Zum gesellschaftlichen Nutzen pharmazeutischer Innovationen

Um den gesellschaftlichen Nutzen pharmazeutischer Innovationen abzuschätzen, bedarf es adäquater Beurteilungskriterien. Nach einem empirischen Abriß über die Entwicklung der Arzneimittelausgaben erörtern die Autoren die beurteilungsrelevanten gesamtwirtschaftlichen Ziele. Auf mikroökonomischer Basis bietet sich zur Ermittlung der Nützlichkeit von Arzneimitteln die Kosten-Nutzen-Analyse an. Im Prozeß gesundheitlicher Leistungserstellung nimmt das Arzneimittel den Rang eines Produktionsfaktors ein, der zumeist in Verbindung mit anderen Behandlungsarten eine Verbesserung des Gesundheitszustandes erzeugt. Dabei besitzen unter Effektivitäts- und Effizienzaspekten Innovations- und Imitationsprodukte unterschiedliche allokative Funktionen. Die beinahe weltweiten gesundheitspolitischen Regulierungen begünstigen die Imitationen und drohen damit die Forschungsanreize zu reduzieren

Simultaneous Acquisition of EEG and NIRS during Cognitive Tasks for an Open Access Dataset

We provide an open access multimodal brain-imaging dataset of simultaneous electroencephalography (EEG) and near-infrared spectroscopy (NIRS) recordings. Twenty-six healthy participants performed three cognitive tasks: 1) n-back (0-, 2- and 3-back), 2) discrimination/selection response task (DSR) and 3) word generation (WG) tasks. The data provided includes: 1) measured data, 2) demographic data, and 3) basic analysis results. For n-back (dataset A) and DSR tasks (dataset B), event-related potential (ERP) analysis was performed, and spatiotemporal characteristics and classification results for “target” vs. “non-target” (dataset A) and symbol “O” vs. symbol “X” (dataset B) are provided. Time-frequency analysis was performed to show the EEG spectral power to differentiate the task-relevant activations. Spatiotemporal characteristics of hemodynamic responses are also shown. For the WG task (dataset C), the EEG spectral power and spatiotemporal characteristics of hemodynamic responses are analyzed, and the potential merit of hybrid EEG-NIRS BCIs was validated with respect to classification accuracy. We expect that the dataset provided will facilitate performance evaluation and comparison of many neuroimaging analysis techniques

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Evaluierung und Optimierung von neuen analytischen Herangehensweisen für In-Vivo-Messungen mit Nah-Infrarot-Spektroskopie

Nah-Infrarot Spektroskopie (NIRS) ist eine nicht-invasive Technik im Bereich der neurowissenschaftlichen Bildgebung um hämodynamische Effekte zu messen, die neuronalen Ereignissen folgen. NIRS verwendet nah-infrarotes Licht um über den Farbunterschied von oxygeniertem und deoxygeniertem Hämoglobin die Konzentrationsdynamiken derselben zu ermitteln. Allerdings existieren Einschränkung für diese Technik: NIRS hat eine geringe Eindringtiefe in das Gewebe und eine hohe Empfindlichkeit gegenüber Artefakten, die von ruckartigen Bewegung oder kardio-vaskulären Oszillationen stammen. Des Weiteren ist die hämodynamische Antwort relativ langsam und überlappt sich bei schnellen Stimulationen. In der vorliegenden Arbeit stelle ich drei Analysekonzepte vor, die versuchen artefaktbedingte Defizite von NIRS überwinden. Diese sind: Allgemeines Lineare Model (GLM), maschinelles Lernen (ML) und funktionelle Konnektivität im Ruhezustand (RS-FC). Für die GLM-Analyse wird ein Model der erwarteten hämodynamischen Antwort generiert und mit gemessenen Daten verglichen. Ich zeige die Machbarkeit einer solchen Analyse für NIRS anhand einer Studie über Spiegelillusionen und einer Studie zur Entwicklung von Inhibition. In zuletzt genannter Studie werden schnelle Stimuluspräsentationen verwendet, weswegen die hämodynamischen Antworten überlappen. Diese können jedoch mit Hilfe des GLM entfaltet werden. Eine ähnliche Analyse wurde durchgeführt um den gemittelten und entfalteten Verlauf der hämodynamischen Antwort zu bestimmen. Beim maschinellen Lernen wird versucht die maximale Trennbarkeit zwischen zwei Konditionen mit Hilfe der gemessenen Daten zu bestimmen. ML-Analyse macht es zudem möglich Daten in Echtzeit zu interpretieren, wie hier am Beispiel von Gehirn-Computer Schnittstellen gezeigt wird. Eine weitere Anwendungsmöglichkeit von ML-Analysen ist die kontinuierliche Vorhersage des Aufmerksamkeitsstadiums eines Menschen. RS-FC hat das Ziel funktionelle, neuronale Netzwerke aus Ruhedaten zu extrahieren. Dies ist insbesondere sinnvoll um Menschen zu untersuchen die Konzentrationsschwierigkeiten haben, wie zum Beispiel Kinder oder Patienten mit schweren Schädigungen. Die RS-FC-Analyse korreliert langsame, spontane Oszillationen zwischen Bereichen des Gehirns die funktionelle Netzwerke bilden. In meiner Arbeit werden Netzwerke vorgestellt, die über weite Distanzen miteinander verbunden sind. Dies ist durch die Abdeckung des gesamten Kopfes mit Sensoren des NIRS möglich. Des Weiteren wird die Entwicklung von funktionellen Netzwerken von Kindern zu Erwachsenen dargestellt. Die RS-FC-Anaylse von NIRS-Daten wird zudem anhand von simultanen Messungen mit dem fMRT überprüft für welches RS-FC eigentlich entwickelt wurde. Alle drei vorgestellten Analysewerkzeuge können für NIRS verwendet werden. Jede Routine hat dabei spezifischen Anwendungsmöglichkeiten in den Neurowissenschaften. Daher öffnen sich viele neue Forschungsgebiete in denen es sinnvoll ist mit NIRS Daten zu erheben.Near-Infrared Spectroscopy (NIRS) is a non-invasive neuroimaging technology. It measures hemodynamic responses after local neuronal activity with near-infrared light. NIRS depends on the different colors of oxygenated and deoxygenated hemoglobin and measures their change of concentration over time. This technique suffers from several limitations as there is its low depth penetration depth and its sensibility to movement and cardio-vascular artifacts. Furthermore, the hemodynamic response is relative slow and tends to overlap in fast experimental design. In this work I present three recent analytical tools to overcome artifact related shortcomings of NIRS. The analyzing tools introduced here are General Linear Model analysis (GLM), Machine Learning tools (ML) and Resting-State Functional Connectivity analysis (RS-FC). For GLM analysis one creates a model of the expected hemodynamic response to stimuli and compares it to the actual measured data. I show the feasibility of GLM analysis for NIRS data in an experiment on mirror illusion and a developmental study on inhibition. The later contains overlapping hemodynamics which can be deconvolved by the GLM analysis. Further work on GLM-like approaches is done to yield a deconvolution of the average hemodynamic responses. ML tools maximize the separability between experimental conditions in the data and are capable of real-time data analysis. I show an example where we use ML techniques for Brain-Computer Interfaces. A second study shows the ability of ML routines to continuously predict the subject's attentional state. RS-FC aims to analyze functional networks between brain areas using resting-state data. This is useful for subjects that are not able to concentrate, like severely ill patients or young children. RS-FC analyzes slow, spontaneous oscillations which are correlated within areas forming a functional network. Here I present functional networks derived by RS-FC analysis in an experiment where the whole-head of the subjects was covered by NIRS sensors allowing also the estimation of long-distance connection between parietal and frontal brain areas. Further results are presented for developmental effects within resting-state networks. This approach is also validated against the \textit{golden standard} of fMRI where RS-FC analysis stems from. All three introduced analyzing techniques are feasible for NIRS data and have their specific applications in neuroscientific research which opens new fields of research for using NIRS

Altered muscle activity during rest and during mental or physical activity is not a trait symptom of migraine - a neck muscle EMG study

Abstract Background Migraineurs have a high prevalence of neck pain prior to or during headache attacks. Whether neck pain is a symptom of migraine or an indicator for a constant neck muscle dysfunction potentially triggering migraine attacks is a topic of scientific debate. The presence of myofascial trigger points in neck muscles including the trapezius muscle, points towards muscle alterations associated with migraine. We measured electromyography (EMG) of the neck muscles in a large cohort to identify whether neck pain and neckmuscle tension reported by migraine patients can be attributed to increased neck muscle activation during rest, mental stress or physical activity. Methods Surface EMG responses of the trapezius muscle were recorded during a paradigm including rest periods, mental stress and physical activity of 102 participants (31 chronic migraine, 43 episodic migraine, 28 healthy participants). Results All groups showed increased trapezius activity during mental stress and physical activity compared to rest. There was no statistically significant difference between migraine patients and healthy controls for any of the 3 conditions except for the initial mental stress situation (F (2,56.022) = 8.302, p = 0.001), where controls increased tension by only 4.75%, episodic migraineurs by 17.39% and chronic migraineurs by 28.61%. Both migraine groups returned to resting EMG levels within the same timeframe as healthy controls. Conclusions Neck pain associated with migraine can therefore not be attributed to increased trapezius activity during rest, mental stress and physical activity or prolonged muscle activity and should not be seen as a constantly underlying trigger but rather as an accompanying symptom of migraine

The effect of botulinum toxin type a on overactive bladder symptoms in patients with multiple sclerosis: a pilot study

PURPOSE: Patients with multiple sclerosis often experience overactive bladder symptoms. High dose intradetrusor botulinum toxin A treatment is effective but often results in urinary retention and urinary diversion via a catheter. In this pilot study we evaluated whether only 100 U botulinum toxin A would significantly decrease overactive bladder symptoms in patients with multiple sclerosis without impairing pretreatment voluntary voiding. MATERIALS AND METHODS: Included in our study were 12 patients with multiple sclerosis who had overactive bladder symptoms such as urgency, frequency and/or urgency incontinence. The treatment effect was evaluated using data on 3 consecutive visits, that is before, and a mean +/- SD of 46.2 +/- 11.9 and 101 +/- 21 days after intradetrusor injection of 100 U Botox, including the results of cystometry and uroflowmetry at visits 1 and 2, and uroflowmetry alone at visit 3. Patients completed a 3-day voiding diary for all 3 visits. RESULTS: Maximum bladder capacity significantly increased and maximum detrusor pressure decreased. Daytime and nighttime frequency, urgency and pad use significantly decreased. Post-void residual volume significantly increased initially but decreased until 12 weeks. Median time to re-injection due to recurrent overactive bladder symptoms was 8 months. CONCLUSIONS: Overactive bladder treatment in patients with multiple sclerosis using 100 U Botox intradetrusor injections seems to be effective and safe. Despite slightly impaired detrusor contractility most patients still voided voluntarily without symptoms. Thus, 100 U Botox may be a reasonable treatment option for overactive bladder symptoms in patients with multiple sclerosis who still void voluntarily