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Climatic extremes are the new normal for large parts of the world. Even temperate places, such as northern Bavaria, have experienced an abundance of extreme weather with significant impacts on the local ecology. Heavy torrential rainstorms are observed more often, while simultaneously, the precipitation required for a healthy ecology does not occur for increasing periods. These droughts, in combination with anthropogenic influences, have severely weakened the vitality of vast stretches of forest in northern Bavaria. In consequence, secondary pests were able to cause wide spread tree mortality. This indicates the need for innovative water management strategies to increase the resilience of forest ecosystems with regard to an increased occurrence of droughts.This study aims at exploring the potential of nature-based solutions to increase the infiltration of surface runoff in forest in order to increase the plant-available soil moisture and therefore the drought resilience during dry periods. Specifically two measures are investigated, which alter the micro-topography of the forest floor. These are:“Dead-wood” left in the forest after timber-harvest and aligned along slopes to act as flow barriers during runoff events and, Small-scale basins of shallow depth that mimic the natural topography of the forest floor and act as retention basins. To be able to understand and evaluate the effectiveness of the nature-based solutions and investigate the relevant hydrological and hydrodynamic processes, a small, forested slope in Northern Bavaria was modeled using an innovative coupling of the 2-dimensional hydrodynamic TELEMAC Model with Green & Ampt infiltration. In preparation of setting up the model, state-of-the-art drone LiDAR measurements were used to produce a high-resolution (10 cm resolution) Digital Elevation Model of the area. This enabled us to set up the model with a high enough resolution to capture and simulate the micro-topographic changes of the measures. We simulated various scenarios representing different implementations of the nature-based solutions and used the change of runoff coefficient as compared to the current state simulations as a measure of efficiency. In general, our findings show a clear link between the implementation of the measures and decreased runoff coefficient. While the aligning of dead wood along the slope reduced the runoff coefficient more as compared to a random distribution of dead-wood, the shallow retention-basins showed a significantly higher impact on the runoff coefficient. However, it is likely that the distribution of soil types, vegetation and soil animal activity are very crucial because they significantly affect the infiltration and therefore the efficiency of these measures for drought resilience. Theses aspects were not considered. Altogether, the results of this study should be considered as qualitative as compared to quantitative, due to the simplifications done, especially with regard to the soil and infiltration processes. Keywords: Drought; Forest ecosystem; TELEMAC; Greene & Ampt; LiDAR

Zusammenfassung Hintergrund Real-world-Daten (RWD) und die aus ihnen durch statistisch-epidemiologische Analysen abgeleitete Real-world-Evidenz (RWE) spielen eine vielversprechende und zunehmend relevante Rolle bei regulatorischen Entscheidungsfindungen entlang des Produktlebenszyklus von Arzneimitteln. Ziel der Arbeit Es wird ein Überblick über den aktuellen Stand, die Entwicklungspotenziale und Initiativen zur verstärkten Nutzung von RWE in der europäischen und internationalen Arzneimittelregulation gegeben. Material und Methoden Die Grundlagen für die Übersichtsarbeit sind Originalarbeiten und Reviews aus der aktuellen internationalen Literatur (inklusive eigener Forschungsergebnisse), aktuelle Beispiele aus der regulatorischen Praxis sowie die Einbindung in europäische und internationale Initiativen zur verstärkten Nutzung von RWD/RWE in regulatorischen Entscheidungsprozessen. Ergebnisse Aktuell primär zur supportiven Evidenz bei regulatorischen Entscheidungsfindungen wird RWE aus RWD eingesetzt. Neben dem etablierten Einsatz in Phasen nach der Zulassung (z. B. Überwachung der Arzneimittelsicherheit), werden RWD zunehmend auch in der Phase vor der Zulassung und in der Evaluation eingesetzt. Aktuell wird durch verstärkte Vernetzung der Datenquellen auf nationaler und internationaler Ebene eine Gesundheitsdateninfrastruktur aufgebaut, um neue Möglichkeiten zur RWD-Nutzung zu schaffen. Schlussfolgerung Neben einer wachsenden Bedeutung von RWD/RWE in der europäischen und internationalen Arzneimittelregulation ergeben sich auch neue Herausforderungen zum Zugang zu und zur Analyse von RWD. Die Variabilität und Heterogenität der RWD-Quellen machen die Entwicklung neuer und optimierter Methoden für RWD-Analysen unerlässlich. Auch neue Leitfaden- und Schulungskonzepte für die beteiligten Stakeholder sind essenziell.

Die Digitalisierung stellt auch im Gesundheitsbereich einen eindeutigen Megatrend dar, der neben der Wegbereitung durch geänderte rechtliche Rahmenbedingungen auch durch die Coronapandemie eine enorme Beschleunigung erfahren hat. Mit Blick in die Zukunft wird dieser Trend durch immer kürzere Entwicklungszyklen und technologischen Fortschritt zu einer zunehmenden Verschmelzung einzelner digitaler und nicht digitaler Produkte, darunter Arzneimittel und digitale Medizinprodukte, zu einem digitalen Ökosystem beitragen. Die Digitalisierung wird nicht nur die Patientensouveränität stärken, sondern unter anderem auch eine patientenzentrierte, stärker auf den individuellen Patienten ausgerichtete Medizin ermöglichen; digitale (patientenberichtete) Endpunkte und „dezentrale“ Studienkonzepte werden die Möglichkeiten klinischer Studien erweitern. Künstliche Intelligenz wird Diagnosestellungen verbessern und beschleunigen und zum besseren Verständnis von Krankheitsbildern beitragen. Um auch zukünftig Innovationen zu ermöglichen, aufkommende Trends im Fokus zu haben und vor allem die Patientensicherheit weiter zu verbessern, trägt das Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) an vielen Stellen dazu bei, die mit der Digitalisierung verbundenen Chancen in Möglichkeiten zu verwandeln – ohne dabei die Risiken aus dem Blick zu verlieren: Dazu gehören der Ausbau des Forschungsdatenzentrums, Aufgaben zu Interoperabilität und Klassifikationen sowie Ansätze zur datengestützten Signalerkennung aus Risikoinformationen. Wie darüber hinaus Forschungsprojekte unter Nutzung von künstlicher Intelligenz, (inter)nationale Kooperationen, die Einbeziehung von Real World Data in Nutzen-Risiko-Bewertungen, die Bewertung digitaler Gesundheits- und Pflegeanwendungen neben weiteren Aktivitäten zur „digital readiness“ in Deutschland und Europa beitragen, dazu im Folgenden ein Überblick. Digitalization is a clear megatrend of our time, also in the health sector, which is currently experiencing enormous acceleration due to the COVID-19 pandemic in addition to paving the way due to changes in the legal framework. Looking to the future, this trend will contribute to further digitalization and the merging of individual digital products, including medicinal products and medical devices, into a digital ecosystem. This will be supported by ever-shorter development cycles and technological progress. Digitization will not only strengthen patient sovereignty, but also enable more patient-centered medicine; artificial intelligence will improve and accelerate diagnoses and will contribute to a better understanding of disease patterns and underlying mechanisms or causes. In order to continue to enable innovations in the future, to focus on emerging trends, and, above all, to further improve patient safety, the BfArM is contributing in many places to transforming the opportunities associated with digitalization into possibilities – without losing sight of the risks. The following is an overview of how, for example, the expansion of the Research Data Center, activities addressing interoperability, research projects using artificial intelligence, (inter-)national cooperation, the utilization and inclusion of “Real World Data” in our benefit/risk assessments, and the evaluation of digital health and digital care applications among other activities of the BfArM contribute to “digital readiness” in Germany and Europe.

Voltage-gated Ca

High voltage-activated Cav2.3 R-type Ca2+ channels and low voltage-activated Cav3.2 T-type Ca2+ channels were reported to be involved in numerous physiological and pathophysiological processes. Many of these findings are based on studies in Cav2.3 and Cav3.2 deficient mice. Recently, it has been proposed that inbreeding of Cav2.3 and Cav3.2 deficient mice exhibits significant deviation from Mendelian inheritance and might be an indication for potential prenatal lethality in these lines. In our study, we analyzed 926 offspring from Cav3.2 breedings and 1142 offspring from Cav2.3 breedings. Our results demonstrate that breeding of Cav2.3 deficient mice shows typical Mendelian inheritance and that there is no indication of prenatal lethality. In contrast, Cav3.2 breeding exhibits a complex inheritance pattern. It might be speculated that the differences in inheritance, particularly for Cav2.3 breeding, are related to other factors, such as genetic specificities of the mutant lines, compensatory mechanisms and altered sperm activity.

Digitalization is a clear megatrend of our time, also in the health sector, which is currently experiencing enormous acceleration due to the COVID-19 pandemic in addition to paving the way due to changes in the legal framework. Looking to the future, this trend will contribute to further digitalization and the merging of individual digital products, including medicinal products and medical devices, into a digital ecosystem. This will be supported by ever-shorter development cycles and technological progress. Digitization will not only strengthen patient sovereignty, but also enable more patient-centered medicine; artificial intelligence will improve and accelerate diagnoses and will contribute to a better understanding of disease patterns and underlying mechanisms or causes.In order to continue to enable innovations in the future, to focus on emerging trends, and, above all, to further improve patient safety, the BfArM is contributing in many places to transforming the opportunities associated with digitalization into possibilities - without losing sight of the risks. The following is an overview of how, for example, the expansion of the Research Data Center, activities addressing interoperability, research projects using artificial intelligence, (inter-)national cooperation, the utilization and inclusion of "Real World Data" in our benefit/risk assessments, and the evaluation of digital health and digital care applications among other activities of the BfArM contribute to "digital readiness" in Germany and Europe.Die Digitalisierung stellt auch im Gesundheitsbereich einen eindeutigen Megatrend dar, der neben der Wegbereitung durch geänderte rechtliche Rahmenbedingungen auch durch die Coronapandemie eine enorme Beschleunigung erfahren hat. Mit Blick in die Zukunft wird dieser Trend durch immer kürzere Entwicklungszyklen und technologischen Fortschritt zu einer zunehmenden Verschmelzung einzelner digitaler und nicht digitaler Produkte, darunter Arzneimittel und digitale Medizinprodukte, zu einem digitalen Ökosystem beitragen. Die Digitalisierung wird nicht nur die Patientensouveränität stärken, sondern unter anderem auch eine patientenzentrierte, stärker auf den individuellen Patienten ausgerichtete Medizin ermöglichen; digitale (patientenberichtete) Endpunkte und „dezentrale“ Studienkonzepte werden die Möglichkeiten klinischer Studien erweitern. Künstliche Intelligenz wird Diagnosestellungen verbessern und beschleunigen und zum besseren Verständnis von Krankheitsbildern beitragen.Um auch zukünftig Innovationen zu ermöglichen, aufkommende Trends im Fokus zu haben und vor allem die Patientensicherheit weiter zu verbessern, trägt das Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) an vielen Stellen dazu bei, die mit der Digitalisierung verbundenen Chancen in Möglichkeiten zu verwandeln – ohne dabei die Risiken aus dem Blick zu verlieren: Dazu gehören der Ausbau des Forschungsdatenzentrums, Aufgaben zu Interoperabilität und Klassifikationen sowie Ansätze zur datengestützten Signalerkennung aus Risikoinformationen. Wie darüber hinaus Forschungsprojekte unter Nutzung von künstlicher Intelligenz, (inter)nationale Kooperationen, die Einbeziehung von Real World Data in Nutzen-Risiko-Bewertungen, die Bewertung digitaler Gesundheits- und Pflegeanwendungen neben weiteren Aktivitäten zur „digital readiness“ in Deutschland und Europa beitragen, dazu im Folgenden ein Überblick.

Voltage-gated Ca2+ channels (VGCCs) are considered to play a key role in auditory perception and information processing within the murine inner ear and brainstem. In the past, Ca(v)1.3 L-type VGCCs gathered most attention as their ablation causes congenital deafness. However, isolated patch-clamp investigation and localization studies repetitively suggested that Ca(v)2.3 R-type VGCCs are also expressed in the cochlea and further components of the ascending auditory tract, pointing to a potential functional role of Ca(v)2.3 in hearing physiology. Thus, we performed auditory profiling of Ca(v)2.3(+/+) controls, heterozygous Ca(v)2.3(+/-) mice and Ca(v)2.3 null mutants (Ca(v)2.3(-/-)) using brainstem-evoked response audiometry. Interestingly, click-evoked auditory brainstem responses (ABRs) revealed increased hearing thresholds in Ca(v)2.3(+/-) mice from both genders, whereas no alterations were observed in Ca(v)2.3(-/-) mice. Similar observations were made for tone burst-related ABRs in both genders. However, Ca(v)2.3 ablation seemed to prevent mutant mice from total hearing loss particularly in the higher frequency range (36-42 kHz). Amplitude growth function analysis revealed, i.a., significant reduction in ABR wave W-I and W-III amplitude in mutant animals. In addition, alterations in W-I-W-IV interwave interval were observed in female Ca(v)2.3(+/-) mice whereas absolute latencies remained unchanged. In summary, our results demonstrate that Ca(v)2.3 VGCCs are mandatory for physiological auditory information processing in the ascending auditory tract.

Background In Germany, physicians who prescribe cannabis-based medicines at the expense of the statutory health insurance are obliged to take part in an accompanying survey. Pain was the most commonly reported diagnosis, making an interim evaluation for the indication of pain feasible. Methods Patient-related data was transmitted to the German Federal Institute for Drugs and Medical Devices via an online portal. In addition to demographic data, information on the treated disease or symptoms, the course of therapy, adverse reactions and treatment success were evaluated. Results A total of 3138 data sets were evaluated for the main diagnosis of pain. Dronabinol was the most frequently (64%) prescribed cannabis-based drug. On average, patients were 57 years old and women and men were equally represented. Patients treated with cannabis flowers were significantly younger (48 years). The proportion of men in this group was 68% and 83% in the group of 18- to 40-year-olds. According to the assessment by treating physicians, pain was significantly improved in 35.5% of the patients. The most frequent side effects (fatigue, dizziness, nausea) corresponded to those already known from the product information of the cannabis-based medicinal products authorized under the pharmaceutical law. Treatment was discontinued in 1179 patients within 1 year. Conclusion Physicians should comply with their legal obligation to participate in the accompanying survey. Pain is by far the most common diagnosis in cannabis drugs. For about one third of these patients, physicians reported a clear improvement in pain. Due to the amount of data hitherto and the limitations in the accompanying survey, the results should not be overinterpreted in terms of efficacy and should always be related to existing reviews. The lower age and higher proportion of men among patients treated with cannabis flowers were remarkable. At 37.6%, the overall drop-out rate was high. The most frequent side effects related to vigilance and are therefore highly relevant in terms of driving ability, work ability and risk of falling. For a differentiated evaluation of treatment success, more data needs to be available.

Master protocols combine several sub-trials, each with their own research objectives, which is usually presented as one single clinical trial application. Master protocols have become increasingly popular in oncology and haematology, as either basket, umbrella, or platform trials. Although master protocols are intended to accelerate drug development and to reduce futility, their use poses challenges to ethics committees, patients, study investigators, and competent authorities during the review and authorisation process of a clinical trial application. In this Personal View, we review the experiences of clinical trial applications from two European medical regulators-the Danish Medicines Agency and the German Federal Institute for Drugs and Medical Devices. We view master protocols as a good opportunity to identify new treatment options more quickly, particularly for patients with cancer. However, the complexity of trial documentation, the amount of information resulting from sub-trials, and the volume of changes and amendments made to clinical trial applications can cause issues during trial supervision, and during the analysis and review of a corresponding application for marketing authorisation. We draw attention to the potential issues arising from these trial concepts and propose possible solutions to avoid problems during clinical trial authorisation and trial conduct.

Background N-Nitrosodimethylamine (NDMA), classified as a probable human carcinogen, has been found as a contaminant in the antihypertensive drug valsartan. Potentially carcinogenic effects associated with the consumption of NDMAcontaminated valsartan have not yet been analyzed in large-scale cohort studies. We therefore carried out the study reported here to explore the association between NDMA-contaminated valsartan and the risk of cancer. Methods This cohort study was based on longitudinal routine data obtained from a large German statutory health insurance provider serving approximately 25 million insurees. The cohort comprised patients who had filled a prescription for valsartan in the period 2012-2017. The endpoint was an incident diagnosis of cancer. Hazard ratios (HR) for cancer in general and for certain specific types of cancer were calculated by means of Cox regression models with time-dependent variables and adjustment for potential confounders. Results A total of 780 871 persons who had filled a prescription for valsartan between 2012 and 2017 were included in the study. There was no association between exposure to NDMA-contaminated valsartan and the overall risk of cancer. A statistically significant association was found, however, between exposure to NDMA-contaminated valsartan and hepatic cancer (adjusted HR 1.16; 95% confidence interval [1.03; 1.31]). Conclusion These findings suggest that the consumption of NDMA-contaminated valsartan is associated with a slightly increased risk of hepatic cancer; no association was found with the risk of cancer overall. Close observation of the potential long-term effects of NDMA-contaminated valsartan seems advisable.

We outline our vision that by 2025 the use of real-world evidence will have been enabled and the value will have been established across the spectrum of regulatory use cases. We are working to deliver this vision through collaboration where we leverage the best that different stakeholders can bring. This vision will support the development and use of better medicines for patients.

T-type Ca2+ channels are assumed to contribute to hippocampal theta oscillations. We used implantable video-EEG radiotelemetry and qPCR to unravel the role of Cav3.2 Ca2+ channels in hippocampal theta genesis. Frequency analysis of spontaneous long-term recordings in controls and Cav3.2−/− mice revealed robust increase in relative power in the theta (4–8 Hz) and theta-alpha (4–12 Hz) ranges, which was most prominent during the inactive stages of the dark cycles. Urethane injection experiments also showed enhanced type II theta activity and altered theta architecture following Cav3.2 ablation. Next, gene candidates from hippocampal transcriptome analysis of control and Cav3.2−/− mice were evaluated using qPCR. Dynein light chain Tctex-Type 1 (Dynlt1b) was significantly reduced in Cav3.2−/− mice. Furthermore, a significant reduction of GABA A receptor δ subunits and GABA B1 receptor subunits was observed in the septohippocampal GABAergic system. Our results demonstrate that ablation of Cav3.2 significantly alters type II theta activity and theta architecture. Transcriptional changes in synaptic transporter proteins and GABA receptors might be functionally linked to the electrophysiological phenotype.

This article provides raw relative electroencephalographic (EEG) power, temperature and activity data from controls and Cav3.2 deficient mice. Radiotransmitter implantation was carried out in male experimental mice under ketamine/xylazine narcosis. Following a recovery period, radiotelemetric EEG recordings from the hippocampal CA1 region were obtained under spontaneous 24 h long-term conditions and post urethane injection. Relative EEG power values (%) for 2 s epochs were analysed for the following frequency ranges: delta 1 ( δ 1 , 0.5–4 Hz), delta 2 ( δ 2 , 1–4 Hz), theta 1 ( θ 1 , 4–8 Hz), theta 2 ( θ 2 , 4–12 Hz), alpha ( α , 8–12 Hz), sigma ( σ , 12–16 Hz), beta 1 ( β 1 , 12–30 Hz), beta 2 ( β 2 , 16–24 Hz), beta 3 ( β 3 , 16–30 Hz), gamma low ( γ l o w , 30–50 Hz), gamma mid ( γ m i d , 50–70 Hz), gamma high ( γ h i g h , 70–100 Hz), gamma ripples ( γ r i p p l e s , 80–200 Hz), and gamma fast ripples ( γ f a s t r i p p l e s , 200–500 Hz). In addition, subcutaneous temperature and relative activity data were analysed for both the light and dark cycle of two long-term recordings. The same type of data was obtained post urethane injection. Detailed information is provided for the age and body weight of the experimental animals, the technical specifications of the radiofrequency transmitter, the stereotaxic coordinates for the intracerebral, deep and epidural, surface EEG electrodes, the electrode features, the filtering and sampling characteristics, the analysed EEG frequency bands and the data acquisition parameters. EEG power data, temperature and activity data are available at MENDELEY DATA (doi: 10.17632/x53km5sby6.1 , URL: http://dx.doi.org/10.17632/x53km5sby6.1 ). Raw EEG data are available at zenodo ( https://zenodo.org/ ).

Early pharmacoepidemiological studies suggested that Proton Pump Inhibitors (PPIs) might increase the risk of Alzheimer’s Disease (AD) and non-AD related dementias. These findings were supported by preclinical studies, specifically stressing the proamyloidogenic and indirect anticholinergic effects of PPIs. However, further large-scale pharmacoepidemiological studies showed inconsistent results on the association between PPIs and dementia. Pharmacodynamically, these findings might be related to the LXR/RXR-mediated amyloid clearance effect and anti-inflammatory action of PPIs. Further aspects that influence PPI effects on AD are related to patient- specific pharmacokinetic and pharmacogenomic characteristics. In conclusion, a personalized (individualized) medicinal approach is necessary to model and predict the potential harmful or beneficial effects of PPIs in AD and non-AD-related dementias in the future.

Neuroinflammation, a key early pathomechanistic alteration of Alzheimer’s disease, may represent either a detrimental or a compensatory mechanism or both (according to the disease stage). YKL-40, a glycoprotein highly expressed in differentiated glial cells, is a candidate biomarker for in vivo tracking neuroinflammation in humans. We performed a longitudinal study in a monocentric cohort of cognitively healthy individuals at risk for Alzheimer’s disease exploring whether age, sex, and the apolipoprotein E e4 allele affect plasma YKL-40 concentrations. We investigated whether YKL-40 is associated with brain amyloid-β (Aβ) deposition, neuronal activity, and neurodegeneration as assessed via neuroimaging biomarkers. Finally, we investigated whether YKL-40 may predict cognitive performance. We found an age-associated increase of YKL-40 and observed that men display higher concentrations than women, indicating a potential sexual dimorphism. Moreover, YKL-40 was positively associated with memory performance and negatively associated with brain Aβ deposition (but not with metabolic signal). Consistent with translational studies, our results suggest a potentially protective effect of glia on incipient brain Aβ accumulation and neuronal homeostasis.

BACKGROUND: N-Nitrosodimethylamine (NDMA), classified as a probable human carcinogen, has been found as a contaminant in the antihypertensive drug valsartan. Potentially carcinogenic effects associated with the consumption of NDMA-contaminated valsartan have not yet been analyzed in large-scale cohort studies. We therefore carried out the study reported here to explore the association between NDMA-contaminated valsartan and the risk of cancer. METHODS: This cohort study was based on longitudinal routine data obtained from a large German statutory health insurance provider serving approximately 25 million insurees. The cohort comprised patients who had filled a prescription for valsartan in the period 2012–2017. The endpoint was an incident diagnosis of cancer. Hazard ratios (HR) for cancer in general and for certain specific types of cancer were calculated by means of Cox regression models with time-dependent variables and adjustment for potential confounders. RESULTS: A total of 780 871 persons who had filled a prescription for valsartan between 2012 and 2017 were included in the study. There was no association between exposure to NDMA-contaminated valsartan and the overall risk of cancer. A statistically significant association was found, however, between exposure to NDMA-contaminated valsartan and hepatic cancer (adjusted HR 1.16; 95% confidence interval [1.03; 1.31]). CONCLUSION: These findings suggest that the consumption of NDMA-contaminated valsartan is associated with a slightly increased risk of hepatic cancer; no association was found with the risk of cancer overall. Close observation of the potential long-term effects of NDMA-contaminated valsartan seems advisable.

T-type Ca2+ channels are assumed to contribute to hippocampal theta oscillations. We used implantable video-EEG radiotelemetry and qPCR to unravel the role of Cav3.2 Ca2+ channels in hippocampal theta genesis. Frequency analysis of spontaneous long-term recordings in controls and Cav3.2−/− mice revealed robust increase in relative power in the theta (4–8 Hz) and theta-alpha (4–12 Hz) ranges, which was most prominent during the inactive stages of the dark cycles. Urethane injection experiments also showed enhanced type II theta activity and altered theta architecture following Cav3.2 ablation. Next, gene candidates from hippocampal transcriptome analysis of control and Cav3.2−/− mice were evaluated using qPCR. Dynein light chain Tctex-Type 1 (Dynlt1b) was significantly reduced in Cav3.2−/− mice. Furthermore, a significant reduction of GABA A receptor δ subunits and GABA B1 receptor subunits was observed in the septohippocampal GABAergic system. Our results demonstrate that ablation of Cav3.2 significantly alters type II theta activity and theta architecture. Transcriptional changes in synaptic transporter proteins and GABA receptors might be functionally linked to the electrophysiological phenotype.

Recent pharmacoepidemiologic studies suggest that pharmacological neuroenhancement (pNE) and mood enhancement are globally expanding phenomena with distinctly different regional characteristics. Sociocultural and regulatory aspects, as well as health policies, play a central role in addition to medical care and prescription practices. The users mainly display self-involved motivations related to cognitive enhancement, emotional stability, and adaptivity. Natural stimulants, as well as drugs, represent substance abuse groups. The latter comprise purines, methylxanthines, phenylethylamines, modafinil, nootropics, antidepressants but also benzodiazepines, β-adrenoceptor antagonists, and cannabis. Predominant pharmacodynamic target structures of these substances are the noradrenergic/dopaminergic and cholinergic receptor/transporter systems. Further targets comprise adenosine, serotonin, and glutamate receptors. Meta-analyses of randomized-controlled studies in healthy individuals show no or very limited verifiability of positive effects of pNE on attention, vigilance, learning, and memory. Only some members of the substance abuse groups, i.e., phenylethylamines and modafinil, display positive effects on attention and vigilance that are comparable to caffeinated drinks. However, the development of new antidementia drugs will increase the availability and the potential abuse of pNE. Social education, restrictive regulatory measures, and consistent medical prescription practices are essential to restrict the phenomenon of neuroenhancement with its social, medical, and ethical implications. This review provides a comprehensive overview of the highly dynamic field of pharmacological neuroenhancement and elaborates the dramatic challenges for the medical, sociocultural, and ethical fundaments of society.

In recent years, heavy precipitation and flash flood events frequently occurred in Germany. The project HiOS (reference map for surface runoff and flash floods) focusses on the analysis of these events using conceptual lumped precipitation runoff models, distributed raster-based water balance models (LARSIM and WaSiM), as well as a hydrodynamic model internally coupled with infiltration routines (TELEMAC-2D). The objective of our research is to analyze which factors and processes foster flash floods, and how they may be represented in models. We show a comprehensive methodological comparison using simulation results of some events in Bavaria. These do not include erosion and log jam scenarios.The catchments distributed across whole Bavaria considering a variety of catchment characteristics and varying in size between 1.2 and 164km². All models are driven by 5 minute pseudo-calibrated radar precipitation data of the German Weather Service (YW product), which are available for entire Germany in a 1km² raster. The distributed water balance models are available using high-resolution cell grids. WaSiM uses a regular grid size of 50m, whereas LARSIM is run using 100m cells and an embedded hydrological response unit scheme. All TELEMAC-2D meshes are built with a standard mesh size of 5m in the catchment and 2m in the settled area of interest, while important hydrodynamic structures are resolved more in detail.We want to highlight the variety of applied hydrological and hydrodynamic model approaches of runoff generation and concentration, whereby both, simple conceptual and complex physical methods are included. Runoff generation processes are represented using the SCS-CN method, a modified Lutz-Südbayern approach, a Xinjiang-bucket model combined with a Green&Ampt infiltration routine, as well as a layer-resolving Richards model. Beyond that, some of these consider silting up and soil crack formation. Runoff concentration processes are assessed by constant translation, Strickler flow time index method, a combination of Williams and Kalinin-Miljukov method, as well as finally with two-dimensionally resolved shallow water equations.As expected, runoff generation is influenced by land use and soil parametrization. However, the amount of created runoff differs a lot changing the method of simulation. Furthermore, the runoff volume reacts quite sensitive to small changes in the preceding saturation conditions. Runoff concentration is influenced by slope, retention capacity of the flood plain, the network of drainages, as well as the formation of polders by water-crossing structures such as traffic infrastructure. Our results therefore clearly show the individual characteristics of extreme events depending on the catchment properties, which are reflected by the demands concerning the modelling techniques. The findings of this study illustrate the importance of improved radar-derived precipitation observations as well as the need for a spatially distributed and layered soil moisture product to enhance flash flood modelling using hydrological models.

Heavy rainfall and resulting flash flood events have been in the focus of research and the public in recent years. The relevance of the topic will become more prominent with increasing temperatures due to climate change. Extreme rainfall events in Germany like 2014 in Münster (North Rhine-Westphalia) or 2016 in Simbach am Inn (Bavaria) and Braunsbach (Baden-Wurttemberg) have also raised public awareness.Hydrodynamic models for the simulation of fluvial events have been developed for a long time and are often used. However, the question arises to what extent these methods can be used for pluvial events. Hydrodynamic models allowing precipitation input are therefore well suited for the simulation of pluvial events, as they can display flow paths, depths, and velocities in high resolution. Nevertheless, defining precipitation without infiltration leads to an overestimation of the surface runoff. For this problem, an improved event simulation can be achieved by nesting hydrological processes into the hydrodynamic simulation procedure. In this study, we are using TELEMAC-2D as a hydrodynamic model because it uses precipitation in a spatially and temporally distributed manner and can be used very well by high-performance computing. LARSIM (Large Area Runoff Simulation Model) and WaSiM (Water Flow and Balance Simulation Model) are used as hydrological models.The methodology for simulating flash floods can be divided into two important processes: runoff generation and runoff concentration. These are divided according to the strength of the respective model types:Runoff generation: SCS-CN value method (TELEMAC-2D), Green Ampt method (LARSIM), layer-resolving Richards method (WaSiM) Runoff concentration: Strickler roughness approach (TELEMAC-2D), Kalinin-Miljukov method (LARSIM), flow time index method (WaSiM) In this study, we examine three different types of couplings:(1) The runoff concentration is calculated using the hydrodynamic model, the runoff generation is carried out using the CN value method. (2) The runoff generation in the entire catchment is calculated using the hydrological processes (LARSIM/WaSiM). The runoff concentration is still generated by the hydrodynamic model. (3) The runoff concentration in the upper catchment area is also calculated using hydrological methods, only the urban area is calculated hydrodynamically. We compare the different coupling types with each other using some real flash flood events. The results are presented with the aim to identify which approach is necessary for a good representation of the flash flood event. This depends mainly on the local conditions in the catchment area (e.g. culverts, land use) and the rainfall event (e.g. rainfall intensity and duration). The findings from this study will be transferred to unobserved catchments in the further course.

TELEMAC-2D is a well known and established hydrodynamic model solving the shallow water equations. Since 2013, the SCS-CN-method has been implemented in TELEMAC-2D. With this supplement, the runoff generation is linked to overland flow and TELEMAC-2D could be extended to a Hydrodynamic Rainfall-Runoff Model (HDRRM). Thus the most important requisites are fulfilled to simulate heavy rainfall and flash flood events. However, changes to the code were necessary concerning spatially distributed rainfall, time-dependent roughness and, the wet/dry boundary. The quality of the resulting method is demonstrated using the flash flood event in the district Rottal-Inn in Bavaria on June 1st in 2016. In the first step, the simulation is calibrated using a gauging station in the catchment Simbach a. Inn. After this, validation follows by applying the same methodology to the adjacent catchment Triftern. The results gained in both catchments showed good agreement with the event data. Using the new spacial rainfall module and changing the wet/dry boundary worked properly. A HPC-Scaling test showed a good scalability with the introduced methods. Therefore, the enhanced TELEMAC-2D model proved to be an accurate, efficient and versatile tool for the simulation of flash floods.

Die zum 1. Januar 2011 in Kraft getretene Fruhe Nutzenbewertung neu zugelassener Arzneimittel mit innovativen Wirkstoffen und neuen Anwendungsgebieten stellt alle Beteiligten auch heute noch vor Herausforderungen. Der Beitrag betrachtet neben Definitionen, regulatorischen Anforderungen an Zulassung und Fruhe Nutzenbewertung auch das Zusammenspiel zwischen Zulassung und Fruher Nutzenbewertung in Deutschland und den Aktivitaten, mit denen sich die Zulassungsbehorden und der G-BA auf nationaler Ebene fruher und konsequenter in den gemeinsamen Beratungsprozess einbringen.

Judicious use of real-world data (RWD) is expected to make all steps in the development and use of pharmaceuticals more effective and efficient, including research and development, regulatory decision making, health technology assessment, pricing, and reimbursement decisions and treatment. A "learning healthcare system" based on electronic health records and other routinely collected data will be required to harness the full potential of RWD to complement evidence based on randomized controlled trials. We describe and illustrate with examples the growing demand for a learning healthcare system; we contrast the exigencies of an efficient pharmaceutical ecosystem in the future with current deficiencies highlighted in recently published Organisation for Economic Co-operation and Development (OECD) reports; and we reflect on the steps necessary to enable the transition from healthcare data to actionable information. A coordinated effort from all stakeholders and international cooperation will be required to increase the speed of implementation of the learning healthcare system, to everybody's benefit.

Background There is evidence that uric acid may have antioxidant and neuroprotective effects and might therefore alter the risk for neurodegenerative diseases such as dementia. So far, the relation between serum uric acid (SUA) levels or hyperuricemia and dementia remains elusive. Most studies focused on the disease or SUA levels. Effects of anti-hyperuricemic treatment have not been considered yet. This study investigated the association between hyperuricemia and dementia taking into account anti-hyperuricemic treatment. Methods We used longitudinal German public health insurance data and analyzed the association between hyperuricemia with and without different treatment options and dementia in a case-control design. Applying logistic regression the analysis was adjusted for several potential confounders including various comorbidities and polypharmacy. Results We identified 27,528 cases and 110,112 matched controls of which 22% had a diagnosis of hyperuricemia or gout and 17% received anti-hyperuricemic drugs. For patients with a diagnosis of hyperuricemia we found a slightly reduced risk for dementia (adjusted odds ratio [OR] 0.94, 95% confidence interval [CI] 0.89 to 0.98). The risk reduction was more pronounced for patients treated with anti-hyperuricemic drugs (adjusted OR 0.89, 95% CI 0.85 to 0.94, for regular treatment). Conclusions Our results showed a slight reduction for dementia risk in patients with hyperuricemia, both with and without anti-hyperuricemic treatment.

This letter comments on the letters by Rani A. Sarkis et al and Christoph Helmstaedter et al.

Objectives Voltage-gated Ca2+ channels (VGCCs) are of central relevance in regulating Ca2+ influx into living cells. The low-voltage activated (LVA) Cav3 T-type Ca2+ channels are widely distributed throughout the brain including the peripheral auditory system and ascending auditory tract. Their exact role in auditory information processing is still not fully understood. Within the LVA subgroup, Cav3.2 T-type Ca2+ channels seem to be of special importance as qPCR revealed a steady increase in Cav3.2 transcript levels over age, e.g. in the cochlea and spiral ganglion neurons (SGN). Furthermore, pharmacological studies suggested an association between Cav3.2 expression and both age-related and noise-induced hearing loss. Given the potential functional relevance of Cav3.2 VGGCs in sensorineural hearing loss, we recorded gender specific auditory evoked brainstem responses (ABRs) upon both click and tone burst presentation. Here we present auditory brainstem response (ABR) data from Cav3.2+/+, Cav3.2+/− and Cav3.2−/− mice from both genders which are of value for researchers who want to evaluate how Cav3.2 loss affects basic auditory parameters, e.g. click and tone burst based hearing thresholds, amplitude growth function and peak latencies. Data description Information presented here includes ABR data from age-matched female and male Cav3.2+/+, Cav3.2+/− and Cav3.2−/− mice and technical aspects of the auditory recording protocol. Data were recorded using a commercially available ABR setup from Tucker Davis Technologies Inc. (TDT). Raw data files (arf.-file format) were exported as txt.-files with free access for analysis.