Clinical Trial Unit

Aus einer umfassenden Erstberatung leiten wir ein auf Ihr Forschungsprojekt zugeschnittenes Servicepaket ab.

Die Clinical Trial Unit Basel ist Teil eines vom Schweizerischen Nationalfonds (SNF) initiierten nationalen Netzwerks von Clinical Trial Units und Gründungsmitglied der Swiss Clinical Trial Organisation.

Sie wurde 2007 im Zuge der Bundesinitiative zur Förderung der Qualität in akademischen klinischen Studien gegründet und ist seither am Universitätsspital Basel angesiedelt. Seit 2012 ist die Clinical Trial Unit eine Abteilung des Departements Klinische Forschung der Universität Basel.

Die Mitarbeitenden der Clinical Trial Unit besitzen langjährige studienrelevante Erfahrungen und unterstützen Sie in folgenden Bereichen:

Publikationen

2018

Antwi K, Fani M, Heye T, Nicolas G, Rottenburger C, Kaul F, Merkle E, Zech CJ, Boll D, Vogt DR, Gloor B, Christ E, Wild D (2018) Comparison of glucagon-like peptide-1 receptor (GLP-1R) PET/CT, SPECT/CT and 3T MRI for the localisation of occult insulinomas: evaluation of diagnostic accuracy in a prospective crossover imaging study. Eur J Nucl Med Mol Imaging (online)
Barro C, Benkert P, Disanto G, Tsagkas C, Amann M, Naegelin Y, Leppert D, Gobbi C, Granziera C, Yaldizli Ö, Michalak Z, Wuerfel J, Kappos L, Parmar K, Kuhle J (2018) Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. Brain 141:2382--2391 (online)
Neuro-axonal injury is a key factor in the development of permanent disability in multiple sclerosis. Neurofilament light chain in peripheral blood has recently emerged as a biofluid marker reflecting neuro-axonal damage in this disease. We aimed at comparing serum neurofilament light chain levels in multiple sclerosis and healthy controls, to determine their association with measures of disease activity and their ability to predict future clinical worsening as well as brain and spinal cord volume loss. Neurofilament light chain was measured by single molecule array assay in 2183 serum samples collected as part of an ongoing cohort study from 259 patients with multiple sclerosis (189 relapsing and 70 progressive) and 259 healthy control subjects. Clinical assessment, serum sampling and MRI were done annually; median follow-up time was 6.5 years. Brain volumes were quantified by structural image evaluation using normalization of atrophy, and structural image evaluation using normalization of atrophy, cross-sectional, cervical spinal cord volumes using spinal cord image analyser (cordial). Results were analysed using ordinary linear regression models and generalized estimating equation modelling. Serum neurofilament light chain was higher in patients with a clinically isolated syndrome or relapsing remitting multiple sclerosis as well as in patients with secondary or primary progressive multiple sclerosis than in healthy controls (age adjusted P < 0.001 for both). Serum neurofilament light chain above the 90th percentile of healthy controls values was an independent predictor of Expanded Disability Status Scale worsening in the subsequent year (P < 0.001). The probability of Expanded Disability Status Scale worsening gradually increased by higher serum neurofilament light chain percentile category. Contrast enhancing and new/enlarging lesions were independently associated with increased serum neurofilament light chain (17.8\% and 4.9\% increase per lesion respectively; P < 0.001). The higher the serum neurofilament light chain percentile level, the more pronounced was future brain and cervical spinal volume loss: serum neurofilament light chain above the 97.5th percentile was associated with an additional average loss in brain volume of 1.5\% (P < 0.001) and spinal cord volume of 2.5\% over 5 years (P = 0.009). Serum neurofilament light chain correlated with concurrent and future clinical and MRI measures of disease activity and severity. High serum neurofilament light chain levels were associated with both brain and spinal cord volume loss. Neurofilament light chain levels are a real-time, easy to measure marker of neuro-axonal injury that is conceptually more comprehensive than brain MRI.
Urech C, Grossert A, Alder J, Scherer S, Handschin B, Kasenda B, Borislavova B, Degen S, Erb J, Faessler A, Gattlen L, Schibli S, Werndli C, Gaab J, Berger T, Zumbrunn T, Hess V (2018) Web-based stress management for newly diagnosed patients with cancer (STREAM): a randomized, wait-list controlled intervention study. J Clin Oncol 36:78--788 (online) (online)
PurposeBeing diagnosed with cancer causes major psychological distress; however, a majority of patients lack psychological support during this critical period. Internet interventions help patients overcome many barriers to seeking face-to-face support and may thus close this gap. We assessed feasibility and efficacy of Web-based stress management (STREAM [Stress-Aktiv-Mindern]) for newly diagnosed patients with cancer.Patients and MethodsIn a randomized controlled trial, patients with cancer who had started first-line treatment within the previous 12 weeks were randomly assigned to a therapist-guided Web-based intervention or a wait-list (control), stratified according to distress level (≥ 5 v < 5 on scale of 0 to 10). Primary efficacy end point was quality of life after the intervention (Functional Assessment of Chronic Illness Therapy–Fatigue). Secondary end points included distress (Distress Thermometer) and anxiety or depression (Hospital Anxiety and Depression Scale). Treatment effect was assessed with analyses of covariance, adjusted for baseline distress.ResultsA total of 222 of 229 screened patients applied online for participation. Between September 2014 and November 2016, 129 newly diagnosed patients with cancer, including 92 women treated for breast cancer, were randomly assigned to the intervention (n = 65) or control (n = 64) group. Adherence was good, with 80.0\% of patients using ≥ six of eight modules. Psychologists spent 13.3 minutes per week (interquartile range, 9.5-17.9 minutes per week) per patient for online guidance. After the intervention, quality of life was significantly higher (Functional Assessment of Chronic Illness Therapy–Fatigue: mean, 8.59 points; 95\% CI, 2.45 to 14.73 points; P = .007) and distress significantly lower (Distress Thermometer: mean, −0.85; 95\% CI, −1.60 to −0.10; P = .03) in the intervention group as compared with the control. Changes in anxiety or depression were not significant in the intention-to-treat population (Hospital Anxiety and Depression Scale: mean, −1.28; 95\% CI, −3.02 to 0.45; P = .15). Quality of life increased in the control group with the delayed intervention.ConclusionThe Web-based stress management program STREAM is feasible and effective in improving quality of life.
Disanto G, Zecca C, MacLachlan S, Sacco R, Handunnetthi L, Meier UC, Simpson A, McDonald L, Rossi A, Benkert P, and Kuhle J, Ramagopalan SV, Gobbi C (2018) Prodromal symptoms of multiple sclerosis in primary care. Ann Neurol (online)
Objective Early diagnosis and treatment initiation significantly influence long‐term disability outcome in multiple sclerosis (MS). We aimed at identifying prodromal symptoms of MS in primary care settings.
Methods This was a nested case–control study comparing the occurrence of various symptoms in MS patients versus controls at 0 to 2, 2 to 5, and 5 to 10 years before index date (first MS record). A total of 10,204 incident MS cases were identified within the United Kingdom Clinical Practice Research Datalink between January 1, 1987 and February 28, 2016 (median age = 47 years, interquartile range [IQR] = 39–57, females = 7,308 [71.6\%]). Patients were matched to 39,448 controls with no MS record by sex, year of birth, general practitioner, and year of registration (age = 47 years, IQR = 39–56, females = 28,248 [71.6\%]). Odds ratios (ORs) with 95\% confidence intervals (CIs) were calculated using conditional logistic regression.
Results MS patients had significantly higher risk of presenting up to 10 years prior to index date with gastric, intestinal, urinary, and anorectal disturbances, anxiety, depression, insomnia, fatigue, headache, and various types of pain. MS risk progressively increased with each additional symptom presented (0–2 years: OR = 1.51, 95\% CI = 1.47–1.55, p < 0.001; 2–5 years: OR = 1.29, 95\% CI = 1.25–1.33, p < 0.001; 5–10 years: OR = 1.20, 95\% CI = 1.15–1.26, p < 0.001). Sensitivity analyses in patients with age at index < 40 years and no neurological disturbances prior to symptoms of interest showed consistent results.
Interpretation Various clinical disturbances precede MS diagnosis by several years, supporting a prodromal phase to the disease and improving our clinical knowledge of early MS. Integrating these symptoms in the diagnostic procedure may help earlier disease identification. Ann Neurol 2018
Fenske W, Refardt J, Chifu I, Schnyder I, Winzeler B, Drummond J, Ribeiro-Oliveira Jr A, Drescher T, Bilz S, Vogt DR, Malzahn U, Kroiss M, Christ E, Henzen C, Fischli S, Tönjes A, Mueller B, Schopohl J, Flitsch J, Brabant G, Fassnacht M, Christ-Crain M (2018) A copeptin-based approach in the diagnosis of Diabetes insipidus. N Engl J Med 379:428--439 (online)
Fladt J, Hofmann L, Coslovsky M, Imhof A, Seiffge DJ, Polymeris A, Thilemann S, Traenka C, Sutter R, Schaer B, Kaufmann BA, Peters N, H BL, Engelter ST, A LP, de Marchis GM (2018) Fast-track versus long-term hospitalizations for patients with non-disabling acute ischemic stroke. Eur J Neurol (online)
Gilgen N, Farah A, Scheller B, Ohlow M, Mangner N, Weilenmann D, Wöhrle J, Jamshidi P, Leibundgut G, Möbius-Winkler S, Zweikler R, Krackhardt F, Butter C, Bruch L, Kaiser C, Hoffmann A, Rickenbacher P, Mueller CuSF, Coslovsky M, Jeger R (2018) Drug‐coated balloons for de novo lesions in small coronary arteries: rationale and design of BASKET‐SMALL 2. Clin Cardiol (online)
Jeger RV, Farah A, Ohlow M, Mangner N, Möbius-Winkler S, Leibundgut G, Weilenmann D, Wöhrle J, Richter S, Schreiber M, Mahfoud F, Linke A, Stephan F, Mueller C, Rickenbacher P, Coslovsky M, Gilgen N, Osswald S, Kaiser C, Scheller B (2018) Drug-coated balloons for small coronary artery disease (BASKET-SMALL 2): an open-label randomised non-inferiority trial. Lancet 392:849--856 (online)
Kappos EA, Engels PE, Tremp M, Sieber P, von Felten S, Madduri S, zu Schwabedissen MM, Fischmann A, Schaefer DJ, Kalbermatten DF (2018) Denervation leads to volume regression in breast cancer. J Plast Reconstr Aesthet Surg 71:833--839 (online)
The nervous system plays a key role in controlling the dynamic functions of multicellular complex organisms. Although peripheral nerves are supposed to play a pivotal role in tumor growth and dissemination, little experimental evidence exists to date. We assessed the effect of denervation on breast cancer growth by magnetic resonance imaging (MRI) in rats. Human breast cancer cells were implanted into adipofascial flaps with intact or surgically excised supplying nerve. Tumor volumes were measured 2 and 8 weeks after implantation by in vivo MRI. Results were validated by histology. Postoperative tumor volumes at 2 and 8 weeks were reduced by 76% (95% CI: 22–93%) in the denervated groups. Tumor area as determined histologically was reduced by 70% (95% CI: 60–78%). Thus, peripheral denervation may be an effective surgical approach for the palliative treatment of locally progressing or uncontrollable breast cancer.
Klähn S, Bolay P, Wright PR, Atilho RM, Brewer KI, Hagemann M, Breaker RR, Hess WR (2018) A glutamine riboswitch is a key element for the regulation of glutamine synthetase in cyanobacteria. Nucleic Acids Res :gky709 (online)
Lorscheider J, Benkert P, Lienert C, Hänni P, Derfuss T, Kuhle J, Kappos L, Yaldizli Ö (2018) Comparative analysis of natalizumab versus fingolimod as second-line treatment in relapsing--remitting multiple sclerosis. Mult Scler 24:777--785 (online)
Background: No randomized controlled trials have compared the efficacy of fingolimod or natalizumab as second-line treatment in patients with relapsing–remitting multiple sclerosis (RRMS).
Objective: To compare clinical outcomes after escalation to fingolimod versus natalizumab in patients with clinically active RRMS.
Methods: Using the registry of the Swiss Federation for Common Tasks of Health Insurances, we identified patients with RRMS and ≥1 relapse in the year before switching from interferon beta or glatiramer acetate to fingolimod or natalizumab. Propensity score matching was used to select patients with comparable baseline characteristics. Relapse and Expanded Disability Status Scale (EDSS) outcomes were compared in paired, pairwise-censored analyses.
Results: Of the 547 included patients, 358 were matched (fingolimod, n = 179; natalizumab, n = 179). Median follow-up time was 1.8 years (interquartile range 0.9–2.9). Patients switching to natalizumab had a lower risk of relapses (incidence rate ratio 0.5, 95\% confidence interval (CI) 0.3–0.8, p = 0.001) and were more likely to experience EDSS improvement (hazard ratio (HR) 1.8, 95\% CI 1.1–2.7, p = 0.01) compared to fingolimod. We found no differences in the proportion of patients free from EDSS progression (HR 0.9, 95\% CI 0.5–1.5, p = 0.62).
Conclusion: Natalizumab seems to be more effective in reducing relapse rate and improving disability compared with fingolimod.
Marbacher S, Grüter B, Schöpf S, Croci D, Nevzati E, D’Alonzo D, Lattmann J, Roth T, Bircher B, Wolfert C, Dutilh G, Fandino J (2018) Systematic review of in vivo animal models of subarachnoid hemorrhage: species, standard parameters, and outcomes. Transl Stroke Res :1--9 (online)
Mujagic E, Marti WR, Coslovsky M, Soysal SD, Mechera R, von Strauss M, Zeindler J, Saxer F, Mueller A, Fux CA, Kindler C, Gurke L, Weber WP (2018) Associations of hospital length of stay with surgical site infections. World J Surg :1--9 (online)
Mujagic E, Zeindler J, Coslovsky M, Hoffmann H, Soysal SD, Mechera R, von Strauss M, Delko T, Saxer F, Glaab R, Kraus R, Mueller A, Curti G, Gurke L, Jakob M, Marti WR, Weber WP (2018) The association of surgical drains with surgical site infections - a prospective observational study. Am J Surg (online)
Müller MD, von Felten S, Algra A, Becquemin JaBMM, Bulbulia R, Calvet D, Eckstein H, Fraedrich G, Halliday A, Hendrikse J, Howard G, Gregson J, Jansen O, Mas J, Brott TG, Ringleb PA, Bonati LH (2018) Immediate and delayed procedural stroke or death in stenting versus endarterectomy for symptomatic carotid stenosis. Stroke (online)
Background: Over the past decades, stroke risk associated with carotid disease has decreased, most likely reflecting to improvements in medical therapy and a more rigorous control of vascular risk factors. It is less clear whether this is also true for the procedural risk of carotid revascularization.
Methods: We analyzed temporal changes in procedural risks among 4,597 patients with symptomatic carotid stenosis treated with carotid artery stenting (CAS; n=2,326) or endarterectomy (CEA; n=2,271) in 4 randomized trials between 2000 and 2008, using generalized linear mixed-effects models with a random intercept for each source trial. Models were additionally adjusted for age and other baseline characteristics predicting treatment risk. The primary outcome event was any procedural stroke or death occurring during or within 30 days after revascularisation.
Results: The procedural stroke or death risk decreased significantly over time in all patients (unadjusted OR per year 0.91, 95% CI 0.85-0.97, p=0.006). This effect was mainly driven by a decrease in the CEA group (unadjusted OR per year 0.82, 95% CI 0.73-0.92, p=0.003), whereas no significant decrease was found after CAS (unadjusted OR 0.96, 95% CI 0.88-1.04, p=0.33). After adjustment for baseline characteristics, the results remained essentially the same. CEA patients had a lower procedural stroke or death risk compared to CAS patients, and the difference significantly increased over time (interaction p=0.031).
Conclusions: The risk of stroke or death associated with carotid endarterectomy for symptomatic carotid stenosis decreased over an 8 year period, independent of clinical predictors of procedural risk. No corresponding reduction in procedural risk was seen in patients treated with stenting.
Nicolas GP, Schreiter N, Kaul F, Uiters J, Bouterfa H, Kaufmann J, Erlanger TE, Cathomas R, Christ E, Fani M, Wild D (2018) Sensitivity comparison of ⁶⁸Ga-OPS202 and ⁶⁸Ga-DOTATOC PET/CT in patients with gastroenteropancreatic neuroendocrine tumors: a prospective phase II imaging study. J Nucl Med :jnumed--117 (online)
Raden M, Ali SM, Alkhnbashi OS, Busch A, Costa F, Davis JA, Eggenhofer F, Gelhausen R, Georg J, Heyne S, Hiller M, Kundu K, Kleinkauf R, Lott SC, Mohamed MM, Mattheis A, Miladi M, Richter AS, Will S, Wolff J, Wright PR, Backofen R (2018) Freiburg RNA tools: a central online resource for RNA-focused research and teaching. Nucleic Acids Res 46:W25--W29 (online)
The Freiburg RNA tools webserver is a well established online resource for RNA-focused research. It provides a unified user interface and comprehensive result visualization for efficient command line tools. The webserver includes RNA-RNA interaction prediction (IntaRNA, CopraRNA, metaMIR), sRNA homology search (GLASSgo), sequence-structure alignments (LocARNA, MARNA, CARNA, ExpaRNA), CRISPR repeat classification (CRISPRmap), sequence design (antaRNA, INFO-RNA, SECISDesign), structure aberration evaluation of point mutations (RaSE), and RNA/protein-family models visualization (CMV), and other methods. Open education resources offer interactive visualizations of RNA structure and RNA-RNA interaction prediction as well as basic and advanced sequence alignment algorithms. The services are freely available at http://rna.informatik.uni-freiburg.de.
Redling K, Schaedelin S, Huhn EA, Hoesli I (2018) Efficacy and safety of misoprostol vaginal insert vs. oral misoprostol for induction of labor. J Perinat Med (online)
Refardt J, Kling B, Krausert K, Fassnacht M, von Felten S, Christ-Crain M, Fenske W (2018) Impact of chronic hyponatremia on neurocognitive and neuromuscular function. Eur J Clin Invest 48:1--9 (online)
Background: Chronic hyponatremia is common and associated with increased morbidity and mortality. However whether treatment improves outcome in patients without significant symptoms is unclear. We here assessed the therapeutic outcome on clinical symptoms, neurocognitive and neuromuscular function in patients with chronic non-profound hyponatremia.
Material and Methods: Prospective case-control study in 19 patients from the University Hospital Würzburg with chronic non-profound and clinically asymptomatic hyponatremia. At baseline and after a 14-day treatment period of hyponatremia patients were assessed by specific clinical symptoms-questionnaire, neurocognitive and neuromuscular function was analysed by five attention tests and a gait test consisting of 3 steps “in tandem”. The results were compared to a control-group of healthy volunteers.
Results: Compared to healthy volunteers, patients with mild (n=10, mean serum sodium 132 ±1.2mmol/l) and moderate hyponatremia (n=9, mean 126 ± 3.3mmol/l) performed significantly worse in the neurocognitive subtests alertness (p=0.018), divided attention (p=0.017) and go/no go (p=0.026). Performance in the neuromuscular sub-tests was also lower in the patient-group without reaching significance. The extent of hyponatremia had no impact on the specific test and questionnaire results. Fourteen-day treatment of hyponatremia improved clinical symptoms in all patients (p=0.003) and neurocognitive function in sodium-normalized patients (go/no go test, p=0.029).
Conclusion: Chronic hyponatremia is symptomatic and impairs neurocognitive and neuromuscular function. Short-time therapeutic intervention led to improved clinical symptoms and neurocognitive function, but had no effect on neuromuscular function. Larger trials with long-term treatment are needed to specify the therapeutic need in chronic hyponatremia.
Sandmeier N, Rothschild SI, Rothermundt C, Cathomas R, Schardt J, Berthold D, von Burg P, Müller B, Beyer J, Vogt DR, Stenner F (2018) Pattern of care study in metastatic renal-cell carcinoma in the preimmunotherapy era in Switzerland. Clin Genitourin Cancer 16:e711--e718 (online)
Introduction: In metastatic renal-cell carcinoma (mRCC), physicians have a plethora of therapeutic choices, with the latest addition of checkpoint inhibitors. However, many questions regarding the best use of the respective drugs remain unanswered. Therefore, it is important to examine and summarize the outcome of real-world experiences to understand the practical value of the various drugs in daily use and foster optimal treatment algorithms for patients with renal-cell carcinoma. We sought to describe the pattern of care in mRCC under circumstances with access to all therapeutic options for patients. Patients and Methods: We examined the outcome of patients with mRCC who were treated at 8 major centers in Switzerland, mainly with vascular endothelial growth factor–targeted therapy and mammalian target of rapamycin inhibitors. Data from 110 patients with mRCC who had undergone more than one systemic therapy were collected and analyzed. We assessed the pattern of care for patients with mRCC in an unrestricted health care system and outcomes with regard to the respective treatment sequences. We also studied the compliance of individual therapies with published guidelines and correlated the adherence to outcome. Finally, immediate versus deferred treatment and the number of received therapeutic drug lines were analyzed. Results: Median survival of patients treated with targeted agents for mRCC was 2.0 years. Conclusion: Exposure to more than 2 lines of systemic drugs did not improve outcome of patients with mRCC.
Schifferli A, Holbro A, Chitlur M, Coslovsky M, Imbach P, Donato H, Elalfy M, Graciela E, Grainger J, Holzhauer S, Riccheri C, Rodeghiero F, Ruggeri M, Tamary H, Uglova T, Wu R, Kühne T (2018) A comparative prospective observational study of children and adults with immune thrombocytopenia: 2-year follow-up. Am J Hematol (online)
Schmidt T, Pargger H, Seeberger E, Eckhart F, von Felten S, Haberthür C (2018) Effect of high-dose sodium selenite in cardiac surgery patients: a randomized controlled bi-center trial. Clin Nutr 37:1172--1180 (online)
Background & aims: Cardiac surgery is accompanied by oxidative stress and systemic inflammatory response, which may be associated with organ dysfunction and increased mortality. Selenium and selenoenzymes are important constituents of anti-oxidative defense. We hypothesized that high-dose sodium selenite supplementation can attenuate the postoperative inflammation and might, therefore, improve clinical outcome.
Methods: Randomized, placebo-controlled, double-blinded, bi-center study on 411 adult patients undergoing elective cardiac surgery. Patients received an intravenous bolus of 4000 μg selenium (in the form of sodium selenite) or placebo after induction of anesthesia and 1000 μg/d selenium or placebo during their intensive care unit (ICU) stay. Primary outcome measure was the Sequential Organ Failure Assessment (SOFA) score on the second postoperative day. Secondary endpoints included the change in perioperative selenium levels, change of inflammatory and cardiac markers, use of vasoactive medication, incidence of acute kidney injury, ICU and hospital length of stay, and mortality.
Results: The perioperative administration of high-dose sodium selenite prevented the postoperative drop of blood and serum selenium levels, reduced the number of patients depending on postoperative vasoactive support but failed to reduce the postoperative SOFA score and its related organ-specific scores compared to placebo. Except for an increase of postoperative procalcitonin and bilirubin levels in the sodium selenite group, other inflammatory markers, organ function variables and clinical endpoints remained unchanged.
Conclusions: The perioperative administration of high-dose sodium selenite in cardiac surgery patients prevented the postoperative fall of blood selenium levels and reduced the need for postoperative vasoactive support by a yet unknown mechanism.
Trial registration: Registered under ClinicalTrials.gov Identifier no. NCT01141556.
Winzeler B, da Conceição I, Refardt J, Sailer CO, Dutilh G, Christ-Crain M (2018) Effects of glucagon-like peptide-1 receptor agonists on hypothalamic-pituitary-adrenal axis in healthy volunteers. J Clin Endocrinol Metab (online)
Naegelin Y, M. MR, Andelova M, Felten Sv, Fischer-Barnicol B, Amann M, Mehling M, Kappos L, Sprenger T, Derfuss T (2018) Shortening the washout to 4 weeks when switching from natalizumab to fingolimod and risk of disease reactivation in multiple sclerosis. Mult Scler Relat Disord 25:14--20 (online)
BACKGROUND: There is limited evidence about the optimal length of washout when switching from natalizumab to fingolimod.
OBJECTIVE: To study if a washout period of 4 weeks is associated with less disease activity compared to 8 weeks.
METHODS: 25 patients with Relapsing Remitting Multiple Sclerosis were included in an open label, prospective study with a follow-up of 108 weeks. The primary endpoint (PE) was defined as “time to first relapse or MRI disease activity up to week 56”. In addition, a recurrent event analysis (REA) was performed up to week 108.
RESULTS: The PE was not met (HR 0.67, 95% CI [0.22,1.97], p=0.462). Number of relapses before stopping natalizumab was positively associated with the hazard of relapse (HR 3.91, p=0.0117, 95% CI [1.36, 11.28]). The REA showed a reduction of the hazard to develop a relapse by 77% (HR 0.23, 95% CI [0.08, 0.69], p=0.00854) in favor of the cohort with 4 week washout.
CONCLUSIONS: Our study suggests that switching from natalizumab to fingolimod with a shorter washout of 4 weeks might reduce the risk of disease reactivation after switching.
von Niederhäusern B, Guyatt GH, Briel M, Pauli-Magnus C (2018) Academic response to improving value and reducing waste: a comprehensive framework for INcreasing QUality In patient-oriented academic clinical REsearch (INQUIRE). PLoS Med 15:e1002580 (online)

2017

Becker C, Achermann S, Rocque M, Kirenko I, Schlack A, Dreher-Hummel T, Zumbrunn T, Bingisser R, Nickel CH (2017) Camera-based measurement of respiratory rates is reliable. Eur J Emerg Med Publish Ahead of Print (online)
Objectives: Respiratory rate (RR) is one of the most important vital signs used to detect whether a patient is in critical condition. It is part of many risk scores and its measurement is essential for triage of patients in emergency departments. It is often not recorded as measurement is cumbersome and time-consuming. We intended to evaluate the accuracy of camera-based measurements as an alternative measurement to the current practice of manual counting. Materials and methods: We monitored the RR of healthy male volunteers with a camera-based prototype application and simultaneously by manual counting and by capnography, which was considered the gold standard. The four assessors were mutually blinded. We simulated normoventilation, hypoventilation and hyperventilation as well as deep, normal and superficial breathing depths to assess potential clinical settings. The volunteers were assessed while being undressed, wearing a T-shirt or a winter coat. Results: In total, 20 volunteers were included. The results of camera-based measurements of RRs and capnography were in close agreement throughout all clothing styles and respiratory patterns (Pearson's correlation coefficient, r=0.90-1.00, except for one scenario, in which the volunteer breathed slowly dressed in a winter coat r=0.84). In the winter-coat scenarios, the camera-based prototype application was superior to human counters. Conclusion: In our pilot study, we found that camera-based measurements delivered accurate and reliable results. Future studies need to show that camera-based measurements are a secure alternative for measuring RRs in clinical settings as well. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
Conen D, Rodondi N, Mueller A, Beer J, Auricchio A, Ammann P, Hayoz D, Kobza R, Moschovitis G, Shah D, Schläpfer J, Novak J, Di Valentino M, Erne P, Sticherling C, Bonati LH, Ehret G, Roten L, Fischer U, Monsch A, Stippich C, Wuerfel J, Schenkglenks M, Kühne M, Osswald S (2017) Design of the Swiss Atrial Fibrillation Cohort Study (Swiss-AF): structural brain damage and cognitive decline among patients with atrial fibrillation.. Swiss Med Wkly 147:w14467 (online)
Disanto G, Barro C, Benkert P, Naegelin Y, Schädelin S, Giardiello A, Zecca C, Blennow K, Zetterberg H, Leppert D, Kappos L, Gobbi C, Kuhle J, Group tSMSCS (2017) Serum neurofilament light: A biomarker of neuronal damage in multiple sclerosis. Ann Neurol (online)
Objective: Neurofilament light chains (NfL) are unique to neuronal cells, are shed to the cerebrospinal fluid (CSF), and are detectable at low concentrations in peripheral blood. Various diseases causing neuronal damage have resulted in elevated CSF concentrations. We explored the value of an ultrasensitive single-molecule array (Simoa) serum NfL (sNfL) assay in multiple sclerosis (MS).
Methods: sNfL levels were measured in healthy controls (HC, n = 254) and two independent MS cohorts: (1) cross-sectional with paired serum and CSF samples (n = 142), and (2) longitudinal with repeated serum sampling (n = 246, median follow-up = 3.1 years, interquartile range [IQR] = 2.0–4.0). We assessed their relation to concurrent clinical, imaging, and treatment parameters and to future clinical outcomes.
Results: sNfL levels were higher in both MS cohorts than in HC (p < 0.001). We found a strong association between CSF NfL and sNfL (β = 0.589, p < 0.001). Patients with either brain or spinal (43.4pg/ml, IQR = 25.2–65.3) or both brain and spinal gadolinium-enhancing lesions (62.5pg/ml, IQR = 42.7–71.4) had higher sNfL than those without (29.6pg/ml, IQR = 20.9–41.8; β = 1.461, p = 0.005 and β = 1.902, p = 0.002, respectively). sNfL was independently associated with Expanded Disability Status Scale (EDSS) assessments (β = 1.105, p < 0.001) and presence of relapses (β = 1.430, p < 0.001). sNfL levels were lower under disease-modifying treatment (β = 0.818, p = 0.003). Patients with sNfL levels above the 80th, 90th, 95th, 97.5th, and 99th HC-based percentiles had higher risk of relapses (97.5th percentile: incidence rate ratio = 1.94, 95\% confidence interval [CI] = 1.21–3.10, p = 0.006) and EDSS worsening (97.5th percentile: OR = 2.41, 95\% CI = 1.07–5.42, p = 0.034).
Interpretation: These results support the value of sNfL as a sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS.
D’Souza M, Yaldizli Ö, John R, Vogt DR, Papadopoulou A, Lucassen E, Menegola M, Andelova M, Dahlke F, Schnyder F, Kappos L (2017) Neurostatus e-Scoring improves consistency of Expanded Disability Status Scale assessments: a proof of concept study. Mult Scler 23:597--603 (online)
BACKGROUND: To improve the consistency of standardized Expanded Disability Status Scale (EDSS) assessments, an electronic data capture tool and analysis tool was developed, Neurostatus e-Scoring (NESC). This tool allows real-time feedback by comparing entries with established scoring rules. OBJECTIVE: To test whether using NESC reduces inconsistencies as compared to the paper-and-pencil version of the Expanded Disability Status Scale (pEDSS). METHODS: In all, 100 multiple sclerosis (MS) patients were assessed in random order on the same day by pairs of neurologists, one using pEDSS and one NESC. We compared inter-rater reliability and frequency of inconsistencies in Neurostatus subscores, functional system (FS) scores, ambulation and EDSS steps. RESULTS: Inconsistencies of any type were more likely to occur when using pEDSS (mean odds ratio (95% confidence interval (CI)) = 2.93 (1.62; 5.29)). This was also the case for FS score inconsistencies (2.54 (1.40; 4.61)) and more likely for patients in the lower EDSS range (⩽3.5 vs >3.5) (5.32 (1.19; 23.77)). Overall, inter-rater agreement for the assessed Neurostatus subscores was high (median and inter-quartile range = 0.84 (0.73, 0.81)). CONCLUSION: Our data provide class II evidence that the use of NESC increases consistency of standardized EDSS assessments, and may thus have the potential to decrease noise and increase power of MS clinical trials.
Edelmann C, Ghiassi R, Vogt DR, Partridge MR, Khatami R, Leuppi JD, Miedinger D (2017) A pictorial Sleepiness and Sleep Apnoea Scale to recognize individuals with high risk for obstructive sleep apnea syndrome. Nat Sci Sleep 9:253--265 (online)
Erne P, Resink TJ, Mueller A, Coslovsky M, Kobza R, Conen D, Bauer P, Arand P (2017) Use of acoustic cardiography immediately following electrical cardioversion to predict relapse of atrial fibrillation. J Atr Fibrillation 10 (online)
Geiger S, Bobylev A, Schädelin S, Mayr J, Holland-Cunz S, Zimmermann P (2017) Single-center, retrospective study of the outcome of laparoscopic inguinal herniorrhaphy in children. Medicine (Baltimore) 96:e9486 (online)
Hemkens L, Saccilotto R, Reyes S, Glinz D, Zumbrunn T, Grolimund O, Gloy V, Raatz H, Widmer A, Zeller A, Bucher H (2017) Personalized prescription feedback using routinely collected data to reduce antibiotic use in primary care: a randomized clinical trial. JAMA Intern Med 177:176--183 (online)
Hollinger A, Ledergerber K, von Felten S, Sutter R, Rüegg S, Gantner L, Zimmermann S, Blum A, Steiner LA, Marsch S, Siegemund M (2017) Comparison of propofol and dexmedetomidine infused overnight to treat hyperactive and mixed ICU delirium: a protocol for the Basel ProDex clinical trial. BMJ Open 7:e015783 (online)
Huhn EA, Visca E, Vogt DR, von Felten S, Tinner Oehler EM, Bührer C, Surbek D, Zimmermann R, Hoesli I (2017) Decreased neonatal pain response after vaginal-operative delivery with Kiwi OmniCup versus metal ventouse. BMC Pregnancy and Childbirth 17:47 (online)
Background: Vaginal delivery, especially operative assisted vaginal delivery, seems to be a major stressor for the neonate. The objective of this study was to evaluate the stress response after metal cup versus Kiwi Omnicup® ventouse delivery. Methods: The study was a secondary observational analysis of data from a former prospective randomised placebo controlled multicentre study on the analgesic effect of acetaminophen in neonates after operative vaginal delivery and took place at three Swiss tertiary hospitals. Healthy pregnant women ≥35 weeks of gestation with an estimated fetal birth weight above 2000 g were recruited after admission to the labour ward. Pain reaction was analysed by pain expression score EDIN scale (Échelle Douleur Inconfort Nouveau-Né, neonatal pain and discomfort scale) directly after delivery. For measurement of the biochemical stress response, salivary cortisol as well as the Bernese Pain Scale of Newborns (BPSN) were evaluated before and after an acute pain stimulus (the standard heel prick for metabolic testing (Guthrie test) at 48–72 h. Results: Infants born by vaginal operative delivery displayed a lower pain response after plastic cup than metal cup ventouse delivery (p < 0.001), but the pain response was generally lower than expected and they recovered fully within 72 h. Conclusions: Neonatal pain response is slightly reduced after use of Kiwi OmniCup® versus metal cup ventouse.
Kaspar M, Imfeld S, Partovi S, Aschwanden M, Baldi T, Dikkes A, Vogt D, Tsakiris D, Staub D (2017) Perivascular perfusion on contrast-enhanced ultrasound (CEUS) is associated with inflammation in patients with acute deep vein thrombosis. Thromb Haemost 117:2146--2155 (online)
Katapodi MC, Viassolo V, Caiata-Zufferey M, Nikolaidis C, Bührer-Landolt R, Buerki N, Graffeo R, Horváth HC, Kurzeder C, Rabaglio M, Scharfe M, Urech C, Erlanger TE, Probst-Hensch N, Heinimann K, Heinzelmann-Schwarz V, Pagani O, Chappuis PO (2017) Cancer predisposition cascade screening for hereditary breast/ovarian cancer and lynch syndromes in Switzerland: study protocol. JMIR Research Protocols 6 (online)
Meyer-Zehnder B, Schleger HA, Tanner S, Schnurrer V, Vogt DR, Reiter-Theil S, Pargger H (2017) How to introduce medical ethics at the bedside - factors influencing the implementation of an ethical decision-making model. BMC Med Ethics 18:16 (online)
Background
As the implementation of new approaches and procedures of medical ethics is as complex and resource-consuming as in other fields, strategies and activities must be carefully planned to use the available means and funds responsibly. Which facilitators and barriers influence the implementation of a medical ethics decision-making model in daily routine? Up to now, there has been little examination of these factors in this field. Methods
A medical ethics decision-making model called METAP was introduced on three intensive care units and two geriatric wards. An evaluation study was performed from 7 months after deployment of the project until two and a half years. Quantitative and qualitative methods including a questionnaire, semi-structured face-to-face and group-interviews were used. Results
Sixty-three participants from different professional groups took part in 33 face-to-face and 9 group interviews, and 122 questionnaires could be analysed. The facilitating factors most frequently mentioned were: acceptance and presence of the model, support given by the medical and nursing management, an existing or developing (explicit) ethics culture, perception of a need for a medical ethics decision-making model, and engaged staff members. Lack of presence and acceptance, insufficient time resources and staff, poor inter-professional collaboration, absence of ethical competence, and not recognizing ethical problems were identified as inhibiting the implementation of the METAP model. However, the results of the questionnaire as well as of explicit inquiry showed that the respondents stated to have had enough time and staff available to use METAP if necessary. Conclusions
Facilitators and barriers of the implementation of a medical ethics decision-making model are quite similar to that of medical guidelines. The planning for implementing an ethics model or guideline can, therefore, benefit from the extensive literature and experience concerning the implementation of medical guidelines. Lack of time and staff can be overcome when people are convinced that the benefits justify the effort.
Mueller SM, Itin P, Vogt DR, Walter M, Lang U, Griffin LL, Euler S (2017) Assessment of “corticophobia” as an indicator of non-adherence to topical corticosteroids: a pilot study. J Dermatolog Treat 28:104--111 (online)
Background: Concerns regarding topical corticosteroid (TCS) use, broadly known as ‘‘corticophobia’’, are highly prevalent among dermatology patients and often result in non-adherence to TCS. This non-adher- ence contributes to poor disease control and increased health care costs. However, it is unknown if assess- ment of these concerns might help to identify patients at risk of TCS-non-adherence. Clinical tools indicating non-adherence could be helpful to improve management of this patient group. Objective: To assess whether the available tools for measuring concerns regarding corticosteroids, the TOPICOP scale and the 0-10 Visual Analogue Scale (VAS), could help to detect non-adherence to TCS. Methods: In 75 patients with concerns regarding TCS use both the TOPICOP scale and VAS were anonym- ously assessed. A comparison was made between TCS-adherent and non-adherent patients regarding the intensity and characteristics of their concerns. Results: The intensity and quality of the concerns varied broadly among the patients. When using the VAS, a score of 5 detected 87% of non-adherent patients. The answers to the TOPICOP scale did not discrimin- ate non-adherent from adherent patients. Conclusion: Using the VAS to assess concerns to use TCS could help identify patients at risk of TCS-non- adherence and facilitate discussion with the patient about potential non-adherence in a more substanti- ated, non-judgemental way.
Mueller SM, Tomaschett D, Vogt DR, Itin P, Cozzio A, Surber C (2017) Topical corticosteroid concerns from the clinicians’ perspective. J Dermatolog Treat 28:464--468 (online)
Purpose: Topical corticosteroids concerns (TCC) are common in dermatology patients, possibly leading to non-adherence to topical corticosteroids (TCS) and poor disease control. Clinicians play a key role in that context, as they can reduce or reinforce these concerns. It is unknown, if clinicians have accurate knowledge of TCC to appropriately address this issue and whether they have concerns themselves to use TCS. This questionnaire-based study aimed to assess these two aspects.
Materials and methods: Accuracy of knowledge was defined by how close the clinicians’ estimates were to reference values of our previous study, in which we had examined TCC in dermatology outpatients. Moreover, clinicians indicated whether they have concerns themselves to use TCS.
Results: Totally 202 clinicians participated. They underestimated both the prevalence of TCC and the resulting non-adherence. Whereas most clinicians correctly estimated characteristics of patients with TCC and the impact of patient information, only 31% of clinicians knew that skin atrophy was the leading concern, and only 30% correctly ranked the reasons for TCC. 74% of the clinicians had at least minor concerns themselves.
Conclusion: The majority of clinicians may have inaccurate knowledge of certain aspects of TCC and own concerns to use TCS.
Mujagic E, Marti WR, Coslovsky M, Zeindler J, Staubli S, Marti R, Mechera R, Soysal SD, Gürke L, Weber WP (2017) The role of preoperative blood parameters to predict the risk of surgical site infection. Am J Surg (online)
Refardt J, Winzeler B, Meienberg F, Vogt DR, Christ-Crain M (2017) Empagliflozin increases short-term urinary volume output in artificially induced syndrome of inappropriate antidiuresis. Int J Endocrinology 2017 (online)
Objective. Syndrome of inappropriate antidiuresis (SIADH) is the predominant cause of hyponatremia, but treatment options are unsatisfying. SGLT2 inhibitors increase urinary glucose excretion with concomitant osmotic diuresis. We therefore hypothesized SGLT2-inhibitors as a novel treatment for SIADH. Design. Double-blind placebo-controlled randomised crossover study in 14 healthy volunteers. Methods. We induced an artificial SIADH model by administration of desmopressin and overhydration. Afterwards, empagliflozin 25 mg or placebo was given in random order. The main outcomes were total urinary excretion, glucosuria, and the area under the curve (AUC) of serum sodium concentration. Outcome measures were obtained 2–8 hours after administration of study drug. Results. 14 participants (64% males), BMI 23 kg/m2 (±2.4), aged 28.6 years (±9), completed the study. Empagliflozin led to significantly increased total urinary excretion (579.3 ml (±194.8) versus 367.3 ml (±158.8); treatment effect 158 ml (CI 48.29, 267.74), ) due to glucosuria (74.18 mmol (±22.3) versus 0.12 mmol (±0.04); treatment effect (log scale) 2.85 (CI 2.75, 2.96), ). There was no difference in the AUC of serum sodium concentration (treatment effect 0.2 (CI −7.38, 6.98), ). Conclusion. In our SIADH model, empagliflozin increased urinary excretion due to osmotic diuresis. Due to the short treatment duration, serum sodium levels remained unchanged. Real-live studies are needed to further examine empagliflozin as a new treatment for SIADH.
Schmidt S, Gocheva V, Zumbrunn T, Rubino-Nacht D, Bonati U, Fischer D, Hafner P (2017) Treatment with L-citrulline in patients with post-polio syndrome: study protocol for a single-center, randomised, placebo-controlled, double-blind trial. Trials 18:116 (online)
Post-polio syndrome (PPS) is a condition that affects polio survivors years after recovery from an initial acute infection by the Poliomyelitis virus. Most often, patients who suffered from polio start to experience gradual new weakening in muscles, a gradual decrease in the size of muscles (muscle atrophy) and fatigue years after the acute illness. L-citrulline is known to change muscular metabolism synthesis by raising nitric oxide (NO) levels and increasing protein synthesis. This investigator-initiated, randomised, placebo-controlled, double-blind, trial aims to demonstrate that L-citrulline positively influences muscle function and increases muscular energy production in patients with PPS.
Schneeberger AR, Kowalinski E, Fröhlich D, Schröder K, von Felten S, Zinkler M, Beine KH, Heinz A, Borgwardt S, Lang UE, Bux DA, Huber CG (2017) Aggression and violence in psychiatric hospitals with and without open door policies: A 15-year naturalistic observational study. J Psychiatr Res 95:189--195 (online)
Sticherling C, Arendacka B, Svendsen JH, Wijers S, Friede T, Stockinger J, Dommasch M, Merkely B, Willems R, Lubinski A, Scharfe M, Braunschweig F, Svetlosak M, Zürn CS, Huikuri H, Flevari P, Lund-Andersen C, Schaer BA, Tuinenburg AE, Bergau L, Schmidt G, Szeplaki G, Vanderberk B, Kowalczy E, Eick C, Juntilla J, Conen D, Zabel MftEi (2017) Sex differences in outcomes of primary prevention implantable cardioverter defibrillator therapy: combined registry data from eleven European countries. EP Europace (online)
Aims: Therapy with an implantable cardioverter defibrillator (ICD) is established for the prevention of sudden cardiac death (SCD) in high risk patients. We aimed to determine the effectiveness of primary prevention ICD therapy by analysing registry data from 14 centres in 11 European countries compiled between 2002 and 2014, with emphasis on outcomes in women who have been underrepresented in all trials.
Methods and results: Retrospective data of 14 local registries of primary prevention ICD implantations between 2002 and 2014 were compiled in a central database. Predefined primary outcome measures were overall mortality and first appropriate and first inappropriate shocks. A multivariable model enforcing a common hazard ratio for sex category across the centres, but allowing for centre-specific baseline hazards and centre specific effects of other covariates, was adjusted for age, the presence of ischaemic cardiomyopathy or a CRT-D, and left ventricular ejection fraction ≤25%. Of the 5033 patients, 957 (19%) were women. During a median follow-up of 33 months (IQR 16–55 months) 129 women (13%) and 807 men (20%) died (HR 0.65; 95% CI: [0.53, 0.79], P-value < 0.0001). An appropriate ICD shock occurred in 66 women (8%) and 514 men (14%; HR 0.61; 95% CI: 0.47–0.79; P = 0.0002). Conclusion: Our retrospective analysis of 14 local registries in 11 European countries demonstrates that fewer women than men undergo ICD implantation for primary prevention. After multivariate adjustment, women have a significantly lower mortality and receive fewer appropriate ICD shocks.
Vogel N, Schandelmaier S, Zumbrunn T, Ebrahim S, de Boer WE, Busse JW, Kunz R (2017) Effect of return-to-work coordination programmes for workers on sick leave. Cochrane Database Syst Rev. (online)
Wein B, Coslovsky M, Jabbari R, Galatius S, Pfisterer M, Kaiser C (2017) Prasugrel vs. clopidogrel in contemporary Western European patients with acute coronary syndromes receiving drug-eluting stents: Comparative cost-effectiveness analysis from the BASKET-PROVE cohorts. Int J Cardiol (online)
Background: Clinical and cost-effectiveness of prasugrel vs clopidogrel in acute coronary syndrome (ACS) was only evaluated using TRITON-TIMI 38 event rates. A comparative analysis of both drugs in contemporary European ACS patients is lacking.
Methods: To address this issue, cardiac and bleeding events of 2 “sister” multicenter stent trials, BASKET-PROVE (BP) I with clopidogrel and BPII with prasugrel (for 12 months each) were used in a hybrid analysis. Medication costs were 2015 sales prices, event costs modelled for Denmark (DNK), Germany (GER) and Switzerland (SUI) and quality adjusted life years (QALY) by EQ-5D-3L questionnaire.
Results: In BPI and II, 1012 and 985 ACS-patients received drug eluting stents, respectively, followed-up for 2 years. Compared to clopidogrel, prasugrel-treated patients had no more major cardiac events (5.2% vs 6.4%, p=0.422) nor cardiac deaths (1.6% vs. 1.0%, p=0.255), but more major bleedings (4.0% vs. 1.7%, p<0.001) and altogether no difference in QALYs (-0.027 (95% CI: -0.064/0.011)). Prasugrel caused higher total expenditures per patient: 1’116.3 (DNK), 1’063.5 (GER) and 880.8 (SUI) EURO, respectively. Accordingly, incremental cost-effectiveness was negativefor prasugrel vs clopidogrel with ratios of -45’907 (DNK), -39’909 (GER) and -33’435 (SUI) EURO/QALY gained, making clopidogrel an economically dominant strategy, even after accounting for the non-randomized comparison.
Conclusion: Findings of this contemporary European ACS-cohort showed markedly lower cardiac event rates than TRITON-TIMI 38 and no significant difference in 2-year QALYs between prasugrel and clopidogrel-treated patients. At current drug prices, clopidogrel use resulted in an economically dominant treatment strategy in Western European patients.
Zbinden R, von Felten S, Wein B, Tueller D, Kurz DJ, Reho I, Galatius S, Alber H, Conen D, Pfisterer M, Kaiser C, Eberli FR (2017) Impact of stent diameter and length on in-stent restenosis after DES vs BMS implantation in patients needing large coronary stents--a clinical and health-economic evaluation. Cardiovasc Ther 35:19--25 (online)
Objectives: To evaluate prevalence, progression, treatment, and outcome of silent coronary artery disease (CAD) in asymptomatic patients with diabetes (DM) at high coronary risk. Background: Despite the close association of diabetes and CAD, general CAD screening in asymptomatic patients with DM is discouraged even though outcome data in patients at high coronary risk are lacking. Methods: Prospective multicenter outcome study—with a pilot randomized treatment substudy. The study comprised 400 asymptomatic patients with DM (type 2) without history or symptoms of CAD at high CAD risk. They underwent clinical evaluation and myocardial perfusion single-photon emission computed tomography (MPS) at baseline and after 2 years. Patients with normal MPS received usual care; those with abnormal MPS received medical or combined invasive and medical management. Results: An abnormal MPS was found in 87 of 400 patients (22%). In patients with normal MPS, MACE occurred in 2.9% and ischemia or new scar in 3.2%. Patients with abnormal MPS had more MACE (9.8%; hazard ratio: 3.44; 95% confidence interval [CI]: 1.32 to 8.95; p = 0.011) and ischemia or new scar (34.2%; odds ratio: 15.91; 95% CI: 7.24 to 38.03; p < 0.001) despite therapy, resulting in “overt or silent CAD progression” of 35.6% versus 4.6% (odds ratio: 11.53; 95% CI: 5.63 to 24.70; p < 0.001). Patients with abnormal MPS randomized to medical versus invasive-medical strategies had similar event rates (p = 0.215), but more ischemic or new scar findings (54.3% vs. 15.8%; p < 0.001). Conclusions: High-risk asymptomatic patients with DM and normal MPS (78%) have a low rate of first manifestations of CAD. Patients with abnormal MPS at baseline (22%) have a 7-fold higher rate of progression to “overt or silent CAD,” despite therapy. Randomized patients’ outcomes suggest that a combined invasive and medical strategy for silent CAD may reduce scintigraphic but not symptomatic CAD progression versus medical therapy alone. (Trial of Invasive versus Medical therapy of Early coronary artery disease in Diabetes Mellitus [TIME-DM]; ISRCTN87953632).
Zimmer A, Coslovsky M, Abraham I, Décard BF (2017) Adherence to fingolimod in multiple sclerosis: an investigator-initiated, prospective, observational, single-center cohort study. Patient Prefer Adherence 11:1815--1830 (online)
von Niederhäusern B, Orleth A, Schädelin S, Rawi N, Velkopolszky M, Becherer C, Benkert P, Satalkar P, Briel M, Pauli-Magnus C (2017) Generating evidence on a risk-based monitoring approach in the academic setting - lessons learned. BMC Med Res Methodol 17:26 (online)
Background: In spite of efforts to employ risk-based strategies to increase monitoring efficiency in the academic setting, empirical evidence on their effectiveness remains sparse. This mixed-methods study aimed to evaluate the risk-based on-site monitoring approach currently followed at our academic institution.
Methods: We selected all studies monitored by the Clinical Trial Unit (CTU) according to Risk ADApted MONitoring (ADAMON) at the University Hospital Basel, Switzerland, between 01.01.2012 and 31.12.2014. We extracted study characteristics and monitoring information from the CTU Enterprise Resource Management system and from monitoring reports of all selected studies. We summarized the data descriptively. Additionally, we conducted semi-structured interviews with the three current CTU monitors.
Results: During the observation period, a total of 214 monitoring visits were conducted in 43 studies resulting in 2961 documented monitoring findings. Our risk-based approach predominantly identified administrative (46.2%) and patient right findings (49.1%). We identified observational study design, high ADAMON risk category, industry sponsorship, the presence of an electronic database, experienced site staff, and inclusion of vulnerable study population to be factors associated with lower numbers of findings. The monitors understand the positive aspects of a risk-based approach but fear missing systematic errors due to the low frequency of visits.
Conclusions: We show that the factors mostly increasing the risk for on-site monitoring findings are underrepresented in the current risk analysis scheme. Our risk-based on-site approach should further be complemented by centralized data checks, allowing monitors to transform their role towards partners for overall trial quality, and success.
von Niederhäusern B, Saccilotto R, Schädelin S, Ziesenitz V, Benkert P, Decker M, Hammann A, Bielicki J, Pfister M, Pauli-Magnus C (2017) Validity of mobile electronic data capture in clinical studies: a pilot study in a pediatric population. BMC Med Res Methodol 17:163 (online)
von Niederhäusern B, Schandelmaier S, Bonde MM, Brunner N, Hemkens LG, Rutquist M, Bhatnagar N, Guyatt GH, Pauli-Magnus C, Briel M (2017) Towards the development of a comprehensive framework: qualitative systematic survey of definitions of clinical research quality. PLoS One 12:e0180635 (online)
Objective: To systematically survey existing definitions, concepts, and criteria of clinical research quality, both developed by stakeholder groups as well as in the medical literature. This study serves as a first step in the development of a comprehensive framework for the quality of clinical research.
Study design and setting: We systematically and in duplicate searched definitions, concepts and criteria of clinical research quality on websites of stakeholders in clinical research until no further insights emerged and in MEDLINE up to February 2015. Stakeholders included governmental bodies, regulatory agencies, the pharmaceutical industry, academic and commercial contract research organizations, initiatives, research ethics committees, patient organizations and funding agencies from 13 countries. Data synthesis involved descriptive and qualitative analyses following the Framework Method on definitions, concepts, and criteria of clinical research quality. Descriptive codes were applied and grouped into clusters to identify common and stakeholder-specific quality themes.
Results: Stakeholder concepts on how to assure quality throughout study conduct or articles on quality assessment tools were common, generally with no a priori definition of the term quality itself. We identified a total of 20 explicit definitions of clinical research quality including varying quality dimensions and focusing on different stages in the clinical research process. Encountered quality dimensions include ethical conduct, patient safety/rights/priorities, internal validity, precision of results, generalizability or external validity, scientific and societal relevance, transparency and accessibility of information, research infrastructure and sustainability. None of the definitions appeared to be comprehensive either in terms of quality dimensions, research stages, or stakeholder perspectives.
Conclusion: Clinical research quality is often discussed but rarely defined. A framework defining clinical research quality across stakeholders’ individual perspectives is desirable to facilitate discussion, assessment, and improvement of quality at all stages of clinical research.

2016

Bachmann M, de Boer W, Schandelmaier S, Leibold A, Marelli R, Jeger J, Hoffmann-Richter U, Mager R, Schaad H, Zumbrunn T, Vogel N, Bänziger O, Busse JW, Fischer K, Kunz R (2016) Use of a structured functional evaluation process for independent medical evaluations of claimants presenting with disabling mental illness: rationale and design for a multi-center reliability study. BMC Psychiatry 16:1--12 (online)
Work capacity evaluations by independent medical experts are widely used to inform insurers whether injured or ill workers are capable of engaging in competitive employment. In many countries, evaluation processes lack a clearly structured approach, standardized instruments, and an explicit focus on claimants' functional abilities. Evaluation of subjective complaints, such as mental illness, present additional challenges in the determination of work capacity. We have therefore developed a process for functional evaluation of claimants with mental disorders which complements usual psychiatric evaluation. Here we report the design of a study to measure the reliability of our approach in determining work capacity among patients with mental illness applying for disability benefits.
Disanto G, Benkert P, Lorscheider J, Mueller S, Vehoff J, Zecca C, Ramseier S, Achtnichts L, Findling O, Nedeltchev K, W. RE, Sprenger T, Stippich C, Derfuss T, Louvion J, Kamm CP, Mattle HP, Lotter C, Du Pasquier R, Schluep M, Pot C, Lalive PH, Yaldizli \, Gobbi C, Kappos L, Kuhle J, Board tSMSCS (2016) The Swiss Multiple Sclerosis Cohort-study (SMSC): a prospective Swiss wide investigation of key phases in disease evolution and new treatment options. PLoS One 11:e0152347 (online)
The mechanisms leading to disability and the long-term efficacy and safety of disease modifying drugs (DMDs) in multiple sclerosis (MS) are unclear. We aimed at building a prospective cohort of MS patients with standardized collection of demographic, clinical, MRI data and body fluids that can be used to develop prognostic indicators and biomarkers of disease evolution and therapeutic response. The Swiss MS Cohort (SMSC) is a prospective observational study performed across seven Swiss MS centers including patients with MS, clinically isolated syndrome (CIS), radiologically isolated syndrome or neuromyelitis optica. Neurological and radiological assessments and biological samples are collected every 6–12 months. We recruited 872 patients (clinically isolated syndrome [CIS] 5.5%, relapsing-remitting MS [RRMS] 85.8%, primary progressive MS [PPMS] 3.5%, secondary progressive MS [SPMS] 5.2%) between June 2012 and July 2015. We performed 2,286 visits (median follow-up 398 days) and collected 2,274 serum, plasma and blood samples, 152 cerebrospinal fluid samples and 1,276 brain MRI scans. 158 relapses occurred and expanded disability status scale (EDSS) scores increased in PPMS, SPMS and RRMS patients experiencing relapses. Most RRMS patients were treated with fingolimod (33.4%), natalizumab (24.5%) or injectable DMDs (13.6%). The SMSC will provide relevant information regarding DMDs efficacy and safety and will serve as a comprehensive infrastructure available for nested research projects.
Hafner P, Bonati U, Rubino D, Gocheva V, Zumbrunn T, Gueven N, Fischer D (2016) Treatment with L-citrulline and metformin in Duchenne muscular dystrophy: study protocol for a single-centre, randomised, placebo-controlled trial. Trials 17:389 (online)
Hemkens LG, Saccilotto R, Reyes SL, Glinz D, Zumbrunn T, Grolimund O, Gloy V, Raatz H, Widmer A, Zeller A, Bucher HC (2016) Personalized prescription feedback to reduce antibiotic overuse in primary care: rationale and design of a nationwide pragmatic randomized trial. BMC Infect Dis 16:1--8 (online)
Antimicrobial resistance has become a serious worldwide public health problem and is associated with antibiotic overuses. Whether personalized prescription feedback to high antibiotic prescribers using routinely collected data can lower antibiotic use in the long run is unknown.
Huber CG, Schneeberger AR, Kowalinski E, Fröhlich D, von Felten S, Walter M, Zinkler M, Beine K, Heinz A, Borgwardt S, Lang UE (2016) Suicide risk and absconding in psychiatric hospitals with and without open door policies: a 15 year, observational study. Lancet Psychiatry 3:842--849 (online)
Background: Inpatient suicide and absconding of inpatients at risk of self-endangering behaviour are important challenges for all medical disciplines, particularly psychiatry. Patients at risk are often admitted to locked wards in psychiatric hospitals to prevent absconding, suicide attempts, and death by suicide. However, there is insufficient evidence that treatment on locked wards can effectively prevent these outcomes. We did this study to compare hospitals without locked wards and hospitals with locked wards and to establish whether hospital type has an effect on these outcomes. Methods: In this 15 year, naturalistic observational study, we examined 349 574 admissions to 21 German psychiatric inpatient hospitals from Jan 1, 1998, to Dec 31, 2012. We used propensity score matching to select 145 738 cases for an analysis, which allowed for causal inference on the effect of ward type (ie, locked, partly locked, open, and day clinic wards) and hospital type (ie, hospitals with and without locked wards) on suicide, suicide attempts, and absconding (with and without return), despite the absence of an experimental design. We used generalised linear mixed-effects models to analyse the data. Findings: In the 145 738 propensity score-matched cases, suicide (OR 1·326, 95% CI 0·803–2·113; p=0·24), suicide attempts (1·057, 0·787–1·412; p=0·71), and absconding with return (1·288, 0·874–1·929; p=0·21) and without return (1·090, 0·722–1·659; p=0·69) were not increased in hospitals with an open door policy. Compared with treatment on locked wards, treatment on open wards was associated with a decreased probability of suicide attempts (OR 0·658, 95% CI 0·504–0·864; p=0·003), absconding with return (0·629, 0·524–0·764; p<0·0001), and absconding without return (0·707, 0·546–0·925; p=0·01), but not completed suicide (0·823, 0·376–1·766; p=0·63). Interpretation: Locked doors might not be able to prevent suicide and absconding. Funding: None.
Huber CG, Schneeberger AR, Kowalinski E, Fröhlich D, von Felten S, Walter M, Zinkler M, Beine K, Heinz A, Borgwardt S, Lang UE (2016) Arbitrary classification of hospital policy regarding open and locked doors – Authors' reply. Lancet Psychiatry 3:1103–-1104 (online)
Jeger R, Pfisterer M, Pfister O, Rickenbacher P, Handke M, Gilgen N, Coslovsky M, Kaiser C (2016) First-generation paclitaxel-vs. second-generation zotarolimus-eluting stents in small coronary arteries: the BASKET-SMALL Pilot Study. Advances in Interventional Cardiology 12:46 (online)
Introduction: Event rates after percutaneous coronary interventions (PCI) are higher in small than large coronary vessels but may vary between different drug-eluting stent (DES) types. Aim: To assess the efficacy of two different DES in small vessel disease. Materials and methods: Patients with small vessel PCI were randomised 1 : 1 to a first-generation paclitaxel- vs. a second-generation zotarolimus-eluting stent. The primary endpoint was a composite of cardiac death, non-fatal myocardial infarction, and target vessel revascularisation after 2 years. Results: Overall, 191 patients were enrolled: 100 with a paclitaxel- and 91 with a zotarolimus-eluting stent. Baseline characteristics were similar in both groups. After 2 years, rates of the primary endpoint were numerically higher for zotarolimus- than paclitaxel-eluting stents (9.9% vs. 5.0%, hazard ratio 2.09, 95% confidence interval (CI) 0.7-6.2, p = 0.19), which was mainly driven by higher rates of target vessel revascularisation (6.6% vs. 2.0%, hazard ratio 3.39, 95% CI: 0.68-16.78, p = 0.14). Based on this, a total of 1,019 patients would be necessary to demonstrate at least non-inferiority between the DES used. Conclusions: In this pilot study, paclitaxel-eluting stents had a favourable efficacy profile in small vessel disease, although the numbers were too small to draw final conclusions. Based on the prohibitively high sample size for a randomized controlled trial between DES, other treatment options should be considered.
Jungo P, Maul J, Djamei V, von Felten S, Kolios AGA, Czernielewsk J, Yawalkar N, Odermatt O, Laffitte E, Anliker M, Streit M, Augustin M, Conrad C, Hafner J, Boehncke W, Gilliet M, Itin P, French LE, Navarini AA, Häusermann P (2016) Superiority in quality of life improvement of biologics over conventional systemic drugs in a swiss real-life psoriasis registry. Dermatology 332:655-663 (online)
Background: Randomized controlled trials have shown the efficacy of systemic treatments in moderate-to-severe psoriasis. Clinical outcomes in psoriasis patients under real-world conditions are less well understood.
Objective: This study compared Psoriasis Area and Severity Index (PASI) and Dermatological Life Quality Index (DLQI) improvement in all psoriasis patients registered in the Swiss Dermatology Network for Targeted Therapies. We asked whether outcomes differed between 4 treatment strategies, namely biologic monotherapy versus conventional systemic monotherapy, versus combined biologic and conventional systemic drugs, and versus therapy adaptation (switching from one type to another).
Methods: PASI and DLQI within 1 year after onset of systemic treatment, measured at 3, 6, and 12 months, were compared among the 4 groups using generalized linear mixed-effects models.
Results: Between March 2011 and December 2014, 334 patients were included; 151 received conventional systemic therapeutics, 145 biologics, 13 combined treatment, and 25 had a therapy adaptation. With regard to the absolute PASI, neither the biologic cohort nor the combined treatment cohort significantly differed from the conventional systemic therapeutics cohort. The odds of reaching PASI90 was significantly increased with combined therapy compared to conventional systemic therapeutics (p = 0.043) and decreased with a higher body mass index (p = 0.041). At visits 3 and 4, the PASI was generally lower than at visit 2 (visit 3 vs. visit 2, p = 0.0019; visit 4 vs. visit 2, p < 0.001). After 12 months, patients with biologic treatment had a significantly lower DLQI than those with conventional systemic therapeutics (p = 0.001).
Conclusion: This study suggests that after 1 year of treatment, biologics are superior in improving the subjective disease burden compared to conventional systemic drugs.
Leu S, von Felten S, Frank S, Boulay J, Mariani L (2016) IDH mutation is associated with higher risk of malignant transformation in low-grade glioma. J Neurooncol 127:363-372 (online)
Acquisition of IDH1 or IDH2 mutation (IDHmut) is among the earliest genetic events that take place in the development of most low-grade glioma (LGG). IDHmut has been associated with longer overall patient survival. However, its impact on malignant transformation (MT) remains to be defined. A collection of 210 archived adult LGG previously stratified by IDHmut, MGMT methylation (MGMTmet), 1p/19q combined loss of heterozygosity (1p19qloh) and TP53 immunopositivity (TP53pos) status was analyzed. We used multistate models to assess MT-free survival, considering one initial, one transient (MT), and one absorbing state (death). Missing explanatory variables were multiply imputed. Overall, although associated with a lower risk of death (HRDEATH = 0.35, P = 0.0023), IDHmut had a non-significantly higher risk of MT (HRMT = 1.84; P = 0.1683) compared to IDH wild type (IDHwt). The double combination of IDHmut and MGMTmet and the triple combination of IDHmut, MGMTmet and 1p/19qloh, despite significantly lower hazards for death (HRDEATH versus IDHwt: 0.35, P = 0.0194 and 0.15, P = 0.0008, respectively), had non-significantly different hazards for MT. Conversely, the triple combination of IDHmut/MGMTmet/TP53pos, with a non-significantly different hazard for death, had a significantly higher hazard for MT than IDHwt (HRMT versus IDHwt: 2.83; P = 0.0452). Although IDHmut status is associated with longer overall patient survival, all IDHmut/MGMTmet subsets consistently showed higher risks of MT than of death, compared to IDHwt LGG. This supports the findings that molecular events relevant to IDH mutations impact early glioma development prior to malignant transformation.
Löytved-Hardegg JJ, Brunner M, Ries J, von Felten S, Heugel C, Lapaire O, Voekt C, Hösli I (2016) Replacement of oxytocin bolus administration by infusion: influences on postpartum outcome. Arch Gynecol Obstet 293:1219--1225 (online)
Purpose: Postpartum haemorrhage (PPH) represents a leading cause of maternal morbidity and mortality. Giving oxytocin after birth reduces the risk for PPH. It has never been tested whether different methods of oxytocin administration affect the maternal outcome. This study aims to compare the infusion versus the bolus application of oxytocin after singleton vaginal delivery. Methods: This retrospective monocentre study compares the incidence of clinically relevant postpartum complications in women receiving 5 IE of oxytocin as a bolus or as a 100 ml-infusion over 5 min, given immediately after birth. Included were women delivering singletons vaginally at term. We used propensity score weighting to compare outcomes between women receiving bolus and infusion and to minimize the selection bias in this retrospective cohort. Results: 1765 patients were included. Patient characteristics were balanced. We found no significant differences for the combined overall postpartum adverse outcome (the incidence of PPH, manual removal of the placenta and/or curettage). For the single outcomes, we observed a significantly higher frequency of manual removal of the placenta (Odds ratio 1.47, 95 % CI 1.02–2.13) and a slightly higher but clinically not relevant estimated blood loss (Relative effect 1.05, 95 % CI 1.01–1.10) in the infusion group. Conclusion: The data show a tendency towards more complications in the infusion group. It is related to a more frequent need for manual removal of the placenta.
Meisel A, von Felten S, Vogt DR, Liewen H, de Wit R, de Bono J, Sartor O, Stenner-Liewen F (2016) Severe neutropenia during cabazitaxel treatment is associated with survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC): a post-hoc analysis of the TROPIC phase III trial. Eur J Cancer 56:93--100 (online)
Background Cabazitaxel significantly improves overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) progressing during or after docetaxel, but is associated with a higher rate of grade ≥3 neutropenia compared with docetaxel. We thus examined the relationship between cabazitaxel-induced grade ≥3 neutropenia, baseline neutrophil-lymphocyte ratio (NLR) and treatment outcomes. Methods Data from the experimental arm of the TROPIC phase 3 trial which randomly assigned men with mCRPC to cabazitaxel or mitoxantrone every 3 weeks, both combined with daily prednisone, were analysed. The influence on OS (primary end-point) and progression-free survival (PFS) of at least one episode of grade ≥3 neutropenia during cabazitaxel therapy was investigated using Cox regression models, adjusted for pain at baseline. The relationships with prostate-specific antigen (PSA) responses during cabazitaxel therapy and baseline NLR were also analysed. Findings The occurrence of grade ≥3 neutropenia during cabazitaxel therapy was associated with a prolonged OS (median 16.3 versus 14.0 months, hazard ratio (HR) [95% confidence interval] = 0.65 [0.43–0.97], p = 0.035), a twice longer PFS (median 5.3 versus 2.6 months, HR = 0.56 [0.40–0.79], p = 0.001) and a higher confirmed PSA response ≥50% (49.8% versus 24.4%, p = 0.005), as compared with patients who did not develop grade ≥3 neutropenia. Grade ≥3 neutropenia was more common in case of NLR <3 as compared with NLR ≥3 at baseline (88.8% versus 75.3%, p = 0.002). Combining low NLR at baseline and grade ≥3 neutropenia during therapy was associated with the longest OS (median 19.2 months) while high NLR at baseline and no grade ≥3 neutropenia was associated with a poor OS (median 12.9 months, HR 0.46 [0.28–0.76], p = 0.002). In the subgroup of neutropenic patients the median OS was 19.7 months in those treated with granulocyte colony-stimulating factor (G-CSF) and 16 months on those without G-CSF support. Interpretation This post-hoc analysis of TROPIC suggests that the occurrence of grade ≥3 neutropenia with cabazitaxel is associated with improved OS and PFS. Patients with a low NLR at baseline were more likely to develop grade ≥3 neutropenia during cabazitaxel therapy and showed the longest OS. High NLR at baseline and no grade ≥3 neutropenia during therapy was associated with poor outcomes which may suggest insufficient drug exposure or a limited impact on the tumour-associated immune response. Primary or secondary prophylactic use of G-CSF had no adverse impact for outcome. If prospectively confirmed, these results would justify maintaining the intended cabazitaxel dose of 25 mg/m2 whenever possible.
Meyer-Zehnder B, Bucher E, Vogt D, Pargger H (2016) Existenzielle Fragen vor einer elektiven Operation. Anaesthesist 65:258--266 (online)
Hintergrund Tritt nach einer Operation eine schwere Komplikation auf, können sich existenzielle Fragen bezüglich einer Therapiebegrenzung oder eines -abbruchs stellen. In dieser Situation kann der Patient meist nicht mehr selber zu seinem Willen befragt werden. Deshalb ist es wichtig, im Vorfeld einer elektiven Operation auch über diese Fragen zu sprechen. Ein solches Gespräch kann die Patienten aber verunsichern und verängstigen. Die vorliegende Arbeit untersuchte die Bereitschaft von Patienten, vor einer Operation über die Behandlung von schweren Komplikationen zu sprechen, wie häufig bereits eine Patientenverfügung (PV) erstellt wurde und wer bei künftiger fehlender Urteilsfähigkeit stellvertretend entscheiden soll. Methode Verteilung eines einseitigen Fragebogens in der präoperativen Anästhesiesprechstunde zwischen dem 1. März und 30. Oktober 2014 Ergebnisse 598 Fragebogen konnten ausgewertet werden: 272 Männer (45,5 %), 321 Frauen (53,7 %); 5‑mal keine Angabe zum Geschlecht; Durchschnittsalter 52,9 Jahre). 377 Patienten (63,0 %) sind bereit und 79 (13,2 %) eher bereit, über die Behandlung von schweren Komplikationen zu sprechen, während dies 47 (7,9 %) eher nicht und 37 (6,2 %) nicht sind. 110 Patienten (18,4 %) haben bereits eine PV ausgefüllt. Die Wahrscheinlichkeit des Vorliegens einer PV nimmt mit steigenden Alter und einer Einschränkung des Gesundheitszustands zu. Im Falle einer Entscheidungsunfähigkeit würden folgende Optionen bevorzugt (Mehrfachantwort möglich): nahestehende Person entscheidet (n = 272), Gespräch mit Arzt vor Operation (n = 212), vorher erstellte PV (n = 198), Behandlungsteam entscheidet (n = 28). Schlussfolgerung Die große Mehrzahl der befragten Patienten ist bereit, vor einer Operation auch über schwierige Fragen zu sprechen. Im präoperativen Aufklärungsgespräch sollte der direkte Patientenwille bzgl. der Behandlung von schweren Komplikationen erhoben und dokumentiert werden, damit dieser besser respektiert werden kann, wenn unerwartet schwierige Entscheide zu treffen sind. Das Projekt wurde finanziell von Verein zur Förderung von Wissenschaft und Ausbildung, Departement Anästhesie, Universitätsspital Basel, unterstützt.
Müller SM, Tomaschett D, Euler S, Vogt DR, Herzog L, Itin P (2016) Topical corticosteroid concerns in dermatological outpatients: a cross-sectional and interventional study. Dermatology 232:444--452 (online)
Background/Aims: Topical corticosteroid concerns (TCC) are an important issue in patients with atopic dermatitis, leading to non-adherence with poor disease control and increased health care costs. However, neither the prevalence of TCC in a more comprehensible dermatological population nor the impact of patient information on topical corticosteroids given by clinicians is known. Therefore, we assessed the prevalence, characteristics, and sources of TCC in a dermatological population and the impact of written and oral patient information on TCC. Methods: A total of 643 outpatients with various skin diseases answered a 12-item questionnaire while waiting for the doctor's visit. Patients with TCC quantified their concerns on a discrete visual analogue scale before and after patient information, which consisted of written and oral information about topical corticosteroids (TCS) given by dermatologists. Results: The prevalence of TCC was 41.5%, and that of TCC-related non-adherence was 28.3%. TCC was positively associated with age <60 years, female gender, use of complementary and alternative medicine (CAM) and non-physician health care profession. The leading concerns were skin atrophy, systemic effects, and impairment of the immune system. The most frequent sources of TCC were negative reports by media, family, or friends. Both written and oral patient information significantly reduced TCC. The number needed to benefit from patient information was approximately 2. Non-responders were more often female, TCS-inexperienced, and users of CAM with an intermediate level of education. Conclusions: TCC are highly prevalent in dermatological patients. Patient information may lower TCC in almost every second patient.
Wu M, Ries J, Proietti E, Vogt D, Hahn S, Hoesli I (2016) Development of late-onset preeclampsia in association with road densities as a proxy for traffic-related air pollution. Fetal Diagn Ther 39:21--27 (online)
Introduction: Previous epidemiological studies indicate an association between maternal exposure to air pollution and an increased risk of hypertensive disorders in pregnancy. We analyzed the association between the occurrence of mild/severe and early-/late-onset preeclampsia (PE) and traffic-related air pollution (TRAP). Materials and Methods: Based on retrospective data, 50 pregnant women with PE were selected and matched with a control group of healthy pregnant women according to their age, parity, and number of fetuses. The total length of major roads around the women's home within a radius of 100, 200, 300, and 500 m and the distances from the domicile to the nearest ‘first class' main road and freeway were used as a proxy indicator of TRAP. We compared a PE subgroup and control group in terms of their exposure to TRAP. Results: Late-onset PE cases showed a significantly higher occurrence with density of major roads within a radius of 100-300 m compared to early onset cases (p = 0.006; 0.02; 0.04). In addition, a significantly shorter distance to the nearest ‘first class' main road was observed in late-onset PE cases (p = 0.0078). Conclusions: Exposure to TRAP during pregnancy was associated with an increased risk for the development of late-onset PE.

2015

Burri E, Beglinger C, von Felten S, Lehmann FS (2015) Fecal calprotectin and the clinical activity index are both useful to monitor medical treatment in patients with ulcerative colitis. Dig Dis Sci 60:485--491 (online)
Background: Non-invasive monitoring of inflammatory bowel disease is an unmet clinical need as patients in clinical remission may have residual mucosal inflammation preceding clinical relapse. Aims: We aimed to assess the value of fecal calprotectin and standardized clinical activity scoring to monitor dis- ease activity in ulcerative colitis under medical treatment. Methods: Forty-one patients with ulcerative colitis were included in a prospective observational study. Medical treatment was guided by clinical judgement of treating physicians. Fecal calprotectin and the clinical activity index (CAI) were measured blinded to treating physicians every 2 months until the end of follow-up. Twenty-six patients received colonoscopy for clinical reason. Results: As defined by the CAI, patients were in clinical remission (63.4 %), having mild (26.8 %) or moderate (11.2 %) disease activity. Of those in clinical remission (CAI B 4), 86.4 % showed residual endoscopic activity (Mayo Score C1). Calprotectin levels were higher in endoscopically active disease (779.0 vs 331.5 lg/g, P = 0.034) and calprotectin testing identified more patients with endoscopic disease activity (86.4 %) than the CAI (45.5 %, P = 0.034). Medical treatment was escalated in 90.2 % during the study. Values of the CAI and cal- protectin correlated with therapy escalation (OR 3.94 and 3.22, respectively). Only for calprotectin, changes between two measurements were related to intensified medical treatment (OR 1.39). Conclusion: Fecal calprotectin was similarly useful to the CAI to monitor disease activity of ulcerative colitis during medical treatment but identified endoscopic disease activ- ity far more reliably. Changes of calprotectin values between measurements might indicate clinical relapse earlier than the CAI.
Kaiser C, Galatius S, Jeger R, Gilgen N, Jensen JS, Naber CK, Alber HF, Wanitschek M, Eberli FR, Kurz DJ, Pedrazzini G, Moccetti T, Rickli H, Weilenmann D, Vuilliomenet AG, Steiner M, von Felten S, Vogt DR, Hansen KW, Rickenbacher P, Conen D, Müller C, Buser P, Hoffmann A, Pfisterer M (2015) Long-term efficacy and safety of biodegradable-polymer biolimus-eluting stents: main results of the Basel Stent Kosten-Effektivitäts Trial-PROspective Validation Examination II (BASKET-PROVE II), a randomized, controlled noninferiority 2-year outcome trial.. Circulation 131:74-81 (online)
Background: Biodegradable-polymer drug-eluting stents (BP-DES) were developed to be as effective as second-generation durable-polymer drug-eluting stents (DP-DES) and as safe >1 year as bare-metal stents (BMS). Thus, very late stent thrombosis (VLST) attributable to durable polymers should no longer appear. Methods and Results: To address these early and late aspects, 2291 patients presenting with acute or stable coronary disease needing stents ?3.0 mm in diameter between April 2010 and May 2012 were randomly assigned to biolimus-A9–eluting BP-DES, second-generation everolimus-eluting DP-DES, or thin-strut silicon-carbide–coated BMS in 8 European centers. All patients were treated with aspirin and risk-adjusted doses of prasugrel. The primary end point was combined cardiac death, myocardial infarction, and clinically indicated target-vessel revascularization within 2 years. The combined secondary safety end point was a composite of VLST, myocardial infarction, and cardiac death. The cumulative incidence of the primary endpoint was 7.6% with BP-DES, 6.8% with DP-DES, and 12.7% with BMS. By intention-to-treat BP-DES were noninferior (predefined margin, 3.80%) compared with DP-DES (absolute risk difference, 0.78%; ?1.93% to 3.50%; P for noninferiority 0.042; per protocol P=0.09) and superior to BMS (absolute risk difference, ?5.16; ?8.32 to ?2.01; P=0.0011). The 3 stent groups did not differ in the combined safety end point, with no decrease in events >1 year, particularly VLST with BP-DES. Conclusions: In large vessel stenting, BP-DES appeared barely noninferior compared with DP-DES and more effective than thin-strut BMS, but without evidence for better safety nor lower VLST rates >1 year. Findings challenge the concept that durable polymers are key in VLST formation. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01166685. (Circulation. 2015;131:00-00.)
Kappos EA, Engels PE, Tremp M, Meyer zu Schwabedissen M, di Summa P, Fischmann A, von Felten S, Scherberich A, Schaefer DJ, Kalbermatten DF (2015) Peripheral nerve repair: multimodal comparison of the long-term regenerative potential of adipose tissue-derived cells in a biodegradable conduit. Stem Cells Dev 24:2127--2141 (online)
Tissue engineering is a popular topic in peripheral nerve repair. Combining a nerve conduit with supporting adipose derived cells could offer an opportunity to prevent time consuming Schwann cell culture or the use of an autograft with its donor site morbidity and eventually improve clinical outcome. Aim of this study was to provide a broad overview over promising transplantable cells under equal experimental conditions over a long term period. A 10mm gap in the sciatic nerve of female Sprague Dawley rats (7 groups of 7 animals, 8 weeks old) was bridged through a biodegradable fibrin conduit filled with rat adipose-derived stem cells (rASCs), differentiated rASC (drASC), human (h-) ASCs from the superficial and deep abdominal layer, human stromal vascular fraction (SVF) or rat Schwann cells respectively. As a control we re-sutured a nerve segment as an autograft. Long-term evaluation was carried out after 12 weeks comprising walking track, morphometric and MRI analysis. The Sciatic Function Index was calculated. Cross sections of the nerve proximal, distal and in between the two sutures were analysed for re-/myelination and axon count. Gastrocnemius muscle weights were compared. MRI proved biodegradation of the conduit. Differentiated rat ASCs performed significantly better than undifferentiated rASCs with less muscle atrophy and superior functional results. Superficial hASC supported regeneration better than deep, in line with published in vitro data. The best regeneration potential was achieved by the drASC group when compared to other adipose tissue derived cells. Considering the ease of procedure from harvesting to transplanting, we conclude that comparison of promising cells for nerve regeneration revealed that particularly differentiated ASCs could be a clinically translatable route towards new methods to enhance peripheral nerve repair.
Klatt E, Zumbrunn T, Bandschapp O, Girard T, Ruppen W (2015) Intra- and postoperative intravenous ketamine does not prevent chronic pain: A systematic review and meta-analysis. Scand J Pain 7:42--54 (online)
Background and aims: The development of postoperative chronic pain (POCP) after surgery is a major problem with a considerable socioeconomic impact. It is defined as pain lasting more than the usual healing, often more than 2–6 months. Recent systematic reviews and meta-analyses demonstrate that the N-methyl-d-aspartate-receptor antagonist ketamine given peri- and intraoperatively can reduce immediate postoperative pain, especially if severe postoperative pain is expected and regional anaesthesia techniques are impossible. However, the results concerning the role of ketamine in preventing chronic postoperative pain are conflicting. The aim of this study was to perform a systematic review and a pooled analysis to determine if peri- and intraoperative ketamine can reduce the incidence of chronic postoperative pain. Methods: Electronic searches of PubMed, EMBASE and Cochrane including data until September 2013 were conducted. Subsequently, the titles and abstracts were read, and reference lists of reviews and retrieved studies were reviewed for additional studies. Where necessary, authors were contacted to obtain raw data for statistical analysis. Papers reporting on ketamine used in the intra- and postoperative setting with pain measured at least 4 weeks after surgery were identified. For meta-analysis of pain after 1, 3, 6 and 12 months, the results were summarised in a forest plot, indicating the number of patients with and without pain in the ketamine and the control groups. The cut-off value used for the VAS/NRS scales was 3 (range 0–10), which is a generally well-accepted value with clinical impact in view of quality of life. Results: Our analysis identified ten papers for the comprehensive meta-analysis, including a total of 784 patients. Three papers, which included a total of 303 patients, reported a positive outcome concerning persistent postsurgical pain. In the analysis, only one of nine pooled estimates of postoperative pain at rest or in motion after 1, 3, 6 or 12 months, defined as a value ≥3 on a visual analogue scale of 0–10, indicated a marginally significant pain reduction. Conclusions: Based on the currently available data, there is currently not sufficient evidence to support a reduction in chronic pain due to perioperative administration of ketamine. Only the analysis of postoperative pain at rest after 1 month resulted in a marginally significant reduction of chronic postoperative pain using ketamine in the perioperative setting. Implications: It can be hypothesised, that regional anaesthesia in addition to the administration of perioperative ketamine might have a preventive effect on the development of persistent postsurgical pain. An additional high-quality pain relief intra- and postoperatively as well after discharge could be more effective than any particular analgesic method per se. It is an assumption that a low dose infusion ketamine has to be administered for more than 72 h to reduce the risk of chronic postoperative pain.
Nordmann TM, Seelig E, Timper K, Cordes M, Coslovsky M, Hanssen H, Schmidt-Trucksäss A, Donath MY (2015) Muscle-derived IL-6 is not regulated by IL-1 during exercise. A double blind, placebo-controlled, randomized crossover study. PLoS One 10:e0139662 (online)
Exercise increases muscle derived Interleukin–6 (IL–6) leading to insulin secretion via glucagon-like peptide–1. IL–1 antagonism improves glycemia and decreases systemic inflammation including IL–6 in patients with type 2 diabetes. However, it is not known whether physiological, exercise-induced muscle-derived IL–6 is also regulated by the IL–1 system. Therefore we conducted a double blind, crossover study in 17 healthy male subjects randomized to receive either the IL–1 receptor antagonist IL-1Ra (anakinra) or placebo prior to an acute treadmill exercise. Muscle activity led to a 2–3 fold increase in serum IL–6 concentrations but anakinra had no effect on this exercise-induced IL–6. Furthermore, the IL–1 responsive inflammatory markers CRP, cortisol and MCP–1 remained largely unaffected by exercise and anakinra. We conclude that the beneficial effect of muscle-induced IL–6 is not meaningfully affected by IL–1 antagonism.
Riediger C, Haschke M, Bitter C, Fabbro T, Schaeren S, Urwyler A, Ruppen W (2015) The analgesic effect of combined treatment with intranasal S-ketamine and intranasal midazolam compared with morphine patient-controlled analgesia in spinal surgery patients: a pilot study. J Pain Res 8:87--94 (online)
Objectives: Ketamine is a well-known analgesic and dose-dependent anesthetic used in emer- gency and disaster medicine. Recently, a new formulation of S-ketamine, as an intranasal spray, was developed and tested in our institution in healthy volunteers. The authors investigated the effect of intranasal S-ketamine spray combined with midazolam intranasal spray in postopera- tive spinal surgery patients. Materials and methods: In this prospective, computer-randomized, double-blinded nonin- feriority study in spinal surgery patients, the effects of intranasal S-ketamine and midazolam were compared with standard morphine patient-controlled analgesia (PCA). The primary end point was the numeric rating scale pain score 24 hours after surgery. Results: Twenty-two patients finished this study, eleven in each group. There were similar numeric rating scale scores in the morphine PCA and the S-ketamine-PCA groups at 1, 2, 4, 24, 48, and 72 hours after surgery during rest as well as in motion. There were no differences in the satisfaction scores at any time between the groups. The number of bolus demands and deliveries was not significantly different. Discussion: In our study, we found that an S-ketamine intranasal spray combined with intra- nasal midazolam was similar in effectiveness, satisfaction, number of demands/deliveries of S-ketamine and morphine, and number/severity of adverse events compared with standard intravenous PCA with morphine. S-ketamine can be regarded as an effective alternative for a traditional intravenous morphine PCA in the postoperative setting.
Suter P, Hemelaers L, Witte U, von Felten S, Benkler K, Geiger M, Spänhauer C, Weick U (2015) Ten Years after the Implementation of Evidence-based Therapy at the Therapy Services of the University Hospital Basel - Survey of the Therapists on Promotive Factors and Barriers. Physioscience 11:47-52 (online)
Background: Evidence-based therapy (EBT) generally enjoys a high status and acceptance among therapists. However, the use of EBT in practice is subject to various barriers. Objective: The study examined the value of EBT among employees of the therapy services at the University Hospital Basel and identifies key barriers hindering the implementation of EBT in daily practice. Method: Survey of employees with a 24 item self-completion questionnaire on the attitude to EBT, the frequency of application and barrier reasons. Results: 54 questionnaires were returned (response rate: 79 %). 96 % of the respondents confirm the necessity of EBT and 94 % consider the use of literature and research results in their daily work to be essential. For 86 % the journal club is an important part of EBT. The majority of employees (63 %) had in-house schooling and 70 % would attend advanced education. No relationship is found between the experience and attitude towards EBT and the number of years of employment. The most common barrier to integrating EBT into therapeutic practice is lack of time (85 %) followed by lack of transferability (50 %) and the absence of clinical relevance (38 %). Conclusions: The majority of the employees have a positive attitude to EBT. The most important intrinsic factor promoting the implementation of evidence-based work is the personal experience and attitude to EBT. Lack of time is referred to as the most important extrinsic barrier. In-house training and regularly held journal clubs are important requirements for EBT in daily practice at the therapy services of the University Hospital Basel. Furthermore, the knowledge of the employees in regard to internet searches and evaluating scientific work should be improved.
Vogel N, Schandelmaier S, Zumbrunn T, Ebrahim S, de Boer WE, Mousavi SM, Guyatt GH, Busse JW, Kunz R (2015) Return to work coordination programmes for improving return to work in workers on sick leave (Protocol). Cochrane Database Syst Rev (online)
Zimmer A, Bläuer C, Coslovsky M, Kappos L, Derfuss T (2015) Optimizing treatment initiation: effects of a patient education program about fingolimod treatment on knowledge, self-efficacy and patient satisfaction. Mult Scler Relat Disord 4:444--450 (online)
von Niederhäusern B, Pauli-Magnus C, Fabbro T (2015) The role of Clinical Trial Units in investigator- and industry-initiated research projects. Swiss Med Wkly 145 (online)
Six multidisciplinary competence centres (Clinical Trial Units, CTUs) in Basel, Berne, Geneva, Lausanne, St. Gallen and Zurich provide professional support to clinical researchers in the planning, implementation, conduct and evaluation of clinical studies. Through their coordinated network, these units promote high-quality, nationally harmonised and internationally standardised clinical research conduct in Switzerland. We will describe why this network has been established, how it has been successful in stilling the growing need for clinical research support, which training and education opportunities it offers, and how it created national awareness for the still-existing hurdles towards clinical research excellence in Switzerland. Taking the CTU Basel as an example, we show that a considerable number (25%) of the studies submitted for regulatory approval in 2013 were supported by the CTU, decreasing the number of findings in ethics reviews by about one-third. We conclude that these achievements, together with a Swiss national funding model for clinical research, and improved national coordination, will be critical factors to successfully position Swiss clinical research at the international forefront.

2014

Azakir BA, Erne B, Di Fulvio S, Stirnimann G, Sinnreich M (2014) Proteasome inhibitors increase missense mutated dysferlin in patients with muscular dystrophy. Sci Transl Med 6:250ra112 (online)
No treatment is available for patients affected by the recessively inherited, progressive muscular dystrophies caused by a deficiency in the muscle membrane repair protein dysferlin. A marked reduction in dysferlin in patients harboring missense mutations in at least one of the two pathogenic DYSF alleles encoding dysferlin implies that dysferlin is degraded by the cell’s quality control machinery. In vitro evidence suggests that missense mutated dysferlin might be functional if salvaged from degradation by the proteasome. We treated three patients with muscular dystrophy due to a homozygous Arg555Trp mutation in dysferlin with the proteasome inhibitor bortezomib and monitored dysferlin expression in monocytes and in skeletal muscle by repeated percutaneous muscle biopsy. Expression of missense mutated dysferlin in the skeletal muscle and monocytes of the three patients increased markedly, and dysferlin was correctly localized to the sarcolemma of muscle fibers on histological sections. Salvaged missense mutated dysferlin was functional in a membrane resealing assay in patient-derived muscle cells treated with three different proteasome inhibitors. We conclude that interference with the proteasomal system increases expression of missense mutated dysferlin, suggesting that this therapeutic strategy may benefit patients with dysferlinopathies and possibly other genetic diseases.
Grossmann FF, Zumbrunn T, Ciprian S, Stephan F, Woy N, Bingisser R, Nickel CH (2014) Undertriage in older emergency department patients – tilting against windmills?. PLoS One 9:e106203 (online)
<sec> <title>Objectives</title> <p>The aim of this study was to investigate the long-term effect of a teaching intervention designed to reduce undertriage rates in older ED patients. Further, to test the hypothesis that non-adherence to the Emergency Severity Index (ESI) triage algorithm is associated with undertriage. Additionally, to detect patient related risk factors for undertriage.</p> </sec><sec> <title>Methods</title> <p>Pre-post-test design. The study sample consisted of all patients aged 65 years or older presenting to the ED of an urban tertiary and primary care center in the study periods. A teaching intervention designed to increase adherence to the triage algorithm. To assess, if the intervention resulted in an increase of factual knowledge, nurses took a test before and immediately after the teaching intervention. Undertriage rates were assessed one year after the intervention and compared to the pre-test period.</p> </sec><sec> <title>Results</title> <p>In the pre-test group 519 patients were included, and 394 in the post-test-group. Factual knowledge among triage nurses was high already before the teaching intervention. Prevalence of undertriaged patients before (22.5%) and one year after the intervention (24.2%) was not significantly different (χ2 = 0.248, df = 1, p = 0.619). Sex, age, mode of arrival, and type of complaint were not identified as independent risk factors for undertriage. However, undertriage rates increased with advancing age. Adherence to the ESI algorithm is associated with correct triage decisions.</p> </sec><sec> <title>Conclusions</title> <p>Undertriage of older ED patients remained unchanged over time. Reasons for undertriage seem to be more complex than anticipated. Therefore, additional contributing factors should be addressed.</p> </sec>
Hutter G, von Felten S, Sailer MH, Schulz M, Mariani L (2014) Risk factors for postoperative CSF leakage after elective craniotomy and the efficacy of fleece-bound tissue sealing against dural suturing alone: a randomized controlled trial. J Neurosurg 121:735--744 (online)
Object: Cerebrospinal fluid leakage is an immanent risk of cranial surgery with dural opening. Recognizing the risk factors for this complication and improving the technique of dural closure may reduce the associated morbidity and its surgical burden. The aim of this paper was to investigate whether the addition of TachoSil on top of the dural suture reduces postoperative CSF leakage compared with dural suturing alone and to assess the frequency and risk factors for dural leakage and potentially related complications after elective craniotomy. Methods: The authors conducted a prospective, randomized, double-blinded single-center trial in patients undergoing elective craniotomy with dural opening. They compared their standard dural closure by running suture alone (with the use of a dural patch if needed) to the same closure with the addition of TachoSil on top of the suture. The primary end point was the incidence of CSF leakage, defined as CSF collection or any open CSF fistula within 30 days. Secondary end points were the incidence of infection, surgical revision, and length of stay in the intensive care unit (ICU) or intermediate care (IMC) unit. The site of craniotomy, a history of diabetes mellitus, a diagnosis of meningioma, the intraoperative need of a suturable dural substitute, and blood parameters were assessed as potential risk factors for CSF leakage. Results: The authors enrolled 241 patients, of whom 229 were included in the analysis. Cerebrospinal fluid leakage, mostly self-limiting subgaleal collections, occurred in 13.5% of patients. Invasive treatment was performed in 8 patients (3.5%) (subgaleal puncture in 6, lumbar drainage in 1, and surgical revision in 1 patient). Diabetes mellitus, a higher preoperative level of C-reactive protein (CRP), and the intraoperative need for a dural patch were positively associated with the occurrence of the primary end point (p = 0.014, 0.01, and 0.049, respectively). Cerebrospinal fluid leakage (9.7% vs 17.2%, OR 0.53 [95% CI 0.23–1.15], p = 0.108) and infection (OR 0.18 [95% CI 0.01–1.18], p = 0.077) occurred less frequently in the study group than in the control group. TachoSil significantly reduced the probability of staying in the IMC unit for 1 day or longer (OR 0.53 [95% CI 0.27–0.99], p = 0.048). Postoperative epidural hematoma and empyema occurred in the control group but not in the study group. Conclusions: Dural leakage after elective craniotomy/durotomy occurs more frequently in association with diabetes mellitus, elevated preoperative CRP levels, and the intraoperative need of a dural patch. This randomized controlled trial showed no statistically significant reduction of postoperative CSF leakage and surgical site infections upon addition of TachoSil on the dural suture, but there was a significant reduction in the length of stay in the IMC unit. Dural augmentation with TachoSil was safe and not related to adverse events. Clinical trial registration no. NCT00999999
Jeger RV, Pfisterer ME, Sørensen R, von Felten S, Alber H, Bonetti PO, Eberli F, Erne P, Pedrazzini G, Rickli H, Galatius S, KaKaiser CftB, investigators B (2014) Tradeoff between bleeding and stent thrombosis in different dual antiplatelet therapy regimes: importance of case fatality rates and effective treatment durations. Am Heart J 168:698--705 (online)
Background: The tradeoff between stent thrombosis (ST) and major bleeding (MB) of 12- versus 6-month dual antiplatelet therapy (DAPT) after coronary stent implantation has not been clearly defined. Methods: Definite/probable ST and MB (TIMI major and Bleeding Academic Research Consortium (BARC) ?3) were compared in 2 subsequent trials with similar inclusion criteria but different DAPT duration, that is, BASKET (6 months; n = 557) and BASKET-PROVE (12 months; n = 2,314), between months 0 to 6 (DAPT in both trials), 7 to 12 (DAPT in BASKET-PROVE only), and 13 to 24 (aspirin in both trials) using propensity score-adjusted, time-stratified Cox proportional hazard models. Results: Overall, event rates were low with fewer ST but similar MB in prolonged DAPT. Analysis of the 3 periods showed a uniform pattern for ST (interaction DAPT/period; P = .145) but an inconsistent pattern for MB (interaction DAPT/period; P < .001 for TIMI major and P = .046 for BARC ?3), with more MB occurring during months 7 to 12 with prolonged DAPT. Considering observed case fatality rates of 31% with ST and 11% with MB, the extrapolated prevention of 27 ST deaths and the excess of 5 MB deaths resulted in an expected benefit of 22 survivors/10,000 patients treated over 2 years with prolonged DAPT. Conclusion: Despite overall low event rates, prolonged DAPT was associated with more MB during months 7 to 12 according to the interaction DAPT/period. Given the higher observed case fatality rates of ST versus MB, 12- versus 6-month DAPT was associated with an extrapolated reduction in mortality. Effective treatment periods and case fatality rates seem important in the analysis of different DAPT durations, specifically with regard to ongoing trials.
Knecht S, Sticherling C, von Felten S, Conen D, Schaer B, Ammann P, Altmann D, Osswald S, Kühne M (2014) Long-term comparison of cryoballoon and radiofrequency ablation of paroxysmal atrial fibrillation: a propensity score matched analysis. Int J Cardiol 176:645--650 (online)
Background: Although radiofrequency (RF) and cryoballoon (CB) based technologies for pulmonary vein isolation (PVI) have both individually been demonstrated to be effective and safe for the treatment of paroxysmal AF, head-to-head comparisons are lacking. The purpose of this study was to compare the outcome of cryoballoon versus radiofrequency ablation in patients with paroxysmal atrial fibrillation undergoing pulmonary vein isolation. Methods: Out of a prospective registry of 327 patients undergoing PVI, 208 patients (age 58 ± 11 years, ejection fraction 59 ± 6%, left atrial size 39 ± 6 mm) with paroxysmal AF were identified. The presented dataset was obtained by 1:1 propensity score matching and contained 142 patients undergoing CB-PVI or RF-PVI in conjunction with a 3D mapping system, respectively. We compared single procedure efficacy of the two methods using a Cox proportional hazards model. Results: After a mean follow-up of 28 months and a single procedure, AF recurred in 37 of 71 (52%) in the CB-PVI group and in 31 of 71 patients (44%) in the RF-PVI group (HR [95% CI] = 1.19 [0.74, 1.92], p = 0.48). Recurrence of AF for PVI using solely the CB was observed in 23 of 51 (45%) patients and in 23 of 51 (45%) patients in the corresponding RF-PVI group (HR [95% CI] = 0.93 [0.52, 1.66], p = 0.81). Complication rate was not different between the groups. Conclusion: A propensity score matched comparison between CB-PVI and RF-PVI using a 3D-mapping system for AF ablation showed similar long-term success rates.
Lehmann FS, Trapani F, Fueglistaler I, Terracciano LM, von Flüe M, Cathomas G, Zettl A, Benkert P, Oertli D, Beglinger C (2014) Clinical and histopathological correlations of fecal calprotectin release in colorectal carcinoma. World J Gastroenterol 20:4994 (online)
AIM: To determine calprotectin release before and after colorectal cancer operation and compare it to tumor and histopathological parameters.
METHODS: The study was performed on patients with diagnosed colorectal cancer admitted for operation. Calprotectin was measured in a single stool sample before and three months after the operation using an enzyme-linked immunosorbent assay (ELISA). Calprotectin levels greater than or equal to 50 μg/g were considered positive. The compliance for collecting stool samples was assessed and the value of calprotectin was correlated to tumor and histopathological parameters of intra- and peri-tumoral inflammation. Surgical specimens were fixed in neutral buffered formalin and stained with hematoxylin and eosin. Staging was performed according to the Dukes classification system and the 7th edition tumor node metastasis classification system. Intra- and peri-tumoral inflammation was graded according to the Klintrup criteria. Immunohistochemical quantification was performed for MPO, CD45R0, TIA-1, CD3, CD4, CD8, CD57, and granzyme B. Statistical significance was measured using Wilcoxon signed rank test, Kruskal Wallis test and Spearman’s rank correlation coefficient as appropriate.
RESULTS: Between March 2009 and May 2011, 80 patients with colorectal cancer (46 men and 34 women, with mean age of 71 ± 11.7 years old) were enrolled in the study. Twenty-six patients had rectal carcinoma, 29 had left-side tumors, 23 had right-side tumors, and 2 had bilateral carcinoma. In total, 71.2% of the patients had increased levels of calprotectin before the operation (median 205 μg/g, range 50-2405 μg/g) and experienced a significant decrease three months after the operation (46 μg/g, range 10-384 μg/g, P < 0001). The compliance for collecting stool samples was 89.5%. Patients with T3 and T4 tumors had significantly higher values than those with T1 and T2 cancers (P = 0.022). For all other tumor parameters (N, M, G, L, V, Pn) and location, no significant difference in calprotectin concentration was found. Furthermore, the calprotectin levels and histological grading of both peri- and intra-tumoral inflammation was not correlated. Additional testing with specific markers for lymphocytes and neutrophils also revealed no statistically significant correlation.
CONCLUSION: Fecal calprotectin decreases significantly after colorectal cancer operation. Its value depends exclusively on the individual T-stage, but not on other tumor or histopathological parameters.
Papadopoulou A, Naegelin Y, Weier K, Amann M, Hirsch J, von Felten S, Yaldizli Ö, Sprenger T, Radue EW, Kappos LP, Gass A (2014) MRI characteristics of periaqueductal lesions in multiple sclerosis. Mult Scler Relat Disord 3:542–-551 (online)
Background: In multiple sclerosis (MS), periaqueductal lesions (PAL) have been described histopathologically. Objectives: We sought to investigate the frequency and characteristics of PAL on magnetic resonance images (MRIs) in patients with MS or clinically isolated syndrome (CIS). Methods: We analysed proton density (PD)-weighted MRIs of 247 MS and 10 CIS patients. PAL were identified based on their abnormal hyperintensity and lesion shape on at least two consecutive slices. Patients with and without PAL were compared for clinical characteristics in a propensity score weighted analysis. Results: We identified PAL in 48/257 patients (18.7%), 34 of which had CIS or relapsing-remitting MS and 14 a progressive disease course. The shape of PAL was often circular (65%), or/and wedge- like (42%). Multi-planar image analysis in a subgroup of patients with double inversion recovery sequences revealed that 36% of PAL were periventricular lesions of the third ventricle extending towards the aqueduct. We found an association of PAL and brainstem functional system. Conclusions: Although PAL may be underreported in MS, they are relatively frequent and found at all clinical stages and in CIS. They could be considered as a variant of periventricular lesions in the supratentorial midbrain and thus be useful in the diagnosis of MS.
Rostamzadeh A, Zumbrunn T, Jongen LM, Nederkoorn PJ, Macdonald S, Lyrer PA, Kappelle LJ, Willem PTM, Brown MM, van der Worp HB, Engelter ST, Bonati LH, Investgators obotIS (2014) Predictors of acute and persisting ischemic brain lesions in patients randomized to carotid stenting or endarterectomy. Stroke 45:591--594 (online)
Zellweger MJ, Maraun M, Osterhues HH, Keller U, Müller-Brand J, Jeger R, Pfister O, Burkard T, Eckstein F, von Felten S, Osswald S, Pfisterer M (2014) Progression to overt or silent CAD in asymptomatic patients with diabetes mellitus at high coronary risk: main findings of the prospective multicenter BARDOT trial with a pilot randomized treatment substudy. JACC Cardiovasc Imaging 7:1001--1010 (online)

2013

Breidthardt T, Balmelli C, Twerenbold R, Mosimann T, Espinola J, Haaf P, Thalmann G, Moehring B, Mueller M, Meller B, Reichlin T, Murray K, Ziller R, Benkert P, Osswald S, Mueller C (2013) Heart failure therapy-induced early ST2 changes may offer long-term therapy guidance. J Card Fail 19:821--828 (online)
Background: Biomarkers may help to monitor and tailor treatment in patients with acute heart failure (AHF).
Methods and Results: Levels of ST2, a novel biomarker integrating hypervolemic cardiac strain and proinflammatory signals, were measured at presentation to the emergency department (ED) and after 48 hours in 207 patients with AHF. Patients were stratified according to their early ST2 response (responders: ST2 decrease ≥25%; nonresponders: ST2 decrease <25%) and beta-blocker, renin-angiotensin-aldosterone system (RAAS) blockade, or diuretic treatment status at hospital discharge. We assessed the utility of ST2 levels and its changes to predict long-term mortality and the interaction between ST2 levels, treatment at discharge, and 1-year mortality. ST2 levels were higher in nonsurvivors than in survivors (median 108 vs 69 ng/mL; P < .01) and decreased significantly during the 1st 48 hours (median decrease 33%). ST2 decrease was less in nonsurvivors compared with survivors (median −25% vs −42%; P < .01). In Cox regression, early ST2 changes independently predicted 1-year mortality (hazard ratio 1.07 for every increase of 10%; P = .02). RAAS blockers at discharge were associated with survival independently from ST2 response, whereas the association of beta-blockers with survival differed markedly according to ST2 response, with beneficial effects restricted to ST2 nonresponders (P interaction = .04). A similar, albeit nonsignificant, trend was observed for diuretics (P interaction = .11).
Conclusions: ED and serial ST2 measurements are independent predictors of 1-year mortality in AHF.
Gensicke H, Zumbrunn T, Jongen LM, Nederkoorn PJ, Macdonald S, Gaines PA, Lyrer PA, Wetzel SG, van der Lugt A, Willem PTM, Mali WPTM, Brown MM, van der Worp HB, Engelter ST, Bonati LH (2013) Characteristics of ischemic brain lesions after stenting or endarterectomy for symptomatic carotid artery stenosis results from the International Carotid Stenting Study - magnetic resonance imaging substudy. Stroke 44:80--86 (online)
Background and purpose: In a substudy of the International Carotid Stenting Study (ICSS), more patients had new ischemic brain lesions on diffusion-weighted magnetic resonance imaging (MRI) after stenting (CAS) than after endarterectomy (CEA). In the present analysis, we compared characteristics of diffusion-weighted MRI lesions. Methods: Number, individual and total volumes, and location of new diffusion-weighted MRI lesions were compared in patients with symptomatic carotid stenosis randomized to CAS (n=124) or CEA (n=107) in the ICSS-MRI substudy. Results: CAS patients had higher lesion numbers than CEA patients (1 lesion, 15% vs 8%; 2–5 lesions, 19% vs 5%; >5 lesions, 16% vs 4%). The overall risk ratio for the expected lesion count with CAS versus CEA was 8.8 (95% confidence interval, 4.4–17.5; P<0.0001) and significantly increased among patients with lower blood pressure at randomization, diabetes mellitus, stroke as the qualifying event, left-side stenosis, and if patients were treated at centers routinely using filter-type protection devices during CAS. Individual lesions were smaller in the CAS group than in the CEA group (P<0.0001). Total lesion volume per patient did not differ significantly. Lesions in the CAS group were more likely to occur in cortical areas and subjacent white matter supplied by leptomeningeal arteries than lesions in the CEA group (odds ratio, 4.2; 95% confidence interval, 1.7–10.2; P=0.002). Conclusions: Compared with patients undergoing CEA, patients treated with CAS had higher numbers of periprocedural ischemic brain lesions, and lesions were smaller and more likely to occur in cortical areas and subjacent white matter. These findings may reflect differences in underlying mechanisms of cerebral ischemia.
Hug BL, Tichelli A, Benkert P, Stirnimann G, Schifferli JA (2013) Diagnosis and treatment of iron deficiency in medical inpatients at a Swiss tertiary university referral hospital: a retrospective observational cohort study of clinical practice. Swiss Med Wkly 143:w13847 (online)
BACKGROUND: Iron deficiency anaemia is a common disease with a prevalence of up to 19.2% in populations at risk. However, the prevalence of iron deficiency (ID) in hospitalised patients is not well known. The aims of this retrospective, observational cohort study were to evaluate the current diagnostic procedures for, and treatment of, ID as well as to estimate the prevalence of undiagnosed ID in hospitalised patients at the division of internal medicine in a Swiss tertiary university referral centre.
METHODS: Within a study period of 6 months, data from all patients hospitalised at the division of internal medicine were analysed for the presence of anaemia (defined as haemoglobin levels for males <130 g/l and for females <120 g/l) and ID (ferritin <15 µg/l or ferritin <50 µg/l and transferrin saturation <20%).
RESULTS: A total of 2,781 hospitalisation cases were analysed (2,251 unique patients, male 55.5%, mean age 66.4 years). In 2,267 cases (81.5%) results of a red blood cell count were available. In 329 cases (14.5%) iron parameters (IP) were determined and 45 (13.7%) cases / unique patients with ID were detected. Among the remaining 1,938 cases without IP determination, statistical estimation predicted 103 (56-329) undiagnosed ID cases. In ID patients, the most prevalent diagnosis was heart failure (24.4%). Of these patients, 72.7% had haemorrhage-facilitating drugs on hospital admission or discharge.
CONCLUSION: Iron deficiency is common in internal medicine and up to two-thirds of cases may not be diagnosed. Every seventh patient who had i
Leu S, von Felten S, Frank S, Vassella E, Vajtai I, Taylor E, Schulz M, Hutter G, Hench J, Schucht P, Boulay J, Mariani L (2013) IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival. Neuro Oncol 15:469--479 (online)
Background: Low-grade gliomas (LGGs) are rare brain neoplasms, with survival spanning up to a few decades. Thus, accurate evaluations on how biomarkers impact survival among patients with LGG require long-term studies on samples prospectively collected over a long period. Methods: The 210 adult LGGs collected in our databank were screened for IDH1 and IDH2 mutations (IDHmut), MGMT gene promoter methylation (MGMTmet), 1p/19q loss of heterozygosity (1p19qloh), and nuclear TP53 immunopositivity (TP53pos). Multivariate survival analyses with multiple imputation of missing data were performed using either histopathology or molecular markers. Both models were compared using Akaike's information criterion (AIC). The molecular model was reduced by stepwise model selection to filter out the most critical predictors. A third model was generated to assess for various marker combinations. Results: Molecular parameters were better survival predictors than histology (ΔAIC = 12.5, P< .001). Forty-five percent of studied patients died. MGMTmet was positively associated with IDHmut (P< .001). In the molecular model with marker combinations, IDHmut/MGMTmet combined status had a favorable impact on overall survival, compared with IDHwt (hazard ratio [HR] = 0.33, P< .01), and even more so the triple combination, IDHmut/MGMTmet/1p19qloh (HR = 0.18, P< .001). Furthermore, IDHmut/MGMTmet/TP53pos triple combination was a significant risk factor for malignant transformation (HR = 2.75, P< .05). Conclusion: By integrating networks of activated molecular glioma pathways, the model based on genotype better predicts prognosis than histology and, therefore, provides a more reliable tool for standardizing future treatment strategies.
Schmidt N, Hess V, Zumbrunn T, Rothermundt C, Bongartz G, Potthast S (2013) Choi response criteria for prediction of survival in patients with metastatic renal cell carcinoma treated with anti-angiogenic therapies. Eur Radiol 23:632--639 (online)
Objective: Anti-angiogenic drugs cause a reduction in tumour density (Choi criteria) first and then in size [Response Evaluation Criteria In Solid Tumours (RECIST)]. The prognostic significance of changes in tumour density in metastatic renal cell carcinoma (mRCC) is unknown and was assessed in this study. Methods: The prognostic significance of partial response (PR) as opposed to non-response [stable disease (SD) + progressive (PD)] to anti-angiogenic therapy was assessed in patients with mRCC separately for both criteria using the log-rank test and Cox regression models. Results: Both criteria were applied to 35 patients. The response was identical for all eight patients with PR and most patients with PD (10/12) when using the RECIST and Choi criteria. Adding tumour density information, 14 patients with SD were re-categorised as having PR (7), SD (4), and PD (3). Patients with PR (Choi) were progression free significantly longer [hazard ratio (HR) 0.24; 95 % CI 0.10–0.57; P = 0.001] and had better overall survival (HR 0.36; 95 % CI 0.15–0.89; P = 0.026) compared to patients with SD or PD. The predictive value of PR according to RECIST was not statistically significant. Conclusions: In mRCC, the Choi criteria separate prognostic groups better when compared with RECIST. This may allow early discrimination of patients benefiting from continued treatment.
Wild D, Bomanji JB, Benkert P, Maecke H, Ell PJ, Reubi JC, Caplin ME (2013) Comparison of ⁶⁸Ga-DOTANOC and ⁶⁸Ga-DOTATATE PET/CT within Patients with gastroenteropancreatic neuroendocrine tumors. J Nucl Med 54:11--12 (online)
Background: Somatostatin receptor PET tracers such as [⁶⁸Ga-DOTA,1-Nal³]-octreotide (⁶⁸Ga-DOTANOC) and [⁶⁸Ga-DOTA,Tyr³]-octreotate (⁶⁸Ga-DOTATATE) have shown promising results in patients with neuroendocrine tumors, with a higher lesion detection rate than is achieved with ¹⁸F-fluorodihydroxyphenyl-L-alanine PET, somatostatin receptor SPECT, CT, or MR imaging. ⁶⁸Ga-DOTANOC has high affinity for somatostatin receptor subtypes 2, 3, and 5 (sst₂﹐₃﹐₅). It has a wider receptor binding profile than ⁶⁸Ga-DOTATATE, which is sst₂-selective. The wider receptor binding profile might be advantageous for imaging because neuroendocrine tumors express different subtypes of somatostatin receptors. The goal of this study was to prospectively compare ⁶⁸Ga-DOTANOC and ⁶⁸Ga-DOTATATE PET/CT in the same patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and to evaluate the clinical impact of ⁶⁸Ga-DOTANOC PET/CT. Methods: Eighteen patients with biopsy-proven GEP-NETs were evaluated with ⁶⁸Ga-DOTANOC and ⁶⁸Ga-DOTATATE using a randomized crossover design. Labeling of DOTANOC and DOTATATE with ⁶⁸Ga was standardized using a fully automated synthesis device. PET/CT findings were compared with 3-phase CT scans and in some patients with MR imaging, 18F-FDG PET/CT, and histology. Uptake in organs and tumor lesions was quantified and compared by calculation of maximum standardized uptake values (SUVmax) using volume computer-assisted reading. Results: Histology revealed low-grade GEP-NETs (G1) in 4 patients, intermediate grade (G2) in 7, and high grade (G3) in 7. ⁶⁸Ga-DOTANOC and ⁶⁸Ga-DOTATATE were false-negative in only 1 of 18 patients. In total, 248 lesions were confirmed by cross-sectional and PET imaging. The lesion-based sensitivity of ⁶⁸Ga-DOTANOC PET was 93.5%, compared with 85.5% for ⁶⁸Ga-DOTATATE PET (P = 0.005). The better performance of ⁶⁸Ga-DOTANOC PET is attributed mainly to the significantly higher detection rate of liver metastases rather than tumor differentiation grade. Multivariate analysis revealed significantly higher SUVmax in G1 tumors than in G3 tumors (P = 0.009). This finding was less pronounced with ⁶⁸Ga-DOTANOC (P > 0.001). Altogether, ⁶⁸Ga-DOTANOC changed treatment in 3 of 18 patients (17%). Conclusion: The sst₂﹐₃﹐₅-specific radiotracer ⁶⁸Ga-DOTANOC detected significantly more lesions than the sst₂-specific radiotracer ⁶⁸Ga-DOTATATE in our patients with GEP-NETs. The clinical relevance of this finding has to be proven in larger studies.

2012

Garcia M, Naraghi R, Zumbrunn T, Rösch J, Hastreiter P, Dörfler A (2012) High-resolution 3D-constructive interference in steady-state MR imaging and 3D time-of-flight MR angiography in neurovascular compression: a comparison between 3T and 1.5T. AJNR Am J Neuroradiol 33:1251--1256 (online)
Background and purpose: High-resolution MR imaging is useful for diagnosis and preoperative planning in patients with NVC. Because high-field MR imaging promises higher SNR and resolution, the aim of this study was to determine the value of high-resolution 3D-CISS and 3D-TOF MRA at 3T compared with 1.5T in patients with NVC. Materials and methods: Forty-seven patients with NVC, trigeminal neuralgia, hemifacial spasm, and glossopharyngeal neuralgia were examined at 1.5T and 3T, including high-resolution 3D-CISS and 3D-TOF MRA sequences. Delineation of anatomic structures, overall image quality, severity of artifacts, visibility of NVC, and assessment of the SNR and CNR were compared between field strengths. Results: SNR and CNR were significantly higher at 3T (P < .001). Significantly better anatomic conspicuity, including delineation of CNs, nerve branches, and assessment of small vessels, was obtained at 3T (P < .02). Severity of artifacts was significantly lower at 3T (P < .001). Consequently, overall image quality was significantly higher at 3T. NVC was significantly better delineated at 3T (P < .001). Six patients in whom NVC was not with certainty identifiable at 1.5T were correctly diagnosed at 3T. Conclusions: Patients with NVC may benefit from the higher resolution and greater sensitivity of 3T for preoperative assessment of NVC, and 3T may be of particular value when 1.5T is equivocal.
Grossmann FF, Zumbrunn T, Frauchiger A, Delport K, Bingisser R, Nickel CH (2012) At risk of undertriage? Testing the performance and accuracy of the Emergency Severity Index in older emergency department patients. Ann Emerg Med 60:317--325 (online)
Study objective: We test predictive validity, interrater reliability, and diagnostic accuracy of the Emergency Severity Index in older emergency department (ED) patients and identify reasons for inadequate triage. Methods: We analyzed data of patients aged 65 years or older who were included in a prospective, single-center cohort study. Predictive validity was assessed by investigating associations of resources, disposition, length of stay, and mortality with Emergency Severity Index levels. Diagnostic accuracy was tested by calculating sensitivity and specificity of Emergency Severity Index level 1 for the prediction of a lifesaving intervention. For the assessment of interrater reliability, 2 experts independently reviewed the triage nurses' notes. Agreement was estimated as raw agreement and as Cohen's weighted κ. Results: In total, 519 older patients were included. Emergency Severity Index level was associated with resource consumption (Spearman's ρ=–0.449; 95% confidence interval [CI] −0.519 to −0.379), disposition (Kendall's τ=–0.452; 95% CI −0.516 to −0.387), ED length of stay (Kruskal-Wallis χ2=92.5; df=4; P<.001), and mortality (log-rank χ2=37.04; df=3; P<.001). The sensitivity of the Emergency Severity Index to predict lifesaving interventions was 0.462 (95% CI 0.232 to 0.709), and the specificity was 0.998 (95% CI 0.989 to 1.000). Interrater reliability between experts was high (raw agreement 0.917, 95% CI 0.894 to 0.944; Cohen's weighted κw=0.934, 95% CI 0.913 to 0.954). Undertriage occurred in 117 cases. Main reasons were neglect of high-risk situations and failure to appropriately interpret vital signs. Conclusion: In our study, older patients were at risk for undertriage. However, our results suggest that the Emergency Severity Index is reliable and valid for triage of older patients.
Nagler M, Fabbro T, Wuillemin WA (2012) Prospective evaluation of the interobserver reliability of the 4Ts score in patients with suspected heparin-induced thrombocytopenia. J Thromb Haemost 10:151--152 (online)
Papadopoulou A, von Felten S, Traud S, Rahman A, Quan J, King R, Garren H, Steinman L, Cutter G, Kappos L, Radue E (2012) Evolution of MS lesions to black holes under DNA vaccine treatment. J Neurol 259:1375--1382 (online)
Persistent black holes (PBH) are associated with axonal loss and disability progression in multiple sclerosis (MS). The objective of this work was to determine if BHT-3009, a DNA plasmid-encoding myelin basic protein (MBP), reduces the risk of new lesions becoming PBH, compared to placebo, and to test if pre-treatment serum anti-MBP antibody levels impact on the effect of BHT-3009 treatment. In this retrospective, blinded MRI study, we reviewed MRI scans of 155 MS patients from a double-blind, randomized, phase II trial with three treatment arms (placebo, 0.5 and 1.5 mg BHT-3009). New lesions at weeks 8 and 16 were tracked at week 48 and those appearing as T1-hypointense were classified as PBH. A subset of 46 patients with available pre-treatment serum anti-MBP IgM levels were analyzed separately. Overall, there was no impact of treatment on the risk for PBH. However, there was a significant interaction between anti-MBP antibodies and treatment effect: patients receiving 0.5 mg BHT-3009 showed a reduced risk of PBH with higher antibody levels compared to placebo (p < 0.01). Although we found no overall reduction of the risk for PBH in treated patients, there may be an effect of low-dose BHT-3009, depending on the patients’ pre-treatment immune responses.
Sarlos D, Kots L, Stevanovic N, von Felten S, Schär G (2012) Robotic compared with conventional laparoscopic hysterectomy: a randomized controlled trial. Obstet Gynecol 120:604--611 (online)
Objective: To compare surgical outcome and quality of life of robot-assisted laparoscopic hysterectomy with conventional laparoscopic hysterectomy. Methods: For this controlled clinical trial, patients with benign indications for hysterectomy were randomized to receive either a robotic (robotic group) or conventional laparoscopic hysterectomy (conventional group). The primary end point was total operating time; secondary end points were perioperative outcome, blood loss, and the change in quality of life. Results: Ninety-five patients out of 100 randomized patients completed the study. Patient age, body mass index, and uterus weight showed no significant differences between both groups. All results are given as mean (±standard deviation; median). Total operating time for the robotic group was significantly higher with 106 (±29; 103) compared with 75 (±21; 74) (conventional group) minutes. Blood loss, complications, analgesics use, and return to activity for both groups were comparable. The change in preoperative to postoperative quality-of-life index (quality of life measured on a linear scale from 0 to 100) was significantly higher in the robotic group, with 13 (±10; 13) compared with 5 (±14; 5) (conventional group). Conclusion: Robot-assisted laparoscopic hysterectomy and conventional laparoscopy compare well in most surgical aspects, but the robotic procedure is associated with longer operating times. Postoperative quality-of-life index was better; however, long-term, there was no difference. However, subjective postoperative parameters such as analgesic use and return to activity showed no significant difference between both groups. Clinical trial registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00683293. Level of evidence: I
Schandelmaier S, Ebrahim S, Burkhardt SCA, de Boer WEL, Zumbrunn T, Guyatt GH, Busse JW, Kunz R (2012) Return to work coordination programmes for work disability: a meta-analysis of randomised controlled trials. PLoS One 7:e49760 (online)
Background: The dramatic rise in chronically ill patients on permanent disability benefits threatens the sustainability of social security in high-income countries. Social insurance organizations have started to invest in promising, but costly return to work (RTW) coordination programmes. The benefit, however, remains uncertain. We conducted a systematic review to determine the long-term effectiveness of RTW coordination compared to usual practice in patients at risk for long-term disability. Methods and Findings: Eligible trials enrolled employees on work absence for at least 4 weeks and randomly assigned them to RTW coordination or to usual practice. We searched 5 databases (to April 2, 2012). Two investigators performed standardised eligibility assessment, study appraisal and data extraction independently and in duplicate. The GRADE framework guided our assessment of confidence in the meta-analytic estimates. We identified 9 trials from 7 countries, 8 focusing on musculoskeletal, and 1 on mental complaints. Most trials followed participants for 12 months or less. No trial assessed permanent disability. Moderate quality evidence suggests a benefit of RTW coordination on proportion at work at end of follow-up (risk ratio = 1.08, 95% CI = 1.03 to 1.13; absolute effect = 5 in 100 additional individuals returning to work, 95% CI = 2 to 8), overall function (mean difference [MD] on a 0 to 100 scale = 5.2, 95% CI = 2.4 to 8.0; minimal important difference [MID] = 10), physical function (MD = 5.3, 95% CI = 1.4 to 9.1; MID = 8.4), mental function (MD = 3.1, 95% CI = 0.7 to 5.6; MID = 7.3) and pain (MD = 6.1, 95% CI = 3.1 to 9.2; MID = 10). Conclusions: Moderate quality evidence suggests that RTW coordination results in small relative, but likely important absolute benefits in the likelihood of disabled or sick-listed patients returning to work, and associated small improvements in function and pain. Future research should explore whether the limited effects persist, and whether the programmes are cost effective in the long term.
Uthoff H, Siegemund M, Aschwanden M, Staub D, Hunziker L, Fabbro T, Baumann U, Imfeld S, Jaeger KA (2012) Prospective comparison of noninvasive, bedside ultrasound methods for assessing central venous pressure. Eur J Ultrasound 33:E256--E262 (online)
Purpose: To prospectively evaluate the accuracy of noninvasive central venous pressure (CVP) assessment by compression ultrasound of a forearm vein (CUS), inferior vena cava (IVC-C) and internal jugular vein collapsibility (IJV-C) compared to invasive CVP measurement (invCVP) as the gold standard. Materials and Methods: CUS, IVC-C and IJV-C were performed in a random sequence in 81 consecutive intensive care patients with simultaneous invCVP monitoring. Examiners were blinded to invCVP and previous examinations. Results: Median invCVP was 12.0 mmHg (range 1 - 23). CUS, IVC-C and IJV-C could be obtained in 89 %, 95 % and 100 % of cases, respectively, within a median time of 188 sec [IQR 125; 270], 133 sec [IQR 100; 211] and 60 sec [IQR 50; 109], respectively. The Spearman correlation coefficient between invCVP and CUS, IVC-C, and IJV-C was 0.485 95 %-CI [0.25; 0.65], -0.186 [-0.42; 0.07], and -0.408 [-0.59; -0.18], respectively. The median absolute difference between CUS and invCVP was 3 mmHg [IQR 2; 6.75]. CVP was categorized as low (< 7 mmHg; collapsibility > 0.6), normal (7 - 12 mmHg; collapsibility 0.6 - 0.2) and high (> 12 mmHg; collapsibility < 0.2) as prespecified. The proportions of identical CVP classifications compared to invCVP were 61.4% 95%-CI [49.3%; 72.4%] with CUS, 48.7% [37.4%; 60%] with IVC-C and 51.3% [40.3%; 62.3%] with IJV-C (p > 0.10 for all pair-wise comparisons). Conclusion: The overall ability of CUS, IVC-C and IJV-C to assess invCVP was only moderate. CUS seems to be the preferable method if absolute CVP values are needed. IJV-C seems to be the fastest and most easily acquirable method, and thus may be especially valuable in emergency rooms.
Weier K, Mazraeh J, Naegelin Y, Thoeni A, Hirsch JG, Fabbro T, Bruni N, Duyar H, Bendfeldt K, Radue E, Kappos L, Gass A (2012) Biplanar MRI for the assessment of the spinal cord in multiple sclerosis. Mult Scler 18:1560--1569 (online)
Objective: To investigate the entire spinal cord (SC) of multiple sclerosis (MS) patients with biplanar MRI and to relate these MRI findings to clinical functional scores. Methods: Two hundred and two patients (140 women, 62 men 24–74 years, Expanded Disability Status Scale (EDSS) scores 0–7.5) were investigated clinically and with biplanar MRI. Sagittal and axial proton density weighted (PDw) and T2 weighted (T2w) images of the whole SC were obtained employing parallel imaging. Data were analyzed by consensus reading using a standardized reporting scheme. Different combinations of findings were compared to EDSS scores with Spearman’s rank correlation coefficient (ρ). Results: The combined analysis of sagittal and axial planes demonstrated slightly differing results in 97/202 (48%) patients. There were 9% additional lesions identified, leading to a higher lesion count in 28% of these patients, but also rejection of equivocal abnormality leading to a lower lesion count in 11% of patients. Considering both sagittal and axial images, SC abnormalities were found in 167/202 (83%) patients. When compared with EDSS scores, the combination of focal lesions, signs of atrophy and diffuse abnormalities showed a moderate correlation (ρ=0.52), that precludes its use for individual patient assessment. Conclusion: Biplanar MRI facilitates a comprehensive identification, localization, and grading of pathological SC findings in MS patients. This improves the confidence and utility of SC imaging.

2011

Plagge H, Ruppen W, Ott N, Fabbro T, Bornand D, Deuster S (2011) Dose calculation in opioid rotation: electronic calculator vs. manual calculation. Int J Clin Pharm 33:25--32 (online)
Objective: To generate, validate and establish a web-based individualised opioid conversion calculator at the University Hospital Basel and to analyse its value and significance. Setting: A 700-bed university hospital. Method: Published data were screened by a Medline search using the keywords: opioid, rotation, switching, potency and dose ratio. Based on this data, the criteria for the conversion calculator were defined. A prospective process validation was performed prior to the approval. Five months after the introduction of the tool, an online survey was performed in order to evaluate its acceptance by users. In the last step, a manual calculation using a written table was compared with the calculator in a cross-over trial with 72 participants in order to assess the findings of the survey. Results: The opioid conversion calculator could be generated for 24 combinations of 6 opioids for 5 different routes of administration. The validation of the calculator was performed successfully without discovering any major or critical defects. The proportion of correct answers increased from 68% using the table to 81% using the calculator (P < 0.001), the median time necessary to answer the ten questions was 8.9 min using the table and 4.8 min using the calculator. Conclusion: A web-based opioid conversion calculator was planned, generated, validated and established at the hospital. Based on the results of the online survey and the results of our cross-over trial we conclude that the tool saves time compared to manual calculation and may contribute to patient safety by avoiding calculation errors. With this tool we contribute to the optimisation of processes in hospital and patient safety.
Rousson V, Zumbrunn T (2011) Decision curve analysis revisited: overall net benefit, relationships to ROC curve analysis, and application to case-control studies. BMC Med Inform Decis Mak 11:45 (online)
Background: Decision curve analysis has been introduced as a method to evaluate prediction models in terms of their clinical consequences if used for a binary classification of subjects into a group who should and into a group who should not be treated. The key concept for this type of evaluation is the "net benefit", a concept borrowed from utility theory. Methods: We recall the foundations of decision curve analysis and discuss some new aspects. First, we stress the formal distinction between the net benefit for the treated and for the untreated and define the concept of the "overall net benefit". Next, we revisit the important distinction between the concept of accuracy, as typically assessed using the Youden index and a receiver operating characteristic (ROC) analysis, and the concept of utility of a prediction model, as assessed using decision curve analysis. Finally, we provide an explicit implementation of decision curve analysis to be applied in the context of case-control studies. Results: We show that the overall net benefit, which combines the net benefit for the treated and the untreated, is a natural alternative to the benefit achieved by a model, being invariant with respect to the coding of the outcome, and conveying a more comprehensive picture of the situation. Further, within the framework of decision curve analysis, we illustrate the important difference between the accuracy and the utility of a model, demonstrating how poor an accurate model may be in terms of its net benefit. Eventually, we expose that the application of decision curve analysis to case-control studies, where an accurate estimate of the true prevalence of a disease cannot be obtained from the data, is achieved with a few modifications to the original calculation procedure. Conclusions: We present several interrelated extensions to decision curve analysis that will both facilitate its interpretation and broaden its potential area of application.
Stoehr S, Bollag Y, Auerbach H, Eichler K, Imhof D, Fabbro T, Gyr N (2011) Quality assessment of a randomly selected sample of Swiss medical expertises: a pilot study. Swiss Med Wkly 141:w13173 (online)
Background: Considerable criticism has lately been raised by the media regarding the quality of Swiss medical expertises. The present investigation was therefore undertaken to assess the professional quality of Swiss medical expertises. The study was part of a market analysis of medical expertises (MGS study). Methods: A sample of 97 anonymised expertises randomly chosen from a total of 3165, collected in the MGS study over a period of 3 months, were evaluated by an international board of medical experts and reviewers, using a stepwise developed questionnaire. Each expertise was independently evaluated by two experts. Data were then tested for plausibility (obvious errors and misunderstandings). The main outcome was the overall quality rating of the expertise that was graded from 1 (very poor) to 6 (excellent) in analogy to the Swiss school grading system. For analysis and interpretation the grades were divided into sufficient (grades >= 4) and insufficient (grades <4). Results: Overall 19.6% (95% confidence interval: 13.1%; 28.3%) of the expertises were rated to be of insufficient quality. The quality was inversely related to the number of involved medical disciplines, the time relapsed since injury and positively related to the difficulty of the expertise. In addition, expertises in the French and Italian languages were rated superior to those in German. Conclusion: Our results confirm recent criticisms that the professional quality of expertises does not suffice. This is hardly acceptable in face of the financial and personal consequences. There is an obvious need for further research using larger samples and for educational programmes on all levels.
Tschopp K, Zumbrunn T, Knaus C, Thomaser E, Fabbro T (2011) Statistical model for postoperative apnea-hypopnea index after multilevel surgery for sleep-disordered breathing. Eur Arch Otorhinolaryngol 268:1679--1685 (online)
The objective of the study was to formulate a statistical model for postoperative apnea–hypopnea index (AHI) 3 and 12 months after multilevel surgery using the predictors preoperative AHI, body mass index (BMI) and age. The study design was a prospective cohort study. Data of 144 patients were collected prospectively 3 and 12 months after multilevel surgery for obstructive sleep apnea syndrome (OSAS) or upper airway resistance syndrome with excessive daytime sleepiness. The primary endpoint postoperative AHI and the secondary endpoint success according to the Sher criteria (postoperative AHI <20 h and >50% reduction of preoperative AHI) were modeled with multiple linear and logistic regression using the predictors preoperative AHI, BMI, age and the indicator whether the patient had undergone a tonsillectomy. Preoperative AHI and tonsillectomy had a highly significant positive influence on postoperative AHI after 3 months, whereas the influence of preoperative BMI was only marginally significant but numerically rather large. Age was not a significant decisive factor. The success according to the Sher criteria was highly significantly determined by the circumstance whether the patient had undergone a tonsillectomy, but not by the other predictors preoperative BMI or age. The responder rate with and without tonsillectomy was 58 and 19%, respectively. The odds ratio to be a responder if a tonsillectomy was conducted was 5.7. This study provides statistical models predicting postoperative AHI and success according to the Sher criteria after multilevel surgery for OSAS.

2010

Kaiser C, Galatius S, Erne P, Eberli F, Alber H, Rickli H, Pedrazzini G, Hornig B, Bertel O, Bonetti P, De Servi S, Brunner-La Rocca HP, Ricard I, Pfisterer M (2010) Drug-eluting versus bare-metal stents in large coronary arteries. N Engl J Med 363:2310--2319 (online)
Background: Recent data have suggested that patients with coronary disease in large arteries are at increased risk for late cardiac events after percutaneous intervention with first-generation drug-eluting stents, as compared with bare-metal stents. We sought to confirm this observation and to assess whether this increase in risk was also seen with second-generation drug-eluting stents. Methods: We randomly assigned 2314 patients needing stents that were 3.0 mm or more in diameter to receive sirolimus-eluting, everolimus-eluting, or bare-metal stents. The primary end point was the composite of death from cardiac causes or nonfatal myocardial infarction at 2 years. Late events (occurring during months 7 to 24) and target-vessel revascularization were the main secondary end points. Results: The rates of the primary end point were 2.6% among patients receiving sirolimus-eluting stents, 3.2% among those receiving everolimus-eluting stents, and 4.8% among those receiving bare-metal stents, with no significant differences between patients receiving either drug-eluting stent and those receiving bare-metal stents. There were also no significant between-group differences in the rate of late events or in the rate of death, myocardial infarction, or stent thrombosis. Rates of target-vessel revascularization for reasons unrelated to myocardial infarction were 3.7% among patients receiving sirolimus-eluting stents, 3.1% among those receiving everolimus-eluting stents, and 8.9% among those receiving bare-metal stents. The rate of target-vessel revascularization was significantly reduced among patients receiving either drug-eluting stent, as compared with a bare-metal stent, with no significant difference between the two types of drug-eluting stents. Conclusions: In patients requiring stenting of large coronary arteries, no significant differences were found among sirolimus-eluting, everolimus-eluting, and bare-metal stents with respect to the rate of death or myocardial infarction. With the two drug-eluting stents, similar reductions in rates of target-vessel revascularization were seen. (Funded by the Basel Cardiovascular Research Foundation and the Swiss National Foundation for Research; Current Controlled Trials number, ISRCTN72444640.)

2008

Walz L, Salzmann GM, Fabbro T, Eichhorn S, Imhoff AB (2008) The anatomic reconstruction of acromioclavicular joint dislocations using 2 tightrope devices: a biomechanical study. Am J Sports Med 36:2398--2406 (online)
Background: For the reconstruction of acromioclavicular (AC) joint separation, several operative procedures have been described; however, the anatomic reconstruction of both coracoclavicular ligaments has rarely been reported. Purpose: The aim of this biomechanical study is to describe a new procedure for anatomic reconstruction of the AC joint. Study Design: Controlled laboratory study. Materials and Methods: Forty fresh-frozen cadaveric shoulders were tested. Cyclic loading and a load-to-failure protocol was performed in vertical (native, n = 10; reconstructed, n = 10) and anterior directions (native, n = 10; reconstructed, n = 10) on 20 AC joints and repeated after anatomic reconstruction. Reconstruction of conoid and trapezoid ligaments was achieved by 2 TightRope devices (Arthrex, Naples, Florida). Dynamic, cyclic, and static loading until failure in vertical (n = 5) and horizontal (n = 5) directions were tested in native as well as reconstructed joints in a standardized setting. Results: The native coracoclavicular ligaments in static load for vertical force measured 598 N (range, 409–687), elongation 10 mm (range, 6–14), and stiffness 99 N/mm (range, 67–130); static load for anterior force was 338 N (range, 186–561), elongation 4 mm (range, 3–7), and stiffness 140 N/mm (range, 70–210). The mean maximum static load until failure in reconstruction for vertical force was 982 N (range, 584–1330) (P =.001), elongation 4 mm (range, 3–6) (P < .001), and stiffness 80 N/mm (range, 66.6–105) (P = .091); and for anterior static force 627 N (range, 364–973) (P < .001), elongation 6.5 mm (range, 4–10) (P = .023), and stiffness 78 N/mm (range, 46–120) (P = .009). During dynamic testing of the native coracoclavicular ligaments, the mean amount of repetitions (100 repetitions per stage, stage 0–100 N, 100–200 N, 200–300 N, etc, and a frequency of 1.5 Hz) in native vertical direction was 593 repetitions (range, 426–683) and an average of 552 N (range, 452–683) load until failure. In vertical reconstructed testing, there were 742 repetitions (range, 488–893) (P = .222) with a load until failure of 768 N (range, 486–900) (P = .095). In the anterior direction load, the native ligament failed after an average of 365 repetitions (range, 330–475) and an average load of 360 N (range, 307–411), while reconstructed joints ended in 549 repetitions (range, 498–566) (P = .008) with a load until failure of 547 N (range, 490–585) (P = .008). In all testing procedures, a preload of 5 N was performed. Conclusion: The anatomic reconstruction of the AC joint using TightRope is a stable and functional anatomic reconstruction procedure. The reconstruction technique led to favorable in vitro results with equal or even higher forces than native ligaments. Clinical Relevance: Through anatomic repair, stable function of the AC joint can be achieved in an anatomic manner.