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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 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.

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.

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.

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.

The new European regulation for in vitro diagnostics (IVD) divides the certification of IVD including companion diagnostics (CDx) by notified bodies (NB) from the market authorization of medicines. With the new regulation, CDx will require conformity assessment which is expected to include clinical evidence by NB. This is a significant change from the current situation: until now most IVD have been certified based on their manufacturers’ assessment. For one medicine assessed by the EMA, certification of several different CDx by different NB is possible. As the benefit–risk balance of the medicine may depend on the performance (e.g., sensitivity and specificity) of its CDx, a close cooperation of EMA and NB will be necessary. The availability of detailed information on CDx used in the pivotal clinical trials for the medicine’s authorization will become crucial for the assessment of alternative or competing CDx.

Introduction Blood-based biomarkers of pathophysiological brain amyloid β (Aβ) accumulation, particularly for preclinical target and large-scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management. Methods We investigated whether plasma concentrations of the Aβ 1–40 /Aβ 1–42 ratio, assessed using the single-molecule array (Simoa) immunoassay, may predict brain Aβ positron emission tomography status in a large-scale longitudinal monocentric cohort (N = 276) of older individuals with subjective memory complaints. We performed a hypothesis-driven investigation followed by a no-a-priori hypothesis study using machine learning. Results The receiver operating characteristic curve and machine learning showed a balanced accuracy of 76.5% and 81%, respectively, for the plasma Aβ 1–40 /Aβ 1–42 ratio. The accuracy is not affected by the apolipoprotein E ( APOE ) e4 allele, sex, or age. Discussion Our results encourage an independent validation cohort study to confirm the indication that the plasma Aβ 1–40 /Aβ 1–42 ratio, assessed via Simoa, may improve future standard of care and clinical trial design.

Voltage-gated Ca2+ channels (VGCCs) play key roles in auditory perception and information processing within the inner ear and brainstem. Pharmacological inhibition of low voltage-activated (LVA) T-type Ca2+ channels is related to both age- and noise induced hearing loss in experimental animals and may represent a promising approach to the treatment of auditory impairment of various etiologies. Within the LVA Ca2+ channel subgroup, Cav3.2 is the most prominently expressed T-type channel entity in the cochlea and auditory brainstem. Thus, we performed a complete gender specific click and tone burst based auditory brainstem response (ABR) analysis of Cav3.2+/- and Cav3.2-/- mice, including i.a. temporal progression in hearing loss, amplitude growth function and wave latency analysis as well as a cochlear qPCR based evaluation of other VGCCs transcripts. Our results, based on a self-programmed automated wavelet approach, demonstrate that both heterozygous and Cav3.2 null mutant mice exhibit age-dependent increases in hearing thresholds at 5 months of age. In addition, complex alterations in WI-IV amplitudes and latencies were detected that were not attributable to alterations in the expression of other VGCCs in the auditory tract. Our results clearly demonstrate the important physiological role of Cav3.2 VGCCs in the spatiotemporal organization of auditory processing in young adult mice and suggest potential pharmacological targets for interventions in the future.

Arzneimittel fur Kinder und Jugendliche werden in Deutschland und Europa erst seit rund einem Jahrzehnt systematisch so erforscht, wie dies bei Erwachsenen schon seit Jahrzehnten erfolgt. Auch heute werden noch viele Arzneimittel bei Kindern ohne systematische padiatrische Studien – zum Beispiel zur Dosierung oder zu Darreichungsformen – angewendet.

Background:Researchers have gained substantial insight into mechanisms of synaptic transmission, hyperexcitability, excitotoxicity and neurodegeneration within the last decades. Voltage-gated Ca2+channels are of central relevance in these processes. In particular, they are key elements in the etiopathogenesis of numerous seizure types and epilepsies. Earlier studies predominantly targeted on Cav2.1 P/Q-type and Cav3.2 T-type Ca2+channels relevant for absence epileptogenesis. Recent findings bring other channels entities more into focus such as the Cav2.3 R-type Ca2+channel which exhibits an intriguing role in ictogenesis and seizure propagation. Cav2.3 R-type voltage gated Ca2+channels (VGCC) emerged to be important factors in the pathogenesis of absence epilepsy, human juvenile myoclonic epilepsy (JME), and cellular epileptiform activity,e.g. in CA1 neurons. They also serve as potential target for various antiepileptic drugs, such as lamotrigine and topiramate.Objective:This review provides a summary of structure, function and pharmacology of VGCCs and their fundamental role in cellular Ca2+homeostasis. We elaborate the unique modulatory properties of Cav2.3 R-type Ca2+channels and point to recent findings in the proictogenic and proneuroapoptotic role of Cav2.3 R-type VGCCs in generalized convulsive tonic–clonic and complex-partial hippocampal seizures and its role in non-convulsive absence like seizure activity.Conclusion:Development of novel Cav2.3 specific modulators can be effective in the pharmacological treatment of epilepsies and other neurological disorders.

During this decade, breakthrough conceptual shifts have commenced to emerge in the field of Alzheimer’s disease (AD) recognizing risk factors and the non-linear dynamic continuum of complex pathophysiologies amongst a wide dimensional spectrum of multi-factorial brain proteinopathies/neurodegenerative diseases. As is the case in most fields of medicine, substantial advancements in detecting, treating and preventing AD will likely evolve from the generation and implementation of a systematic precision medicine strategy. This approach will likely be based on the success found from more advanced research fields, such as oncology. Precision medicine will require integration and transfertilization across fragmented specialities of medicine and direct reintegration of Neuroscience, Neurology and Psychiatry into a continuum of medical sciences away from the silo approach. Precision medicine is biomarker-guided medicine on systems-levels that takes into account methodological advancements and discoveries of the comprehensive pathophysiological profiles of complex multi-factorial neurodegenerative diseases, such as late-onset sporadic AD. This will allow identifying and characterizing the disease processes at the asymptomatic preclinical stage, where pathophysiological and topographical abnormalities precede overt clinical symptoms by many years to decades. In this respect, the uncharted territory of the AD preclinical stage has become a major research challenge as the field postulates that early biomarker guided customized interventions may offer the best chance of therapeutic success. Clarification and practical operationalization is needed for comprehensive dissection and classification of interacting and converging disease mechanisms, description of genomic and epigenetic drivers, natural history trajectories through space and time, surrogate biomarkers and indicators of risk and progression, as well as considerations about the regulatory, ethical, political and societal consequences of early detection at asymptomatic stages. In this scenario, the integrated roles of genome sequencing, investigations of comprehensive fluid-based biomarkers and multimodal neuroimaging will be of key importance for the identification of distinct molecular mechanisms and signaling pathways in subsets of asymptomatic people at greatest risk for progression to clinical milestones due to those specific pathways. The precision medicine strategy facilitates a paradigm shift in Neuroscience and AD research and development away from the classical “one-size-fits-all” approach in drug discovery towards biomarker guided “molecularly” tailored therapy for truly effective treatment and prevention options. After the long and winding decade of failed therapy trials progress towards the holistic systems-based strategy of precision medicine may finally turn into the new age of scientific and medical success curbing the global AD epidemic.

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.