 86 patients and enrolled 84; 42 were randomly assigned to each group. The cumulative incidence of grade 2-4 acute graft-versus-host disease was 46% (95% CI 32-62) in the rituximab group and 42% (95% CI 29-59) in the no rituximab group (hazard ratio [HR] 0·91, 95% CI 0·52-1·60; p=0·74). Overall survival at 1 year for the whole study population was 52% (95% CI 41-62). Grade 4 haematological toxic effects and grade 3 alopecia occurred in all patients. The most common non-haematological grade 5 toxic effects were pneumonia (nine in the no rituximab group vs ten in the rituximab group) and other infections (seven vs four). INTERPRETATION: The lymphoma-directed myeloablative conditioning regimen developed here is promising for patients with refractory and relapsed aggressive B-cell and T-cell lymphomas. However, the addition of rituximab did not affect the incidence of graft-versus-host disease or overall survival. FUNDING: Hoffmann-La Roche, Amgen, Astellas Pharma.

A randomized, double-blind, phase 2 study of erythropoietin in optic neuritis.

OBJECTIVE: Based on findings in animal models of autoimmune optic nerve inflammation, we have assessed the safety and efficacy of erythropoietin in patients presenting with a first episode of optic neuritis. METHODS: Patients with optic neuritis who attended the University Hospitals of Homburg/Saar, Göttingen, or Hamburg (Germany) were included in this double-blind, placebo-controlled, phase 2 study (ClinicalTrials.gov, NCT00355095). They were randomly assigned to groups receiving either 33,000IU recombinant human erythropoietin intravenously daily for 3 days or placebo as an add-on therapy to methylprednisolone. The primary outcome parameter was change in retinal nerve fiber layer (RNFL) thickness after 16 weeks. Secondary outcome parameters included optic nerve atrophy as assessed by magnetic resonance imaging, and changes in visual acuity, visual field, and visual evoked potentials (VEPs). RESULTS: Forty patients were assigned to the treatment groups (21/19 erythropoietin/placebo). Safety monitoring revealed no relevant issues. Thirty-seven patients (20/17 erythropoietin/placebo) were analyzed for the primary endpoint according to the intention-to-treat protocol. RNFL thinning was less apparent after erythropoietin treatment. Thickness of the RNFL decreased by a median of 7.5µm by week 16 (mean ± standard deviation, 10.55 ± 17.54µm) compared to a median of 16.0µm (22.65 ± 29.18µm) in the placebo group (p = 0.0357). Decrease in retrobulbar diameter of the optic nerve was smaller in the erythropoietin group (p = 0.0112). VEP latencies at week 16 were shorter in erythropoietin-treated patients than in the placebo group (p = 0.0011). Testing of visual functions revealed trends toward an improved outcome after erythropoietin treatment. INTERPRETATION: These results give the first indications that erythropoietin might be neuroprotective in optic neuritis.

Tape functionality: position, change in shape, and outcome after TVT procedure--mid-term results.

INTRODUCTION AND HYPOTHESIS: This study evaluates the relevance of the tape position and change in shape (tape functionality) under in vivo conditions for mid-term outcome. METHODS: Changes in the sonographic tension-free vaginal tape (TVT) position relative to the percentage urethral length and the tape-urethra distance were determined after 6 and 48 months in 41 women with stress urinary incontinence. RESULTS: At 48 months, 76% (31/41) of women were cured, 17% (7/41) were improved, and 7% (3/41) were failures. Disturbed bladder voiding was present in 12% (5/41), de novo urge incontinence in 7% (3/41). The median TVT position was at 63% of urethral length. Median tape-urethra distance was 2.7 mm, ranging from 2.9 mm in continent patients without complications to 1.1 mm in those with obstructive complications. Patients with postoperative urine loss had a median distance of 3.9 mm. The tape was stretched at rest and C-shaped during straining in 15 of 41 women (37%) at 48 months (all continent). Patients with this tape functionality at 6 months were also cured at 48 months in 86% of cases (19/22), and only 14% (3/22) showed recurrent incontinence. CONCLUSIONS: Mid-term data suggest an optimal outcome if the tape is positioned at least 2 mm from the urethra at the junction of the middle and distal thirds. Patients with optimal tape functionality at 6 months are likely to show mid-term therapeutic success.

Frequency and individual severity of arterial blood pressure changes in children and adolescents with attention-deficit/hyperactivity disorder treated with methylphenidate hydrochloride: a prospective non-interventional study.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common behavioural disorder in childhood. The psychostimulant methylphenidate hydrochloride (MPH) is one of the major pharmacological options for ADHD. MPH is known to result, on average, in a small increase in arterial blood pressure (BP). However, there are few clinical data regarding the individual influences of MPH on BP among children and adolescents with ADHD. According to the European Union-wide standardised patient information sheet for MPH, BP changes >10 mm Hg compared with baseline values are 'common' (ie, ≥1% to <10%) in children and adolescents with ADHD during MPH therapy. AIM: To investigate the frequency and individual severity of BP changes in children and adolescents with ADHD during the first 6 months of new MPH therapy. METHODS: In this study, 44 (77% male) children and adolescents (mean age (SD) 9.13 (1.86) years) with a diagnosis of ADHD according to the International Classification of Diseases, tenth revision, underwent ambulatory BP monitoring before and during the first 6 months of routine MPH therapy. Exclusion criteria were pre-existing MPH therapy and other medications that potentially influence BP or interfere with MPH. The non-interventional study was conducted prospectively at 10 paediatric cardiology centres in Germany and Austria. RESULTS: After beginning MPH therapy, 34% of participants (99% CI 15.52% to 52.66%) had BP increases/decreases >10 mm Hg. The mean changes in systolic BP and diastolic BP were 0.87 mm Hg (95% CI -1.75 mm Hg to 3.48 mm Hg) and 1.96 mm Hg (95% CI 0.21 mm Hg to 3.7 mm Hg), respectively. The proportion of participants with initial prehypertension/hypertension was 54.55%. CONCLUSIONS: In our sample with a high baseline rate of prehypertension/hypertension, BP changes >10 mm Hg during MPH therapy were more frequent than those indicated by the patient information sheet. Moreover, individual BP changes, including increases and decreases >10 mm Hg, resulted in a small average BP increase in the sample, thus reflecting neither the severity nor the direction of individual BP changes. Therefore, the frequency and, due to the common use of the arithmetic mean, the individual severity of BP changes during MPH therapy may be underestimated. Further studies without averaging and with larger samples including patients in primary care settings are warranted.

ROCK-ALS: Protocol for a Randomized, Placebo-Controlled, Double-Blind Phase IIa Trial of Safety, Tolerability and Efficacy of the Rho Kinase (ROCK) Inhibitor Fasudil in Amyotrophic Lateral Sclerosis.

Objectives: Disease-modifying therapies for amyotrophic lateral sclerosis (ALS) are still not satisfactory. The Rho kinase (ROCK) inhibitor fasudil has demonstrated beneficial effects in cell culture and animal models of ALS. For many years, fasudil has been approved in Japan for the treatment of vasospasm in patients with subarachnoid hemorrhage with a favorable safety profile. Here we describe a clinical trial protocol to repurpose fasudil as a disease-modifying therapy for ALS patients. Methods: ROCK-ALS is a multicenter, double-blind, randomized, placebo-controlled phase IIa trial of fasudil in ALS patients (EudraCT: 2017-003676-31, NCT: 03792490). Safety and tolerability are the primary endpoints. Efficacy is a secondary endpoint and will be assessed by the change in ALSFRS-R, ALSAQ-5, slow vital capacity (SVC), ECAS, and the motor unit number index (MUNIX), as well as survival. Efficacy measures will be assessed before (baseline) and immediately after the infusion therapy as well as on days 90 and 180. Patients will receive a daily dose of either 30 or 60 mg fasudil, or placebo in two intravenous applications for a total of 20 days. Regular assessments of safety will be performed throughout the treatment period, and in the follow-up period until day 180. Additionally, we will collect biological fluids to assess target engagement and evaluate potential biomarkers for disease progression. A total of 120 patients with probable or definite ALS (revised El Escorial criteria) and within 6-18 months of the onset of weakness shall be included in 16 centers in Germany, Switzerland and France. Results and conclusions: The ROCK-ALS trial is a phase IIa trial to evaluate the ROCK-inhibitor fasudil in early-stage ALS-patients that started patient recruitment in 2019.

Contact-to-balloon time and door-to-balloon time after initiation of a formalized data feedback in patients with acute ST-elevation myocardial infarction.

For many patients with ST-segment elevation myocardial infarctions (STEMIs), the time from presentation to percutaneous coronary intervention exceeds established goals. This study was conducted to examine the effects of formalized data assessment and systematic feedback on treatment times. All patients with STEMIs treated with percutaneous coronary intervention in a semi-rural 3-hospital network from January 1, 2006, to December 31, 2006, were prospectively analyzed (n = 114). Patients presenting during the first 3-month period (January 1, 2006, to March 31, 2006) were included as the reference group (n = 33). Time points from initial contact with the medical system to revascularization were assessed, analyzed, and presented in an interactive session to hospital and emergency services staff members. Data from patients with STEMIs presenting during the next 3 quarters were presented in the same manner (n = 28, 25, and 28). The median contact-to-balloon time was 113 minutes in the reference quarter, decreasing to 83, 66, and 74 minutes in the intervention groups (p <0.0001), whereas the median door-to-balloon time decreased from 54 minutes in the reference group to 35, 31, and 26 minutes in the intervention groups (p <0.0001). The proportion of patients with contact-to-balloon times <90 minutes increased from 21% to 79% (p <0.0001). There were significant reductions in the durations of initial treatment on location and in the emergency room and in puncture-to-balloon-time in the catheterization laboratory, and more patients were transported directly to the catheterization laboratory, bypassing the emergency room (from 23% in the reference quarter to 76% in the last intervention quarter, p <0.0001). In conclusion, formalized data feedback leads to marked reduction in revascularization times in patients with STEMIs.

Tape functionality: sonographic tape characteristics and outcome after TVT incontinence surgery.

AIM: To investigate tension-free vaginal tape (TVT) position and shape using ultrasound (US) and correlate the findings to outcome. MATERIAL AND METHODS: The results of TVT surgery were investigated in 72 women with urodynamic stress urinary incontinence. The main outcome parameters were US tape position in relation to the urethra and dynamic changes in TVT shape at rest and during straining. RESULTS: Sixty-two patients (86%) were continent, 6 (8%) significantly improved, and the operation failed in four cases (6%). The median tape position was at 66% of the urethral length measured by US. The median tape-urethra-lumen distance was 3.8 mm at rest. Tape placement in the upper or lower quarter of the urethra was associated with a higher failure rate. Tapes positioned less than 3 mm from the urethra significantly increased postoperative complications (P < 0.0001). The tape was flat at rest and curved during straining in 44 (61%) patients; 98% (43/44) of these women were continent after surgery. An unchanged tape shape was associated with a poorer outcome (P = 0.00038). Patients with a flat tape at rest and during straining failed in 25% and patients with a permanent curved shape in 10%. CONCLUSIONS: TVT position relative to the patient's urethra seems to play a role in treatment outcome. Outcome was best in patients with dynamic change in tape shape during straining and location of the tape at the junction between the lower and middle urethra and at least 3 mm from the urethral lumen.

The impact of the severity of sepsis on the risk of hypoglycaemia and glycaemic variability.

INTRODUCTION: The purpose of this study was to assess the relation between glycaemic control and the severity of sepsis in a cohort of patients treated with intensive insulin therapy (IIT). METHODS: In a prospective, observational study, all patients in the intensive care unit (ICU) (n = 191) with sepsis, severe sepsis or septic shock were treated with IIT (target blood glucose (BG) level 80 to 140 mg/dl instead of strict normoglycaemia). BG values were analysed by calculating mean values, rate of BG values within different ranges, rate of patients experiencing BG values within different levels and standard deviation (SD) of BG values as an index of glycaemic variability. RESULTS: The number of patients with hypoglycaemia and hyperglycaemia was highly dependent on the severity of sepsis (critical hypoglycaemia < or = 40 mg/dl: sepsis: 2.1%, severe sepsis: 6.0%, septic shock: 11.5%, p = 0.1497; hyperglycaemia: >140 mg/dl: sepsis: 76.6%, severe sepsis: 88.0%, septic shock: 100%, p = 0.0006; >179 mg/dl: sepsis: 55.3%, severe sepsis: 73.5%, septic shock: 88.5%, p = 0.0005; >240 mg/dl: sepsis: 17.0%, severe sepsis: 48.2%, septic shock: 45.9%, p = 0.0011). Multivariate analyses showed a significant association of SD levels with critical hypoglycaemia especially for patients in septic shock (p = 0.0197). In addition, SD levels above 20 mg/dl were associated with a significantly higher mortality rate relative to those with SD levels below 20 mg/dl (24% versus 2.5%, p = 0.0195). CONCLUSIONS: Patients with severe sepsis and septic shock who were given IIT had a high risk of hypoglycaemia and hyperglycaemia. Among these patients even with a higher target BG level, IIT mandates an increased awareness of the occurrence of critical hypoglycaemia, which is related to the severity of the septic episode.

Adequate cytogenetic examination in myelodysplastic syndromes: analysis of 529 patients.

In myelodysplastic syndromes (MDS), the karyotype is one of the most significant prognostic markers with profound impact on differential diagnosis and therapeutic decisions. In a retrospective study, we examined karyotypes of bone marrow specimens of an oligocentric cohort comprising 529 patients with MDS to address the question how many metaphases need to be analyzed to detect even small cell clones with an appropriate expenditure. We found a statistically significant difference of the frequency of normal karyotypes in the patient group with 19 or less analyzed metaphases compared to the group with 20 or more metaphases analyzed (56% versus 47%, p=0.041). Furthermore, we demonstrate that the analysis of 25 or more metaphases can further improve the sensitivity of karyotype analysis and leads to the identification of additional clinically relevant abnormal clones or subclones in a substantial proportion of patients. In summary, our data suggest the examination of at least 20 metaphases in MDS.

Acupuncture treatment of chronic low-back pain -- a randomized, blinded, placebo-controlled trial with 9-month follow-up.

There is some evidence for the efficacy of acupuncture in chronic low-back pain (LBP), but it remains unclear whether acupuncture is superior to placebo. In a randomized, blinded, placebo-controlled trial, we evaluated the effect of traditional acupuncture in chronic LBP. A total of 131 consecutive out-patients of the Department of Orthopaedics, University Goettingen, Germany, (age=48.1 years, 58.5% female, duration of pain: 9.6 years) with non-radiating LBP for at least 6 months and a normal neurological examination were randomized to one of three groups over 12 weeks. Each group received active physiotherapy over 12 weeks. The control group (n=46) received no further treatment, the acupuncture group (n=40) received 20 sessions of traditional acupuncture and the sham-acupuncture group (n=45) 20 sessions of minimal acupuncture. Changes from baseline to the end of treatment and to 9-month follow-up were assessed in pain intensity and in pain disability, and secondary in psychological distress and in spine flexion, compared by intervention groups. Acupuncture was superior to the control condition (physiotherapy) regarding pain intensity (P=0.000), pain disability (P=0.000), and psychological distress (P=0.020) at the end of treatment. Compared to sham-acupuncture, acupuncture reduced psychological distress (P=0.040) only. At 9-month follow-up, the superiority of acupuncture compared to the control condition became less and acupuncture was not different to sham-acupuncture. We found a significant improvement by traditional acupuncture in chronic LBP compared to routine care (physiotherapy) but not compared to sham-acupuncture. The trial demonstrated a placebo effect of traditional acupuncture in chronic LBP.

Increased risk for therapy-associated hematologic malignancies in patients with carcinoma of the breast and combined homozygous gene deletions of glutathione transferases M1 and T1.

The most serious long-term complications of anti-tumor therapy are secondary malignancies. Parameters which might allow an estimation of the individual risk to develop a therapy-induced neoplasia are urgently needed. We examined whether the genotypes of the glutathione S-transferases (GST) M1 and T1, which metabolize various cytostatic drugs, as well as reactive oxygen species, influence the risk for secondary neoplasia. In a retrospective study, we analyzed peripheral blood lymphocyte or bone marrow DNA samples from 213 patients with acute myeloid leukemia (AML) and 128 with myelodysplastic syndromes (MDS) 44 of whom suffered from therapy-associated AML/MDS. The control group consisted of 239 healthy individuals with comparable composition as to race and sex. GSTM1 and GSTT1 were analyzed by multiplex PCR. Comparison between patients and control group revealed a significant (P=0.0003) overrepresentation of combined deletions of both GSTM1 and GSTT1 (double null genotype) in the group of patients with AML/MDS secondary to chemo- and/or radiotherapy of a carcinoma of the breast. In this group, 55% of the patients displayed the double null genotype as compared with 8.8% in the control group. We conclude that patients with carcinoma of the breast and inheritance of a combined gene deletion of GSTM1 and GSTT1 might bear an increased risk to develop a secondary therapy-induced hematologic neoplasia. An insufficient detoxification of cytostatic drugs such as cyclophosphamide is suggested to represent the underlying pathomechanism.

Comparison of Two Clinical Protocols for Total Intravenous Anesthesia (TIVA) for Breast Surgery Using Propofol Combined With Either Sufentanil or Alfentanil.

BACKGROUND: Sufentanil and alfentanil have pharmacokinetic and dynamic properties which make them favourable substances for total intravenous anesthesia (TIVA) in combination with propofol. OBJECTIVES: We planned to compare two clinical protocols for TIVA with propofol, and either sufentanil or alfentanil in regards to postoperative pain, hemodynamic stability during the case and time for emergence from anesthesia. PATINETS AND METHODS: Treaty eight patients scheduled for general anesthesia for breast surgery were included in this Double-blind, randomized, controlled trial. All patients received a standardized TIVA with propofol and either 0.2 µg kg(-1) sufentanil or 20 µg kg(-1) alfentanil for induction and 0.3 µg kg(-1) h(-1) sufentanil or 30 µg kg(-1) h(-1) alfentanil for maintenance with additional propofol boluses as needed. During anesthesia, heart rate, non-invasive blood-pressure, peripheral oxygen saturation and depth of anesthesia, were recorded. In the post anesthesia care unit, pain scores, nausea and vomiting as well as medications were recorded. RESULTS: Patients in the sufentanil group required less often additional opioid and propofol boluses to maintain adequate anesthesia. We did not observe a significant difference in time to extubation. Postoperatively, patients in the sufentanil group had less pain (P = 0.03) and required less i.v. opioids (0.4 vs. 1.9 mg piritramid, P = 0.04). CONCLUSIONS: Both protocols provide excellent anesthesia, but patients receiving sufentnail had more stable anesthesia and less postoperative pain.

Challenges for academic investigator-initiated pediatric trials for rare diseases.

BACKGROUND: Clinical trials require great effort, time, expertise, and money. For clinicians at university hospitals with their full work load of teaching and medical care, the planning of an investigator-initiated clinical trial seems almost unthinkable. Despite their expertise in distinct diseases, university clinicians lack the time necessary to organize the funding and to initiate and conduct Phase III clinical trials in adults or in children. OBJECTIVE: We sought to determine whether the difficulties faced by a clinician conducting a pediatric clinical trial can be overcome by passionate motivation and external support. METHODS: Critical aspects of the application process of the world's first clinical trial in children with the rare hereditary kidney disease Alport syndrome treated with an angiotensin-converting enzyme inhibitor (Early Prospective Therapy Trial to Delay Renal Failure in Children With Alport Syndrome [EARLY PRO-TECT Alport]; http://www.clinicaltrials.gov NCT01485978; EudraCT 2010-024300-10) are described. RESULTS: The following crucial factors enabled the investigator to complete this trial: (1) support through clinical trial, biometrician, and regulatory experts (Institute for Applied Research and Clinical Studies [IFS], Göttingen, Germany); (2) advice from the university's ethics committee (University Medicine Göttingen, Göttingen, Germany); (3) public funding (€1 million from the German Federal Ministry of Education and Research); (4) support from the respective medical society, aiming at the resolution of an important clinical problem (German Society of Pediatric Nephrology); and (5) support from the investigator's university as the official sponsor of the trial, providing long-term commitment and covering financial risks (University Medical Center Göttingen, Göttingen, Germany). CONCLUSIONS: The study could pave the way for approval of ramipril as a drug to treat children with Alport syndrome. Even though the study might not result in label changes, the EARLY PRO-TECT Alport trial provides the basis of an educational campaign to sensitize physicians, especially pediatricians, general practitioners, and nephrologists, to pay special attention to the early detection of kidney diseases in children, which could improve medical care for all children with kidney diseases.

Safety and Efficacy of the ACE-Inhibitor Ramipril in Alport Syndrome: The Double-Blind, Randomized, Placebo-Controlled, Multicenter Phase III EARLY PRO-TECT Alport Trial in Pediatric Patients.

Introduction. Retrospective observational data show that ACE-inhibitor therapy delays renal failure and improves life expectancy in Alport patients with proteinuria. The EARLY PRO-TECT Alport trial assesses the safety and efficacy of early therapy onset with ramipril in pediatric Alport patients. Methods and analysis. This double-blind, randomized, placebo-controlled, multicenter phase III trial (NCT01485978; EudraCT-number 2010-024300-10) includes 120 pediatric patients aged 24 months to 18 years with early stages of Alport syndrome (isolated hematuria or microalbuminuria). From March 2012, up to 80 patients will be randomized 1:1 to ramipril or placebo. In the event of disease progression during 3-year treatment, patients are unblinded and ramipril is initiated, if applicable. Approximately 40 patients receive open-label ramipril contributing to the safety database. Primary end-points are "time to progression to next disease level" and "incidence of adverse drug events before disease progression." Treatment effect estimates from the randomized comparison and Alport registry data will be combined in supportive analyses to maximize evidence. Conclusion. Without this trial, ACE inhibitors may become standard off-label treatment in Alport syndrome without satisfactory evidence base. The results are expected to be of relevance for therapy of all pediatric patients with kidney disease, and the trial protocol might serve as a model for other rare pediatric glomerulopathies.

Reduction in treatment times through formalized data feedback: results from a prospective multicenter study of ST-segment elevation myocardial infarction.

OBJECTIVES: This study sought to evaluate the effect of systematic data analysis and standardized feedback on treatment times and outcome in a prospective multicenter trial. BACKGROUND: Formalized data feedback may reduce treatment times in ST-segment elevation myocardial infarction (STEMI). METHODS: Over a 15-month period, 1,183 patients presenting with STEMI were enrolled. Six primary percutaneous coronary intervention hospitals in Germany and 29 associated nonpercutaneous coronary intervention hospitals participated. Data from patient contact to balloon inflation were collected and analyzed. Pre-defined quality indicators, including the percentage of patients with pre-announced STEMI, direct handoff in the catheterization laboratory, contact-to-balloon time <90 min, door-to-balloon time <60 min, and door-to-balloon time <30 min were discussed with staff on a quarterly basis. RESULTS: Median door-to-balloon time decreased from 71 to 58 min and contact-to-balloon time from 129 to 103 min between the first and the fifth quarter (p < 0.05 for both). Contributing were shorter stays in the emergency department, more direct handoffs from ambulances to the catheterization laboratory (from 22% to 38%, p < 0.05), and a slight increase in the number of patients transported directly to the percutaneous coronary intervention facility (primary transport). One-year mortality was reduced in the total group of patients and in the subgroup of patients with primary transport (p < 0.05). The sharpest fall in mortality was observed in patients with primary transport and TIMI (Thrombolysis In Myocardial Infarction) risk score ≥ 3 (n = 521) with a decrease in 30-day mortality from 23.1% to 13.3% (p < 0.05) and in 1-year mortality from 25.6% to 16.7% (p < 0.05). CONCLUSIONS: Formalized data feedback is associated with a reduction in treatment times for STEMI and with an improved prognosis, which is most pronounced in high-risk patients. (Feedback Intervention and Treatment Times in ST-Elevation Myocardial Infarction [FITT-STEMI]; NCT00794001).

Influence of irradiated lung volumes on perioperative morbidity and mortality in patients after neoadjuvant radiochemotherapy for esophageal cancer.

PURPOSE: In some randomized trials, the treatment outcome of locally advanced esophageal cancer has been significantly improved by neoadjuvant radiochemotherapy (RCT). However, increased perioperative pulmonary toxicity in terms of acute respiratory distress syndrome (ARDS) has been linked to radiation exposure of the lungs. In our study we evaluated perioperative morbidity and mortality in patients with cancer Stages IIA-IVA treated with curative intent either with surgery alone (S) or with neoadjuvant RCT followed by surgery (RCTS). PATIENTS AND METHODS: Between 1996 and 2003, 55 patients received S, and 98 received RCTS. In the RCTS group, most patients received two cycles of 5-fluorouracil plus cisplatinum simultaneously with normofractionated radiotherapy (40Gy). Four weeks later they underwent surgery. Endpoints were the incidence of acute lung injury (ALI), ARDS, other postoperative complications, and mortality within 31 days. RESULTS: Between both groups there were no significant differences between the incidence and severity of ALI and ARDS (RCTS: 42.9%, 42.9%; S: 45.5%, 38.2%). Furthermore, there were no significant differences in the incidences of pneumonia, pleural effusion, and pneumothorax (RCTS 29.6% vs. S 16.4%, p = 0.07). Perioperative complication rates and mortality did not vary significantly (mortality after RCTS 5.1% vs. S 3.6%). A detailed analysis of 54 RCTS patients according to lung dose-volume histograms did not show any correlation between ARDS and pulmonary exposure. In univariate analysis, only respiratory comorbidity correlated with ARDS. CONCLUSION: Neoadjuvant cisplatinum and 5-fluorouracil-based RCT apparently has no detrimental impact on the postoperative course.

Recent in vitro findings of negative inotropy of pantoprazole did not translate into clinically relevant effects on left ventricular function in healthy volunteers.

PURPOSE: Reports on cardiac problems with oral proton pump inhibitors have caused extensive safety reviews by the US Food and Drug Administration. We provide additional data on acute cardiac effects of an intravenous application. METHODS: Echocardiography was performed in 18 healthy volunteers after administration of a common high-dose regimen of pantoprazole (80 mg i.v. bolus followed by 8 mg/h for 1 h) or placebo. DESIGN: The design included a randomized, double-blind, placebo-controlled cross-over trial. RESULTS: Ejection fraction (%, mean +/- SE) in the treatment group (placebo group) was 60.7 +/- 1.1 (61.2 +/- 1.7) at baseline, and 62.6 +/- 1.1 (62.1 +/- 1.9), 64.7 +/- 1.6 (63.5 +/- 1.3), 62.6 +/- 1.6 (61.0 +/- 1.6) and 63.0 +/- 1.4 (61.8 +/- 1.5) at 7.5, 15, 30 and 60 min after bolus application, respectively (p = n.s.). Similarly, no significant changes were found for cardiac output, cardiac index, blood pressure and heart rate. In contrast, gastric pH that was used as a treatment control was significantly increased 60 min after the application of pantoprazole as compared to baseline and to placebo. CONCLUSIONS: Pantoprazole as injection is safe in healthy subjects with respect to cardiac contractile function. However, in view of recent reports of negative inotropy of the drug, further studies in heart failure patients are required.