The FTLD risk factor TMEM106B controls lysosomal trafficking and dendrite outgrowth

Frontotemporal dementia is the second most common neurodegenerative disease in people younger than 65 years. Patients suffer from behavioral changes, language deficits and speech impairment. Unfortunately, there is no effective treatment available at the moment. Cytoplasmic inclusions of the DNA/RNA-binding protein TDP-43 are the pathological hallmark in the majority of FTLD cases, which are accordingly classified as FTLD-TDP. Mutations in GRN, the gene coding for the trophic factor progranulin, are responsible for the majority of familiar FTLD-TDP cases. The first genome-wide association study performed for FTLD-TDP led to the identification of risk variants in the so far uncharacterized gene TMEM106B. Initial cell culture studies revealed intracellular localization of TMEM106B protein in lysosomes but its neuronal function remained elusive. Based on these initial findings, I investigated the physiological function of TMEM106B in primary rat neurons during this thesis. I demonstrated that endogenous TMEM106B is localized to late endosomes and lysosomes in primary neurons, too. Notably, knockdown of the protein does neither impair general neuronal viability nor the protein level of FTLD associated proteins, such as GRN or TDP-43. However, shRNA-mediated knockdown of TMEM106B led to a pronounced withering of the dendritic arbor in developing and mature neurons. Moreover, the strong impairment of dendrite outgrowth and maintenance was accompanied by morphological changes and loss of dendritic spines. To gain mechanistic insight into the loss-of-function phenotypes, I searched for coimmunoprecipitating proteins by LC-MS/MS. I specifically identified the microtubule-binding protein MAP6 as interaction partner and was able to validate binding. Strikingly, overexpression of MAP6 in primary neurons phenocopied the TMEM106B knockdown effect on dendrites and loss of MAP6 restored dendritic branching in TMEM106B knockdown neurons, indicating functional interaction of the two proteins. The link between a lysosomal and a microtubule-binding protein made me study the microtubule dependent transport of dendritic lysosomes. Remarkably, live cell imaging studies revealed enhanced movement of dendritic lysosomes towards the soma in neurons devoid of TMEM106B. Again, MAP6 overexpression phenocopied and MAP6 knockdown rescued this effect, strengthening the functional link. The MAP6-independent rescue of dendrite outgrowth by enhancing anterograde lysosomal movement provided additional evidence that dendritic arborization is directly controlled by lysosomal trafficking. From these findings I suggest the following model: TMEM106B and MAP6 together act as a molecular brake for the retrograde transport of dendritic lysosomes. Knockdown of TMEM106B and (the presumably dominant negative) overexpression of MAP6 release this brake and enhance the retrograde movement of lysosomes. Subsequently, the higher protein turnover and the net loss of membranes in distal dendrites may cause the defect in dendrite outgrowth. The findings of this study suggest that lysosomal misrouting in TMEM106B risk allele carrier might further aggravate lysosomal dysfunction seen in patients harboring GRN mutations and thereby contribute to disease progression. Taken together, I discovered the first neuronal function for the FTLD-TDP risk factor TMEM106B: This lysosomal protein acts together with its novel, microtubule-associated binding partner MAP6 as molecular brake for the dendritic transport of lysosomes and thereby controls dendrite growth and maintenance.Frontotemporale Demenz ist die zweithäufigste Form neurodegenerativer Erkrankungen bei Menschen unter 65 Jahren. Patienten leiden an Verhaltensauffälligkeiten und Sprach- sowie Artikulationsstörungen. Leider steht zurzeit keine wirksame medikamentöse Therapie zur Verfügung. Das pathologische Hauptmerkmal der meisten FTLD-Fälle sind zytoplasmatische Einschlüsse des DNA/RNA-bindenden Proteins TDP-43. Diese Fälle werden entsprechend als FTLD-TDP klassifiziert. Für einen Großteil der familiären FTLD-TDP Fälle sind Mutationen in GRN, dem für den Wachstumsfaktor Progranulin kodierenden Gen, verantwortlich. Die erste für FTLD-TDP durchgeführte genomweite Assoziationsstudie führte zur Entdeckung von genetischen Varianten im bis dato uncharakterisierten Gen TMEM106B. Diese Varianten sind mit einem erhöten Risiko an FTLD zu erkranken assoziiert. Initiale Studien in Zellkultur zeigten eine Lokalisierung des TMEM106B Proteins in Lysosomen, die Frage nach der neuronale Funktion des Proteins blieb allerdings bisher unbeantwortet. Auf diesen ersten Ergebnissen aufbauend untersuchte ich während meiner Dissertation die physiologische Funktion von TMEM106B in primären Ratten-neuronen. Ich konnte zeigen, dass endogenes TMEM106B auch in primären Neuronen in späten Endsosomen und Lysosomen lokalisiert ist. Beachtenswerterweise verminderte die Herunterregulierung (shRNA-vermittelter Gen-Knockdown) des Proteins weder das generelle Überleben der Neuronen noch die Level von anderen FTLD-assoziierten Proteinen, wie GRN oder TDP-43. Die Herunterregulierung von TMEM106B führte jedoch zu einem ausgeprägten Verlust von Dendriten in sich entwickelnden und ausgereiften Neuronen. Des Weiteren war die starke Beeinträchtigung dendritischen Wachstums und Aufrechterhaltung von einer morphologischen Veränderung und dem Verlust der Dornfortsätze begleitet. Um den Mechanismus dieser Phänotypen zu erklären, suchte ich nach TMEM106B coimmunopräzipitierenden Proteinen mittels Massenspektrometrie. Ich konnte das Mikrotubuli bindende Protein MAP6 als spezifischen Bindungspartner identifizieren und die Interaktion beider Proteine validieren. Hervorzuheben ist, dass die Überexpression von MAP6 in primären Neuronen den Effekt der Herunterregulation von TMEM106B auf die Dendriten kopierte und die Herunterregulation von MAP6 die dendritischen Verästelungen in TMEM106B depletierten Neuronen sogar wiederherstellen konnte. Diese Ergebnisse legen eine funktionelle Interaktion beider Proteine nahe. Die Verbindung zwischen einem lysosomalen und einem an die Mikrotubuli bindenden Protein brachte mich dazu, den Mikrotubuli abhängigen Transport von dendritischen Lysosomen zu untersuchen. Bemerkenswerterweise zeigten mittels Lebendzellmikroskopie erzeugte Aufnahmen eine erhöhte Bewegung dendritischer Lysosomen Richtung Zellsoma in TMEM106B depletierten Neuronen. Auch in diesem Kontext konnte die Überexpression von MAP6 den Effekt kopieren und die Herunterregulation von MAP6 den Effekt aufheben und somit die These einer funktionellen Interaktion festigen. Die MAP6 unabhängige Wiederherstellung des dendritischen Wachstums durch die Erhöhung des lysosomalen Transports in anterograder Richtung lieferte einen zusätzlichen Beweis dafür, dass das dendritische Wachstum direkt von lysosomalem Transport abhängt. Ausgehend von diesen Ergebnissen schlage ich folgendes Modell vor: TMEM106B und MAP6 wirken zusammen als molekulare Bremse für den retrograden Transport dendritischer Lysosomen. Die Herunterregulation von TMEM106B und die (wahrscheinlich dominant negative wirkende) Überexpression von MAP6 lösen diese Bremse und verstärken die retrograde Bewegung von Lysosomen. Daraufhin könnten der gestiegene Proteinumsatz und der Verlust von Plasmamembranbestandteilen zu einem Fehler im dendritischen Wachstum führen. Die Ergebnisse dieser Arbeit legen nahe, dass fehlerhafter, lysosomaler Transport in TMEM106B Risikoallelträgern zu einer Verstärkung der lysosomalen Fehlfunktion in Patienten mit GRN Mutation führt und dabei zur Krankheitsentwicklung beiträgt. Zusammengefasst habe ich die erste neuronale Funktion für den FTLD-TDP Risikofaktor TMEM106B entdeckt: Dieses lysosomale Protein wirkt zusammen mit seinem neuentdeckten, Mikrotubuli assoziierten Bindungspartner MAP6 als molekulare Bremse für den dendritischen Transport von Lysosomen und kontrolliert dadurch Wachstum und Aufrechterhaltung von Dendriten

Three-nucleon interactions: A frontier in nuclear structure

Three-nucleon interactions are a frontier in understanding and predicting the structure of strongly-interacting matter in laboratory nuclei and in the cosmos. We present results and discuss the status of first calculations with microscopic three-nucleon interactions beyond light nuclei. This coherent effort is possible due to advances based on effective field theory and renormalization group methods in nuclear physics.Comment: 7 pages, 11 figures, talk at International Symposium on New Facet of Three-Nucleon Force (FM50), Tokyo, October, 200

The FTLD risk factor TMEM106B controls lysosomal trafficking and dendrite outgrowth

Frontotemporal dementia is the second most common neurodegenerative disease in people younger than 65 years. Patients suffer from behavioral changes, language deficits and speech impairment. Unfortunately, there is no effective treatment available at the moment. Cytoplasmic inclusions of the DNA/RNA-binding protein TDP-43 are the pathological hallmark in the majority of FTLD cases, which are accordingly classified as FTLD-TDP. Mutations in GRN, the gene coding for the trophic factor progranulin, are responsible for the majority of familiar FTLD-TDP cases. The first genome-wide association study performed for FTLD-TDP led to the identification of risk variants in the so far uncharacterized gene TMEM106B. Initial cell culture studies revealed intracellular localization of TMEM106B protein in lysosomes but its neuronal function remained elusive. Based on these initial findings, I investigated the physiological function of TMEM106B in primary rat neurons during this thesis. I demonstrated that endogenous TMEM106B is localized to late endosomes and lysosomes in primary neurons, too. Notably, knockdown of the protein does neither impair general neuronal viability nor the protein level of FTLD associated proteins, such as GRN or TDP-43. However, shRNA-mediated knockdown of TMEM106B led to a pronounced withering of the dendritic arbor in developing and mature neurons. Moreover, the strong impairment of dendrite outgrowth and maintenance was accompanied by morphological changes and loss of dendritic spines. To gain mechanistic insight into the loss-of-function phenotypes, I searched for coimmunoprecipitating proteins by LC-MS/MS. I specifically identified the microtubule-binding protein MAP6 as interaction partner and was able to validate binding. Strikingly, overexpression of MAP6 in primary neurons phenocopied the TMEM106B knockdown effect on dendrites and loss of MAP6 restored dendritic branching in TMEM106B knockdown neurons, indicating functional interaction of the two proteins. The link between a lysosomal and a microtubule-binding protein made me study the microtubule dependent transport of dendritic lysosomes. Remarkably, live cell imaging studies revealed enhanced movement of dendritic lysosomes towards the soma in neurons devoid of TMEM106B. Again, MAP6 overexpression phenocopied and MAP6 knockdown rescued this effect, strengthening the functional link. The MAP6-independent rescue of dendrite outgrowth by enhancing anterograde lysosomal movement provided additional evidence that dendritic arborization is directly controlled by lysosomal trafficking. From these findings I suggest the following model: TMEM106B and MAP6 together act as a molecular brake for the retrograde transport of dendritic lysosomes. Knockdown of TMEM106B and (the presumably dominant negative) overexpression of MAP6 release this brake and enhance the retrograde movement of lysosomes. Subsequently, the higher protein turnover and the net loss of membranes in distal dendrites may cause the defect in dendrite outgrowth. The findings of this study suggest that lysosomal misrouting in TMEM106B risk allele carrier might further aggravate lysosomal dysfunction seen in patients harboring GRN mutations and thereby contribute to disease progression. Taken together, I discovered the first neuronal function for the FTLD-TDP risk factor TMEM106B: This lysosomal protein acts together with its novel, microtubule-associated binding partner MAP6 as molecular brake for the dendritic transport of lysosomes and thereby controls dendrite growth and maintenance.Frontotemporale Demenz ist die zweithäufigste Form neurodegenerativer Erkrankungen bei Menschen unter 65 Jahren. Patienten leiden an Verhaltensauffälligkeiten und Sprach- sowie Artikulationsstörungen. Leider steht zurzeit keine wirksame medikamentöse Therapie zur Verfügung. Das pathologische Hauptmerkmal der meisten FTLD-Fälle sind zytoplasmatische Einschlüsse des DNA/RNA-bindenden Proteins TDP-43. Diese Fälle werden entsprechend als FTLD-TDP klassifiziert. Für einen Großteil der familiären FTLD-TDP Fälle sind Mutationen in GRN, dem für den Wachstumsfaktor Progranulin kodierenden Gen, verantwortlich. Die erste für FTLD-TDP durchgeführte genomweite Assoziationsstudie führte zur Entdeckung von genetischen Varianten im bis dato uncharakterisierten Gen TMEM106B. Diese Varianten sind mit einem erhöten Risiko an FTLD zu erkranken assoziiert. Initiale Studien in Zellkultur zeigten eine Lokalisierung des TMEM106B Proteins in Lysosomen, die Frage nach der neuronale Funktion des Proteins blieb allerdings bisher unbeantwortet. Auf diesen ersten Ergebnissen aufbauend untersuchte ich während meiner Dissertation die physiologische Funktion von TMEM106B in primären Ratten-neuronen. Ich konnte zeigen, dass endogenes TMEM106B auch in primären Neuronen in späten Endsosomen und Lysosomen lokalisiert ist. Beachtenswerterweise verminderte die Herunterregulierung (shRNA-vermittelter Gen-Knockdown) des Proteins weder das generelle Überleben der Neuronen noch die Level von anderen FTLD-assoziierten Proteinen, wie GRN oder TDP-43. Die Herunterregulierung von TMEM106B führte jedoch zu einem ausgeprägten Verlust von Dendriten in sich entwickelnden und ausgereiften Neuronen. Des Weiteren war die starke Beeinträchtigung dendritischen Wachstums und Aufrechterhaltung von einer morphologischen Veränderung und dem Verlust der Dornfortsätze begleitet. Um den Mechanismus dieser Phänotypen zu erklären, suchte ich nach TMEM106B coimmunopräzipitierenden Proteinen mittels Massenspektrometrie. Ich konnte das Mikrotubuli bindende Protein MAP6 als spezifischen Bindungspartner identifizieren und die Interaktion beider Proteine validieren. Hervorzuheben ist, dass die Überexpression von MAP6 in primären Neuronen den Effekt der Herunterregulation von TMEM106B auf die Dendriten kopierte und die Herunterregulation von MAP6 die dendritischen Verästelungen in TMEM106B depletierten Neuronen sogar wiederherstellen konnte. Diese Ergebnisse legen eine funktionelle Interaktion beider Proteine nahe. Die Verbindung zwischen einem lysosomalen und einem an die Mikrotubuli bindenden Protein brachte mich dazu, den Mikrotubuli abhängigen Transport von dendritischen Lysosomen zu untersuchen. Bemerkenswerterweise zeigten mittels Lebendzellmikroskopie erzeugte Aufnahmen eine erhöhte Bewegung dendritischer Lysosomen Richtung Zellsoma in TMEM106B depletierten Neuronen. Auch in diesem Kontext konnte die Überexpression von MAP6 den Effekt kopieren und die Herunterregulation von MAP6 den Effekt aufheben und somit die These einer funktionellen Interaktion festigen. Die MAP6 unabhängige Wiederherstellung des dendritischen Wachstums durch die Erhöhung des lysosomalen Transports in anterograder Richtung lieferte einen zusätzlichen Beweis dafür, dass das dendritische Wachstum direkt von lysosomalem Transport abhängt. Ausgehend von diesen Ergebnissen schlage ich folgendes Modell vor: TMEM106B und MAP6 wirken zusammen als molekulare Bremse für den retrograden Transport dendritischer Lysosomen. Die Herunterregulation von TMEM106B und die (wahrscheinlich dominant negative wirkende) Überexpression von MAP6 lösen diese Bremse und verstärken die retrograde Bewegung von Lysosomen. Daraufhin könnten der gestiegene Proteinumsatz und der Verlust von Plasmamembranbestandteilen zu einem Fehler im dendritischen Wachstum führen. Die Ergebnisse dieser Arbeit legen nahe, dass fehlerhafter, lysosomaler Transport in TMEM106B Risikoallelträgern zu einer Verstärkung der lysosomalen Fehlfunktion in Patienten mit GRN Mutation führt und dabei zur Krankheitsentwicklung beiträgt. Zusammengefasst habe ich die erste neuronale Funktion für den FTLD-TDP Risikofaktor TMEM106B entdeckt: Dieses lysosomale Protein wirkt zusammen mit seinem neuentdeckten, Mikrotubuli assoziierten Bindungspartner MAP6 als molekulare Bremse für den dendritischen Transport von Lysosomen und kontrolliert dadurch Wachstum und Aufrechterhaltung von Dendriten

Customized Uncertainty Quantification of Parking Duration Predictions for EV Smart Charging

As Electric Vehicle (EV) demand increases, so does the demand for efficient Smart Charging (SC) applications. However, SC is only acceptable if the EV user’s mobility requirements and risk preferences are fulfilled, i.e. their respective EV has enough charge to make their planned journey. To fulfill these requirements and risk preferences, the SC application must consider the predicted parking duration at a given location and the uncertainty associated with this prediction. However, certain regions of uncertainty are more critical than others for user-centric SC applications, and therefore, such uncertainty must be explicitly quantified. Therefore, the present paper presents multiple approaches to customize the uncertainty quantification of parking duration predictions specifically for EV user-centric SC applications. We decompose parking duration prediction errors into a critical component which results in undercharging, and a non-critical component. Furthermore, we derive quantile-based security levels that can minimize the probability of a critical error given a user’s risk preferences. We evaluate our customized uncertainty quantification with four different probabilistic prediction models on an openly available semi-synthetic mobility data set and a data set consisting of real EV trips. We show that our customized uncertainty quantification can regulate critical errors, even in challenging real-world data with high fluctuation and uncertainty

A Component-Based Middleware for a Reliable Distributed and Reconfigurable Spacecraft Onboard Computer

Emerging applications for space missions require increasing processing performance from the onboard computers. DLR's project “Onboard Computer - Next Generation” (OBC-NG) develops a distributed, reconfigurable computer architecture to provide increased performance while maintaining the high reliability of classical spacecraft computer architectures. Growing system complexity requires an advanced onboard middleware, handling distributed (realtime) applications and error mitigation by reconfiguration. The OBC-NG middleware follows the Component-Based Software Engineering (CBSE) approach. Using composite components, applications and management tasks can easily be distributed and relocated on the processing nodes of the network. Additionally, reuse of components for future missions is facilitated. This paper presents the flexible middleware architecture, the composite component framework, the middleware services and the model-driven Application Programming Interface (API) design of OBC-NG. Tests are conducted to validate the middleware concept and to investigate the reconfiguration efficiency as well as the reliability of the system. A relevant use case shows the advantages of CBSE for the development of distributed reconfigurable onboard software

Multi-ciphersuite security of the Secure Shell (SSH) protocol

The Secure Shell (SSH) protocol is widely used to provide secure remote access to servers, making it among the most important security protocols on the Internet. We show that the signed-Diffie--Hellman SSH ciphersuites of the SSH protocol are secure: each is a secure authenticated and confidential channel establishment (ACCE) protocol, the same security definition now used to describe the security of Transport Layer Security (TLS) ciphersuites. While the ACCE definition suffices to describe the security of individual ciphersuites, it does not cover the case where parties use the same long-term key with many different ciphersuites: it is common in practice for the server to use the same signing key with both finite field and elliptic curve Diffie--Hellman, for example. While TLS is vulnerable to attack in this case, we show that SSH is secure even when the same signing key is used across multiple ciphersuites. We introduce a new generic multi-ciphersuite composition framework to achieve this result in a black-box way

Dense matter with eXTP

In this White Paper we present the potential of the Enhanced X-ray Timing and Polarimetry (eXTP) mission for determining the nature of dense matter; neutron star cores host an extreme density regime which cannot be replicated in a terrestrial laboratory. The tightest statistical constraints on the dense matter equation of state will come from pulse profile modelling of accretion-powered pulsars, burst oscillation sources, and rotation-powered pulsars. Additional constraints will derive from spin measurements, burst spectra, and properties of the accretion flows in the vicinity of the neutron star. Under development by an international Consortium led by the Institute of High Energy Physics of the Chinese Academy of Science, the eXTP mission is expected to be launched in the mid 2020s.Comment: Accepted for publication on Sci. China Phys. Mech. Astron. (2019

A study of sertraline in dialysis (ASSertID) : a protocol for a pilot randomised controlled trial of drug treatment for depression in patients undergoing haemodialysis

© 2015 Friedli et al. Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise statedBACKGROUND: The prevalence of depression in people receiving haemodialysis is high with estimates varying between 20 and 40 %. There is little research on the effectiveness of antidepressants in dialysis patients with the few clinical trials suffering significant methodological issues. We plan to carry out a study to evaluate the feasibility of conducting a randomised controlled trial in patients on haemodialysis who have diagnosed Major Depressive Disorder.METHODS/DESIGN: The study has two phases, a screening phase and the randomised controlled trial. Patients will be screened initially with the Beck Depression Inventory to estimate the number of patients who score 16 or above. These patients will be invited to an interview with a psychiatrist who will invite those with a diagnosis of Major Depressive Disorder to take part in the trial. Consenting patients will be randomised to either Sertraline or placebo. Patients will be followed-up for 6 months. Demographic and clinical data will be collected at screening interview, baseline interview and 2 weeks, and every month (up to 6 months) after baseline. The primary outcome is to evaluate the feasibility of conducting a randomised, double blind, placebo pilot trial in haemodialysis patients with depression. Secondary outcomes include estimation of the variability in the outcome measures for the treatment and placebo arms, which will allow for a future adequately powered definitive trial. Analysis will primarily be descriptive, including the number of patients eligible for the trial, drug exposure of Sertraline in haemodialysis patients and the patient experience of participating in this trial.DISCUSSION: There is an urgent need for this research in the dialysis population because of the dearth of good quality and adequately powered studies. Research with renal patients is particularly difficult as they often have complex medical needs. This research will therefore not only assess the outcome of anti-depressants in haemodialysis patients with depression but also the process of running a randomised controlled trial in this population. Hence, the outputs of this feasibility study will be used to inform the design and methodology of a definitive study, adequately powered to determine the efficacy of anti-depressants in patient on haemodialysis with depression.TRIAL REGISTRATION: ISRCTN registry ISRCTN06146268 and EudraCT reference: 2012-000547-27.Peer reviewedFinal Published versio

SeamlessM4T-Massively Multilingual & Multimodal Machine Translation

What does it take to create the Babel Fish, a tool that can help individuals translate speech between any two languages? While recent breakthroughs in text-based models have pushed machine translation coverage beyond 200 languages, unified speech-to-speech translation models have yet to achieve similar strides. More specifically, conventional speech-to-speech translation systems rely on cascaded systems that perform translation progressively, putting high-performing unified systems out of reach. To address these gaps, we introduce SeamlessM4T, a single model that supports speech-to-speech translation, speech-to-text translation, text-to-speech translation, text-to-text translation, and automatic speech recognition for up to 100 languages. To build this, we used 1 million hours of open speech audio data to learn self-supervised speech representations with w2v-BERT 2.0. Subsequently, we created a multimodal corpus of automatically aligned speech translations. Filtered and combined with human-labeled and pseudo-labeled data, we developed the first multilingual system capable of translating from and into English for both speech and text. On FLEURS, SeamlessM4T sets a new standard for translations into multiple target languages, achieving an improvement of 20% BLEU over the previous SOTA in direct speech-to-text translation. Compared to strong cascaded models, SeamlessM4T improves the quality of into-English translation by 1.3 BLEU points in speech-to-text and by 2.6 ASR-BLEU points in speech-to-speech. Tested for robustness, our system performs better against background noises and speaker variations in speech-to-text tasks compared to the current SOTA model. Critically, we evaluated SeamlessM4T on gender bias and added toxicity to assess translation safety. Finally, all contributions in this work are open-sourced and accessible at https://github.com/facebookresearch/seamless_communicatio

Recommendations for effective documentation in regional anesthesia: an expert panel Delphi consensus project

Background and objectives: Documentation is important for quality improvement, education, and research. There is currently a lack of recommendations regarding key aspects of documentation in regional anesthesia. The aim of this study was to establish recommendations for documentation in regional anesthesia. Methods: Following the formation of the executive committee and a directed literature review, a long list of potential documentation components was created. A modified Delphi process was then employed to achieve consensus amongst a group of international experts in regional anesthesia. This consisted of 2 rounds of anonymous electronic voting and a final virtual round table discussion with live polling on items not yet excluded or accepted from previous rounds. Progression or exclusion of potential components through the rounds was based on the achievement of strong consensus. Strong consensus was defined as ≥75% agreement and weak consensus as 50%-74% agreement. Results: Seventy-seven collaborators participated in both rounds 1 and 2, while 50 collaborators took part in round 3. In total, experts voted on 83 items and achieved a strong consensus on 51 items, weak consensus on 3 and rejected 29. Conclusion: By means of a modified Delphi process, we have established expert consensus on documentation in regional anesthesia