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1. Improved thresholds for e-values

Author

Blier-Wong, Christopher and Wang, Ruodu

Subjects
Mathematics - Statistics Theory, 62G10, 62F03, 60E15
Abstract

The rejection threshold used for e-values and e-processes is by default set to $1/\alpha$ for a guaranteed type-I error control at $\alpha$, based on Markov's and Ville's inequalities. This threshold can be wasteful in practical applications. We discuss how this threshold can be improved under additional distributional assumptions on the e-values; some of these assumptions are naturally plausible and empirically observable, without knowing explicitly the form or model of the e-values. For small values of $\alpha$, the threshold can roughly be improved (divided) by a factor of $2$ for decreasing or unimodal densities, and by a factor of $e$ for decreasing or unimodal-symmetric densities of the log-transformed e-value. Moreover, we propose to use the supremum of comonotonic e-values, which is shown to preserve the type-I error guarantee. We also propose some preliminary methods to boost e-values in the e-BH procedure under some distributional assumptions while controlling the false discovery rate. Through a series of simulation studies, we demonstrate the effectiveness of our proposed methods in various testing scenarios, showing enhanced power.

Published
2024

3. A representation-learning approach for insurance pricing with images

Author

Blier-Wong, Christopher, Lamontagne, Luc, and Marceau, Etienne

Subjects
Statistics - Applications
Abstract

Unstructured data are a promising new source of information that insurance companies may use to understand their risk portfolio better and improve the customer experience. However, these novel data sources are difficult to incorporate into existing ratemaking frameworks due to the size and format of the unstructured data. In this paper, we propose a framework to use street view imagery within a generalized linear model. To do so, we use representation learning to extract an embedding vector containing useful information from the image. This embedding is dense and low-dimensional, making it appropriate to use within existing ratemaking models. We find that there is useful information included in street view imagery to predict the frequency of claims for certain types of perils. This model can be used as-is in a ratemaking framework but also opens the door to future empirical research on attempting to extract the causal effect from images that lead to increased or decreased predicted claim frequencies. Throughout, we discuss the practical difficulties (technical and social) of using this type of data for insurance pricing.

Published
2023
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4. Modulation of neural oscillations in escitalopram treatment: a Canadian biomarker integration network in depression study

Author

Benjamin Schwartzmann, Raaj Chatterjee, Yasaman Vaghei, Lena C. Quilty, Timothy A. Allen, Stephen R. Arnott, Sravya Atluri, Pierre Blier, Prabhjot Dhami, Jane A. Foster, Benicio N. Frey, Stefan Kloiber, Raymond W. Lam, Roumen Milev, Daniel J. Müller, Claudio N. Soares, Chloe Stengel, Sagar V. Parikh, Gustavo Turecki, Rudolf Uher, Susan Rotzinger, Sidney H. Kennedy, and Faranak Farzan

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Current pharmacological agents for depression have limited efficacy in achieving remission. Developing and validating new medications is challenging due to limited biological targets. This study aimed to link electrophysiological data and symptom improvement to better understand mechanisms underlying treatment response. Longitudinal changes in neural oscillations were assessed using resting-state electroencephalography (EEG) data from two Canadian Biomarker Integration Network in Depression studies, involving pharmacological and cognitive behavioral therapy (CBT) trials. Patients in the pharmacological trial received eight weeks of escitalopram, with treatment response defined as ≥ 50% decrease in Montgomery–Åsberg Depression Rating Scale (MADRS). Early (baseline to week 2) and late (baseline to week 8) changes in neural oscillation were investigated using relative power spectral measures. An association was found between an initial increase in theta and symptom improvement after 2 weeks. Additionally, late increases in delta and theta, along with a decrease in alpha, were linked to a reduction in MADRS after 8 weeks. These late changes were specifically observed in responders. To assess specificity, we extended our analysis to the independent CBT cohort. Responders exhibited an increase in delta and a decrease in alpha after 2 weeks. Furthermore, a late (baseline to week 16) decrease in alpha was associated with symptom improvement following CBT. Results suggest a common late decrease in alpha across both treatments, while modulatory effects in theta may be specific to escitalopram treatment. This study offers insights into electrophysiological markers indicating a favorable response to antidepressants, enhancing our comprehension of treatment response mechanisms in depression.

Published
2024
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5. Modulation of neural oscillations in escitalopram treatment: a Canadian biomarker integration network in depression study

Author

Schwartzmann, Benjamin, Chatterjee, Raaj, Vaghei, Yasaman, Quilty, Lena C., Allen, Timothy A., Arnott, Stephen R., Atluri, Sravya, Blier, Pierre, Dhami, Prabhjot, Foster, Jane A., Frey, Benicio N., Kloiber, Stefan, Lam, Raymond W., Milev, Roumen, Müller, Daniel J., Soares, Claudio N., Stengel, Chloe, Parikh, Sagar V., Turecki, Gustavo, Uher, Rudolf, Rotzinger, Susan, Kennedy, Sidney H., and Farzan, Faranak

Published
2024
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6. Descriptions of Centrifugation Manipulations in the Literature Illustrate the Need for Better Laboratory Training of Biologists

Author

Rioux, Pierre and Blier, Pierre

Abstract

Students in environmental sciences, ecology, or wildlife management are often reluctant to acquire training in basic laboratory techniques. To advocate the importance of this training, we reviewed literature in the fields of biological and environmental science for one frequently used technique--centrifugation--and evaluated whether centrifugation parameters are properly expressed. Centrifugation is used to extract and purify different types of biomolecules for further characterization or quantification. The repeatability of the procedure depends on the proper identification of parameters defining the gravitational force applied to a solution, for example the duration, distance from central axis, and angular velocity. Correctly expressing rotation velocity--the "speed"--is therefore crucial to ensuring repeatability and the possibility of using the same protocols in different laboratories. When scrutinizing the materials and methods sections of publications in ecology, zoology, botany, or general biology journals, we noticed that velocity is expressed in different ways and essential information is often missing. We sampled 2000 articles in different fields of biological sciences that recorded centrifugation as a technique in the materials and methods section. We found centrifugation velocity to be properly expressed in gravitational force "g" in only 47.8% of the papers. The score dropped to 40.4% in journals specialized in ecology. We use this analysis to advocate for a minimum of training in the techniques of biochemistry that are of common use in environmental sciences. Better training would allow higher reproducibility of results in scientific publications.

Published
2021

7. Collective risk models with FGM dependence

Author

Blier-Wong, Christopher, Cossette, Hélène, and Marceau, Etienne

Subjects
Statistics - Applications
Abstract

We study copula-based collective risk models when the dependence structure is defined by a Farlie-Gumbel-Morgenstern (FGM) copula. By leveraging a one-to-one correspondence between the class of FGM copulas and multivariate symmetric Bernoulli distributions, we find convenient representations for the moments and Laplace-Stieltjes transform for the aggregate random variable defined from collective risk models with FGM dependence. We examine different components of this collective risk model, aiming to better understand the impact of the assumed dependence between a claim's frequency and severity. Relying on stochastic ordering, we analyze the impact of dependence on the aggregate claim amount random variable. Even if the FGM copula may only induce moderate dependence, we illustrate through numerical examples that the cumulative effect of FGM dependence can lead to substantial variations in key risk measures on aggregate random variables defined from collective risk models.

Published
2022

8. A new method to construct high-dimensional copulas with Bernoulli and Coxian-2 distributions

Author

Blier-Wong, Christopher, Cossette, Hélène, Legros, Sébastien, and Marceau, Etienne

Subjects
Mathematics - Statistics Theory
Abstract

We propose an approach to construct a new family of generalized Farlie-Gumbel-Morgenstern (GFGM) copulas that naturally scales to high dimensions. A GFGM copula can model moderate positive and negative dependence, cover different types of asymmetries, and admits exact expressions for many quantities of interest such as measures of association or risk measures in actuarial science or quantitative risk management. More importantly, this paper presents a new method to construct high-dimensional copulas based on mixtures of power functions, and may be adapted to more general contexts to construct broader families of copulas. We construct a family of copulas through a stochastic representation based on multivariate Bernoulli distributions and Coxian-2 distributions. This paper will cover the construction of a GFGM copula, study its measures of multivariate association and dependence properties. We explain how to sample random vectors from the new family of copulas in high dimensions. Then, we study the bivariate case in detail and find that our construction leads to an asymmetric modified Huang-Kotz FGM copula. Finally, we study the exchangeable case and provide some insights into the most negative dependence structure within this new class of high-dimensional copulas.

Published
2022

9. Risk aggregation with FGM copulas

Author

Blier-Wong, Christopher, Cossette, Hélène, and Marceau, Etienne

Subjects
Mathematics - Statistics Theory, Statistics - Applications
Abstract

We offer a new perspective on risk aggregation with FGM copulas. Along the way, we discover new results and revisit existing ones, providing simpler formulas than one can find in the existing literature. This paper builds on two novel representations of FGM copulas based on symmetric multivariate Bernoulli distributions and order statistics. First, we detail families of multivariate distributions with closed-form solutions for the cumulative distribution function or moments of the aggregate random variables. We order aggregate random variables under the convex order and provide methods to compute the cumulative distribution function of aggregate rvs when the marginals are discrete. Finally, we discuss risk-sharing and capital allocation, providing numerical examples for each.

Published
2022

10. Generating function method for the efficient computation of expected allocations

Author

Blier-Wong, Christopher, Cossette, Hélène, and Marceau, Etienne

Subjects
Statistics - Applications
Abstract

Consider a risk portfolio with aggregate loss random variable $S=X_1+\dots +X_n$ defined as the sum of the $n$ individual losses $X_1, \dots, X_n$. The expected allocation, $E[X_i \times 1_{\{S = k\}}]$, for $i = 1, \dots, n$ and $k \in \mathbb{N}$, is a vital quantity for risk allocation and risk-sharing. For example, one uses this value to compute peer-to-peer contributions under the conditional mean risk-sharing rule and capital allocated to a line of business under the Euler risk allocation paradigm. This paper introduces an ordinary generating function for expected allocations, a power series representation of the expected allocation of an individual risk given the total risks in the portfolio when all risks are discrete. First, we provide a simple relationship between the ordinary generating function for expected allocations and the probability generating function. Then, leveraging properties of ordinary generating functions, we reveal new theoretical results on closed-formed solutions to risk allocation problems, especially when dealing with Katz or compound Katz distributions. Then, we present an efficient algorithm to recover the expected allocations using the fast Fourier transform, providing a new practical tool to compute expected allocations quickly. The latter approach is exceptionally efficient for a portfolio of independent risks.

Published
2022

11. Exchangeable FGM copulas

Author

Blier-Wong, Christopher, Cossette, Hélène, and Marceau, Etienne

Subjects
Mathematics - Statistics Theory
Abstract

Copulas are a powerful tool to model dependence between the components of a random vector. One well-known class of copulas when working in two dimensions is the Farlie-GumbelMorgenstern (FGM) copula since their simple analytic shape enables closed-form solutions to many problems in applied probability. However, the classical definition of high-dimensional FGM copula does not enable a straightforward understanding of the effect of the copula parameters on the dependence, nor a geometric understanding of their admissible range. We circumvent this issue by studying the FGM copula from a probabilistic approach based on multivariate Bernoulli distributions. This paper studies high-dimensional exchangeable FGM copulas, a subclass of FGM copulas. We show that dependence parameters of exchangeable FGM can be expressed as convex hulls of a finite number of extreme points and establish partial orders for different exchangeable FGM copulas (including maximal and minimal dependence). We also leverage the probabilistic interpretation to develop efficient sampling and estimating procedures and provide a simulation study. Throughout, we discover geometric interpretations of the copula parameters that assist one in decoding the dependence of high-dimensional exchangeable FGM copulas.

Published
2022

12. Characteristics and outcomes of COVID-19 patients admitted to hospital with and without respiratory symptoms

Author

Barbara Wanjiru Citarella, Christiana Kartsonaki, Elsa D. Ibáñez-Prada, Bronner P. Gonçalves, Joaquin Baruch, Martina Escher, Mark G. Pritchard, Jia Wei, Fred Philippy, Andrew Dagens, Matthew Hall, James Lee, Demetrios James Kutsogiannis, Evert-Jan Wils, Marília Andreia Fernandes, Bharath Kumar Tirupakuzhi Vijayaraghavan, Prasan Kumar Panda, Ignacio Martin-Loeches, Shinichiro Ohshimo, Arie Zainul Fatoni, Peter Horby, Jake Dunning, Jordi Rello, Laura Merson, Amanda Rojek, Michel Vaillant, Piero Olliaro, Luis Felipe Reyes, S.A. Moharam, Sabriya Abdalasalam, Alaa Abdalfattah Abdalhadi, Naana Reyam Abdalla, Walaa Abdalla, Almthani Hamza Abdalrheem, Ashraf Abdalsalam, Saedah Abdeewi, Esraa Hassan Abdelgaum, Mohamed Abdelhalim, Mohammed Abdelkabir, Israa Abdelrahman, Sheryl Ann Abdukahil, Lamees Adil Abdulbaqi, Salaheddin Abdulhamid, Widyan Abdulhamid, Nurul Najmee Abdulkadir, Eman Abdulwahed, Rawad Abdunabi, Ryuzo Abe, Laurent Abel, Ahmed Mohammed Abodina, Amal Abrous, Lara Absil, Kamal Abu Jabal, Nashat Abu Salah, Abdurraouf Abusalama, Tareg Abdallah Abuzaid, Subhash Acharya, Andrew Acker, Elisabeth Adam, Safia Adem, Manuella Ademnou, Francisca Adewhajah, Diana Adrião, Anthony Afum-Adjei Awuah, Melvin Agbogbatey, Saleh Al Ageel, Aya Mustafa Ahmed, Musaab Mohammed Ahmed, Shakeel Ahmed, Zainab Ahmed Alaraji, Abdulrahman Ahmed Elhefnawy Enan, Reham Abdelhamid Ahmed Khalil, Ali Mostafa Ahmed Mohamed Abdelaziz, Kate Ainscough, Eka Airlangga, Tharwat Aisa, Ali Aisha, Bugila Aisha, Ali Ait Hssain, Younes Ait Tamlihat, Takako Akimoto, Ernita Akmal, Chika Akwani, Eman Al Qasim, Ahmed Alajeeli, Ahmed Alali, Razi Alalqam, Aliya Mohammed Alameen, Mohammed Al-Aquily, Zinah A. Alaraji, Khalid Albakry, Safa Albatni, Angela Alberti, Osama Aldabbourosama, Tala Al-dabbous, Amer Aldhalia, Abdulkarim Aldoukali, Senthilkumar Alegesan, Marta Alessi, Beatrice Alex, Kévin Alexandre, Abdulrahman Al-Fares, Asil Alflite, Huda Alfoudri, Qamrah Alhadad, Hoda Salem Alhaddad, Maali Khalid Mohamed Abdalla Alhasan, Ahmad Nabil Alhouri, Hasan Alhouri, Adam Ali, Imran Ali, Maha TagElser Mohammed Ali, Syed Ali Abbas, Yomna Ali Abdelghafar, Naseem Ali Sheikh, Kazali Enagnon Alidjnou, Mahmoud Aljadi, Sarah Aljamal, Mohammed Alkahlout, Akram Alkaseek, Qabas Alkhafajee, Clotilde Allavena, Nathalie Allou, Lana Almasri, Abdulrahman Almjersah, Raja Ahmed Alqandouz, Walaa Alrfaea, Moayad Alrifaee, Rawan Alsaadi, Yousef Al-Saba'a, Entisar Alshareea, Eslam Alshenawy, Aneela Altaf, João Melo Alves, João Alves, Rita Alves, Joana Alves Cabrita, Maria Amaral, Amro Essam Amer, Nur Amira, Amos Amoako Adusei, John Amuasi, Roberto Andini, Claire Andrejak, Andrea Angheben, François Angoulvant, Sophia Ankrah, Séverine Ansart, Sivanesen Anthonidass, Massimo Antonelli, Carlos Alexandre Antunes de Brito, Ardiyan Apriyana, Yaseen Arabi, Irene Aragao, Francisco Arancibia, Carolline Araujo, Antonio Arcadipane, Patrick Archambault, Lukas Arenz, Jean-Benoît Arlet, Christel Arnold-Day, Lovkesh Arora, Rakesh Arora, Elise Artaud-Macari, Diptesh Aryal, Angel Asensio, Elizabeth A. Ashley, Muhammad Ashraf, Muhammad Sheharyar Ashraf, Abir Ben Ashur, Franklin Asiedu-Bekoe, Namra Asif, Mohammad Asim, Grace Assi, Jean Baptiste Assie, Amirul Asyraf, Fouda Atangana, Ahmed Atia, Minahel Atif, Asia Atif Abdelrhman Abdallahrs, Anika Atique, Moad Atlowly, AM Udara Lakshan Attanyake, Johann Auchabie, Hugues Aumaitre, Adrien Auvet, Abdelmalek Awad Ali Mohammed, Eyvind W. Axelsen, Ared Ayad, Ahmed Ayman Hassan Helmi, Laurène Azemar, Mohammed Azizeldin, Cecile Azoulay, Hakeem Babatunde, Benjamin Bach, Delphine Bachelet, Claudine Badr, Roar Bævre-Jensen, Nadia Baig, John Kenneth Baillie, J Kevin Baird, Erica Bak, Agamemnon Bakakos, Nazreen Abu Bakar, Hibah Bileid Bakeer, Ashraf Bakri, Andriy Bal, Mohanaprasanth Balakrishnan, Irene Bandoh, Firouzé Bani-Sadr, Renata Barbalho, Nicholas Yuri Barbosa, Wendy S. Barclay, Saef Umar Barnett, Michaela Barnikel, Helena Barrasa, Cleide Barrigoto, Marie Bartoli, Joaquín Baruch, Romain Basmaci, Muhammad Fadhli Hassin Basri, AbdAlkarim Batool, Denise Battaglini, Jules Bauer, Diego Fernando Bautista Rincon, Denisse Bazan Dow, Abigail Beane, Alexandra Bedossa, Ker Hong Bee, Husna Begum, Sylvie Behilill, Albertus Beishuizen, Aleksandr Beljantsev, David Bellemare, Anna Beltrame, Beatriz Amorim Beltrão, Marine Beluze, Nicolas Benech, Lionel Eric Benjiman, Suzanne Bennett, Luís Bento, Jan-Erik Berdal, Lamis Berdeweel, Delphine Bergeaud, Hazel Bergin, Giulia Bertoli, Lorenzo Bertolino, Simon Bessis, Sybille Bevilcaqua, Karine Bezulier, Amar Bhatt, Krishna Bhavsar, Isabella Bianchi, Claudia Bianco, Sandra Bichoka, Farah Nadiah Bidin, Felwa Bin Humaid, Mohd Nazlin Bin Kamarudin, Muhannud Binnawara, Zeno Bisoffi, Patrick Biston, Laurent Bitker, Mustapha Bittaye, Jonathan Bitton, Pablo Blanco-Schweizer, Catherine Blier, Frank Bloos, Mathieu Blot, Filomena Boccia, Laetitia Bodenes, Debby Bogaert, Anne-Hélène Boivin, Ariel Bolanga, Isabela Bolaños, Pierre-Adrien Bolze, François Bompart, Aurelius Bonifasius, Joe Bonney, Diogo Borges, Raphaël Borie, Hans Martin Bosse, Elisabeth Botelho-Nevers, Lila Bouadma, Olivier Bouchaud, Sabelline Bouchez, Damien Bouhour, Kévin Bouiller, Laurence Bouillet, Camile Bouisse, Latsaniphone Bountthasavong, Anne-Sophie Boureau, John Bourke, Maude Bouscambert, Aurore Bousquet, Marielle Boyer-Besseyre, Maria Boylan, Fernando Augusto Bozza, Axelle Braconnier, Cynthia Braga, Timo Brandenburger, Filipa Brás Monteiro, Luca Brazzi, Dorothy Breen, Patrick Breen, David Brewster, Kathy Brickell, Tessa Broadley, Helen Brotherton, Alex Browne, Nicolas Brozzi, Sonja Hjellegjerde Brunvoll, Marjolein Brusse-Keizer, Petra Bryda, Nina Buchtele, Polina Bugaeva, Marielle Buisson, Danilo Buonsenso, Erlina Burhan, Donald Buri, Aidan Burrell, Ingrid G. Bustos, Denis Butnaru, André Cabie, Susana Cabral, Joana Cabrita, Eder Caceres, Cyril Cadoz, Rui Caetano Garcês, Kate Calligy, Jose Andres Calvache, João Camões, Valentine Campana, Paul Campbell, Josie Campisi, Cecilia Canepa, Mireia Cantero, Janice Caoili, Pauline Caraux-Paz, Sheila Cárcel, Filipa Cardoso, Filipe Cardoso, Nelson Cardoso, Sofia Cardoso, Simone Carelli, Nicolas Carlier, Thierry Carmoi, Gayle Carney, Inês Carqueja, Marie-Christine Carret, François Martin Carrier, Ida Carroll, Gail Carson, Maire-Laure Casanova, Mariana Cascão, Siobhan Casey, José Casimiro, Bailey Cassandra, Silvia Castañeda, Nidyanara Castanheira, Guylaine Castor-Alexandre, Ivo Castro, Ana Catarino, François-Xavier Catherine, Paolo Cattaneo, Roberta Cavalin, Giulio Giovanni Cavalli, Alexandros Cavayas, Adrian Ceccato, Masaneh Ceesay, Shelby Cerkovnik, Minerva Cervantes-Gonzalez, Muge Cevik, Anissa Chair, Catherine Chakveatze, Adrienne Chan, Meera Chand, Jean-Marc Chapplain, Charlotte Charpentier, Julie Chas, Muhammad Mobin Chaudry, Jonathan Samuel Chávez Iñiguez, Anjellica Chen, Yih-Sharng Chen, Léo Chenard, Matthew Pellan Cheng, Antoine Cheret, Thibault Chiarabini, Julian Chica, Suresh Kumar Chidambaram, Leong Chin Tho, Catherine Chirouze, Davide Chiumello, Sung-Min Cho, Bernard Cholley, Danoy Chommanam, Marie-Charlotte Chopin, Yock Ping Chow, Ting Soo Chow, Nathaniel Christy, Hiu Jian Chua, Jonathan Chua, Jose Pedro Cidade, José Miguel Cisneros Herreros, Anna Ciullo, Jennifer Clarke, Rolando Claure-Del Granado, Sara Clohisey, Cassidy Codan, Caitriona Cody, Jennifer Coles, Megan Coles, Gwenhaël Colin, Michael Collins, Pamela Combs, Jennifer Connolly, Marie Connor, Anne Conrad, Elaine Conway, Graham S. Cooke, Hugues Cordel, Amanda Corley, Sabine Cornelis, Alexander Daniel Cornet, Arianne Joy Corpuz, Andrea Cortegiani, Grégory Corvaisier, Camille Couffignal, Sandrine Couffin-Cadiergues, Roxane Courtois, Stéphanie Cousse, Juthaporn Cowan, Rachel Cregan, Gloria Crowl, Jonathan Crump, Claudina Cruz, Marc Csete, Ailbhe Cullen, Matthew Cummings, Gerard Curley, Elodie Curlier, Colleen Curran, Paula Custodio, Ana da Silva Filipe, Charlene Da Silveira, Al-Awwab Dabaliz, John Arne Dahl, Darren Dahly, Umberto D'Alessandro, Peter Daley, Zaina Dalloul, Heidi Dalton, Jo Dalton, Seamus Daly, Juliana Damas, Joycelyn Dame, Cammandji Damien, Nick Daneman, Jorge Dantas, Frédérick D'Aragon, Gillian de Loughry, Diego de Mendoza, Etienne De Montmollin, Rafael Freitas de Oliveira França, Ana Isabel de Pinho Oliveira, Rosanna De Rosa, Cristina De Rose, Thushan de Silva, Peter de Vries, Jillian Deacon, David Dean, Alexa Debard, Bianca DeBenedictis, Marie-Pierre Debray, Nathalie DeCastro, William Dechert, Romain Decours, Eve Defous, Isabelle Delacroix, Alexandre Delamou, Eric Delaveuve, Karen Delavigne, Nathalie M. Delfos, Ionna Deligiannis, Andrea Dell'Amore, Christelle Delmas, Pierre Delobel, Corine Delsing, Elisa Demonchy, Emmanuelle Denis, Dominique Deplanque, Pieter Depuydt, Diane Descamps, Mathilde Desvallées, Santi Dewayanti, Pathik Dhangar, Alpha Diallo, Souleymane Taran Diallo, Sylvain Diamantis, André Dias, Fernanda Dias Da Silva, Rodrigo Diaz, Juan Jose Diaz, Priscila Diaz, Bakary K. Dibba, Kévin Didier, Jean-Luc Diehl, Wim Dieperink, Jérôme Dimet, Vincent Dinot, Fara Diop, Alphonsine Diouf, Yael Dishon, Cedric Djadda, Félix Djossou, Annemarie B. Docherty, Helen Doherty, Arjen M. Dondorp, Christl A. Donnelly, Yoann Donohue, Sean Donohue, Peter Doran, Céline Dorival, Eric D'Ortenzio, Yash Doshi, Phouvieng Douangdala, James Joshua Douglas, Renee Douma, Nathalie Dournon, Joanne Downey, Mark Downing, Thomas Drake, Aoife Driscoll, Ibrahim Kwaku Duah, Claudio Duarte Fonseca, Vincent Dubee, François Dubos, Audrey Dubot-Pérès, Alexandre Ducancelle, Toni Duculan, Susanne Dudman, Abhijit Duggal, Paul Dunand, Mathilde Duplaix, Emanuele Durante-Mangoni, Lucian Durham, III, Bertrand Dussol, Juliette Duthoit, Xavier Duval, Anne Margarita Dyrhol-Riise, Sim Choon Ean, Ada Ebo, Marco Echeverria-Villalobos, Michael Edelstein, Siobhan Egan, Linn Margrete Eggesbø, Khadeja Ehzaz, Carla Eira, Mohammed El Sanharawi, Marwan El Sayed, Mohammed Elabid, Mohamed Bashir Elagili, Subbarao Elapavaluru, Mohammad Elbahnasawy, Sohail Elboshra, Brigitte Elharrar, Jacobien Ellerbroek, Merete Ellingjord-Dale, Hamida ELMagrahi, Mohammad Muatasm Elmubark, Loubna Elotmani, Lauren Eloundou, Philippine Eloy, Basma Elshaikhy, Tarek Elshazly, Wafa Elsokni, Aml Ahmed Eltayeb, Iqbal Elyazar, Zarief Kamel Emad, Hussein Embarek, Isabelle Enderle, Tomoyuki Endo, Gervais Eneli, Chan Chee Eng, Ilka Engelmann, Vincent Enouf, Olivier Epaulard, Haneen Esaadi, Mariano Esperatti, Hélène Esperou, Catarina Espírito Santo, Marina Esposito-Farese, Rachel Essaka, Lorinda Essuman, João Estevão, Manuel Etienne, Anna Greti Everding, Mirjam Evers, Isabelle Fabre, Marc Fabre, Ismaila Fadera, Asgad Osman Abdalla Fadlalla, Amna Faheem, Arabella Fahy, Cameron J. Fairfield, Zul Fakar, Komal Fareed, Pedro Faria, Ahmed Farooq, Hanan Fateena, Mohamed Fathi, Salem Fatima, Karine Faure, Raphaël Favory, Mohamed Fayed, Niamh Feely, Jorge Fernandes, Susana Fernandes, François-Xavier Ferrand, Eglantine Ferrand Devouge, Joana Ferrão, Mário Ferraz, Benigno Ferreira, Isabel Ferreira, Bernardo Ferreira, Sílvia Ferreira, Nicolas Ferriere, Céline Ficko, Claudia Figueiredo-Mello, William Finlayson, Thomas Flament, Tom Fletcher, Aline-Marie Florence, Letizia Lucia Florio, Brigid Flynn, Deirdre Flynn, Jean Foley, Victor Fomin, Tatiana Fonseca, Patricia Fontela, Karen Forrest, Simon Forsyth, Denise Foster, Giuseppe Foti, Berline Fotso, Erwan Fourn, Robert A. Fowler, Marianne Fraher, Diego Franch-Llasat, Christophe Fraser, John F. Fraser, Marcela Vieira Freire, Ana Freitas Ribeiro, Craig French, Caren Friedrich, Ricardo Fritz, Stéphanie Fry, Nora Fuentes, Masahiro Fukuda, G. Argin, Valérie Gaborieau, Rostane Gaci, Massimo Gagliardi, Jean-Charles Gagnard, Amandine Gagneux-Brunon, Abdou Gai, Sérgio Gaião, Linda Gail Skeie, Adham Mohamed Galal Mohamed Ramadan, Phil Gallagher, Carrol Gamble, Yasmin Gani, Arthur Garan, Rebekha Garcia, Julia Garcia-Diaz, Esteban Garcia-Gallo, Navya Garimella, Denis Garot, Valérie Garrait, Basanta Gauli, Anatoliy Gavrylov, Alexandre Gaymard, Johannes Gebauer, Eva Geraud, Louis Gerbaud Morlaes, Nuno Germano, Malak Ghemmeid, Praveen Kumar Ghisulal, Jade Ghosn, Marco Giani, Tristan Gigante, Elaine Gilroy, Guillermo Giordano, Michelle Girvan, Valérie Gissot, Gezy Giwangkancana, Daniel Glikman, Petr Glybochko, Eric Gnall, Geraldine Goco, François Goehringer, Siri Goepel, Jean-Christophe Goffard, Jin Yi Goh, Brigitta Golács, Jonathan Golob, Kyle Gomez, Joan Gómez-Junyent, Marie Gominet, Alicia Gonzalez, Patricia Gordon, Isabelle Gorenne, Laure Goubert, Cécile Goujard, Tiphaine Goulenok, Margarite Grable, Jeronimo Graf, Edward Wilson Grandin, Pascal Granier, Giacomo Grasselli, Lorenzo Grazioli, Christopher A. Green, Courtney Greene, William Greenhalf, Segolène Greffe, Domenico Luca Grieco, Matthew Griffee, Fiona Griffiths, Ioana Grigoras, Albert Groenendijk, Fassou Mathias Grovogui, Heidi Gruner, Yusing Gu, Jérémie Guedj, Martin Guego, Anne-Marie Guerguerian, Daniela Guerreiro, Romain Guery, Anne Guillaumot, Laurent Guilleminault, Maisa Guimarães de Castro, Thomas Guimard, Marieke Haalboom, Daniel Haber, Ali Hachemi, Abdurrahman Haddud, Nadir Hadri, Wael Hafez, Fakhir Raza Haidri, Fatima Mhd Rida Hajij, Sheeba Hakak, Adam Hall, Sophie Halpin, Shaher Hamdan, Abdelhafeez Hamdi, Jawad Hameed, Ansley Hamer, Raph L. Hamers, Rebecca Hamidfar, Bato Hammarström, Naomi Hammond, Terese Hammond, Lim Yuen Han, Matly Hanan, Rashan Haniffa, Kok Wei Hao, Hayley Hardwick, Ewen M. Harrison, Janet Harrison, Samuel Bernard Ekow Harrison, Alan Hartman, Sulieman Hasan, Mohammad Ali Nabil Hasan, Mohd Shahnaz Hasan, Junaid Hashmi, Madiha Hashmi, Amoni Hassan, Ebtisam Hassanin, Muhammad Hayat, Ailbhe Hayes, Leanne Hays, Jan Heerman, Lars Heggelund, Ahmed Helmi, Ross Hendry, Martina Hennessy, Aquiles Rodrigo Henriquez-Trujillo, Maxime Hentzien, Diana Hernandez, Andrew Hershey, Liv Hesstvedt, Astarini Hidayah, Eibhlin Higgins, Rupert Higgins, Samuel Hinton, Hiroaki Hiraiwa, Haider Hirkani, Hikombo Hitoto, Antonia Ho, Yi Bin Ho, Alexandre Hoctin, Isabelle Hoffmann, Wei Han Hoh, Oscar Hoiting, Rebecca Holt, Jan Cato Holter, Juan Pablo Horcajada, Ikram Houas, Mabrouka Houderi, Catherine L. Hough, Stuart Houltham, Jimmy Ming-Yang Hsu, Jean-Sébastien Hulot, Abby Hurd, Iqbal Hussain, Aliae Mohamed Hussein, Mahmood Hussein, Fatima Ibrahim, Bashir Ibran, Samreen Ijaz, M. Arfan Ikram, Carlos Cañada Illana, Patrick Imbert, Muhammad Imran Ansari, Rana Imran Sikander, Hugo Inácio, Carmen Infante Dominguez, Yun Sii Ing, Mariachiara Ippolito, Vera Irawany, Sarah Isgett, Tiago Isidoro, Nadiah Ismail, Margaux Isnard, Mette Stausland Istre, Junji Itai, Daniel Ivulich, Danielle Jaafar, Salma Jaafoura, Hamza Jaber, Julien Jabot, Clare Jackson, Abubacarr Jagne, Stéphane Jaureguiberry, Denise Jaworsky, Florence Jego, Anilawati Mat Jelani, Synne Jenum, Ruth Jimbo-Sotomayor, Ong Yiaw Joe, Ruth Noemí Jorge García, Silje Bakken Jørgensen, Cédric Joseph, Mark Joseph, Swosti Joshi, Mercé Jourdain, Philippe Jouvet, Anna Jung, Hanna Jung, Dafsah Juzar, Ouifiya Kafif, Florentia Kaguelidou, Neerusha Kaisbain, Thavamany Kaleesvran, Sabina Kali, Karl Trygve Kalleberg, Smaragdi Kalomoiri, Muhammad Aisar Ayadi Kamaluddin, Armand Saloun Kamano, Zul Amali Che Kamaruddin, Nadiah Kamarudin, Kavita Kamineni, Darshana Hewa Kandamby, Kong Yeow Kang, Darakhshan Kanwal, Dyah Kanyawati, Mohamed Karghul, Pratap Karpayah, Todd Karsies, Daisuke Kasugai, Kevin Katz, Christy Kay, Lamees Kayyali, Seán Keating, Pulak Kedia, Andrea Kelly, Aoife Kelly, Claire Kelly, Niamh Kelly, Sadie Kelly, Yvelynne Kelly, Maeve Kelsey, Kalynn Kennon, Sommay Keomany, Maeve Kernan, Younes Kerroumi, Sharma Keshav, Shams Khail, Sarah Khaled, Imrana Khalid, Antoine Khalil, Irfan Khan, Quratul Ain Khan, Sushil Khanal, Abid Khatak, Krish Kherajani, Michelle E. Kho, Denisa Khoo, Ryan Khoo, Saye Khoo, Muhammad Nasir Khoso, Amin Khuwaja, Khor How Kiat, Yuri Kida, Peter Kiiza, Beathe Kiland Granerud, Anders Benjamin Kildal, Jae Burm Kim, Antoine Kimmoun, Detlef Kindgen-Milles, Nobuya Kitamura, Eyrun Floerecke Kjetland Kjetland, Paul Klenerman, Rob Klont, Gry Kloumann Bekken, Stephen R. Knight, Robin Kobbe, Paa Kobina Forson, Chamira Kodippily, Malte Kohns Vasconcelos, Sabin Koirala, Mamoru Komatsu, Franklina Korkor Abebrese, Volkan Korten, Stephanie Kouba, Mohamed Lamine Kourouma, Karifa Kourouma, Arsène Kpangon, Karolina Krawczyk, Ali Kredan, Vinothini Krishnan, Sudhir Krishnan, Oksana Kruglova, Anneli Krund, Pei Xuan Kuan, Ashok Kumar, Deepali Kumar, Ganesh Kumar, Mukesh Kumar, Dinesh Kuriakose, Ethan Kurtzman, Demetrios Kutsogiannis, Galyna Kutsyna, Ama Kwakyewaa Bedu-Addo, Sylvie Kwedi, Konstantinos Kyriakoulis, Marie Lachatre, Marie Lacoste, John G. Laffey, Nadhem Lafhej, Marie Lagrange, Fabrice Laine, Olivier Lairez, Sanjay Lakhey, Marc Lambert, François Lamontagne, Marie Langelot-Richard, Vincent Langlois, Eka Yudha Lantang, Marina Lanza, Cédric Laouénan, Samira Laribi, Delphine Lariviere, Stéphane Lasry, Sakshi Lath, Naveed Latif, Youssef Latifeh, Odile Launay, Didier Laureillard, Yoan Lavie-Badie, Andy Law, Cassie Lawrence, Teresa Lawrence, Minh Le, Clément Le Bihan, Cyril Le Bris, Georges Le Falher, Lucie Le Fevre, Quentin Le Hingrat, Marion Le Maréchal, Soizic Le Mestre, Gwenaël Le Moal, Vincent Le Moing, Hervé Le Nagard, Ema Leal, Marta Leal Santos, Biing Horng Lee, Heng Gee Lee, Su Hwan Lee, Jennifer Lee, Todd C. Lee, Yi Lin Lee, Gary Leeming, Bénédicte Lefebvre, Laurent Lefebvre, Benjamin Lefèvre, Sylvie LeGac, Merili-Helen Lehiste, Jean-Daniel Lelievre, François Lellouche, Adrien Lemaignen, Véronique Lemee, Anthony Lemeur, Gretchen Lemmink, Ha Sha Lene, Jenny Lennon, Rafael León, Marc Leone, Tanel Lepik, Quentin Lepiller, François-Xavier Lescure, Olivier Lesens, Mathieu Lesouhaitier, Amy Lester-Grant, Andrew Letizia, Sophie Letrou, Bruno Levy, Yves Levy, Claire Levy-Marchal, Katarzyna Lewandowska, Erwan L'Her, Gianluigi Li Bassi, Janet Liang, Ali Liaquat, Geoffrey Liegeon, Kah Chuan Lim, Wei Shen Lim, Chantre Lima, Bruno Lina, Lim Lina, Andreas Lind, Maja Katherine Lingad, Guillaume Lingas, Sylvie Lion-Daolio, Keibun Liu, Marine Livrozet, Patricia Lizotte, Antonio Loforte, Navy Lolong, Leong Chee Loon, Diogo Lopes, Dalia Lopez-Colon, Anthony L. Loschner, Paul Loubet, Bouchra Loufti, Guillame Louis, Silvia Lourenco, Lara Lovelace-Macon, Lee Lee Low, Marije Lowik, Jia Shyi Loy, Jean Christophe Lucet, Carlos M. Luna, Olguta Lungu, Miles Lunn, Liem Luong, Nestor Luque, Dominique Luton, Olavi Maasikas, Moïse Machado, Sara Machado, Gabriel Macheda, Mustafa Magzoub, Rafael Mahieu, Sophie Mahy, Ana Raquel Maia, Lars S. Maier, Oumou Maiga Ascofare, Mylène Maillet, Thomas Maitre, Nimisha Abdul Majeed, Maximilian Malfertheiner, Nadia Malik, Paddy Mallon, Fernando Maltez, Denis Malvy, Victoria Manda, Laurent Mandelbrot, Frank Manetta, Julie Mankikian, Edmund Manning, Aldric Manuel, Veronika Maráczi, Ceila Maria Sant′Ana Malaque, Flávio Marino, Samuel Markowicz, Ana Marques, Catherine Marquis, Laura Marsh, Brian Marsh, Megan Marshal, John Marshall, Celina Turchi Martelli, Dori-Ann Martin, Emily Martin, Guillaume Martin-Blondel, Alessandra Martinelli, F. Eduardo Martinez, Martin Martinot, Alejandro Martín-Quiros, Ana Martins, João Martins, Nuno Martins, Caroline Martins Rego, Gennaro Martucci, Olga Martynenko, Eva Miranda Marwali, Marsilla Marzukie, David Maslove, Sabina Mason, Sobia Masood, Fatma Masoud, Moise Massoma, Palmer Masumbe, Mohd Basri Mat Nor, Moshe Matan, Henrique Mateus Fernandes, Meghena Mathew, Christina Mathew, Mathieu Mattei, Laurence Maulin, Juergen May, Javier Maynar, Mayfong Mayxay, Thierry Mazzoni, Lisa Mc Sweeney, Colin McArthur, Naina McCann, Peter McCanny, Aine McCarthy, Anne McCarthy, Colin McCloskey, Rachael McConnochie, Sherry McDermott, Sarah E. McDonald, Aine McElroy, Samuel McElwee, Natalie McEvoy, Allison McGeer, Kenneth A. McLean, Paul McNally, Bairbre McNicholas, Edel Meaney, Cécile Mear-Passard, Maggie Mechlin, Nastia Medombou, Omar Mehkri, Ferruccio Mele, Luis Melo, Kashif Ali Memon, João João Mendes, Ogechukwu Menkiti, Kusum Menon, France Mentré, Alexander J. Mentzer, Emmanuelle Mercier, Noémie Mercier, Antoine Merckx, Mayka Mergeay-Fabre, Blake Mergler, António Mesquita, Roberta Meta, Osama Metwally, Agnès Meybeck, Dan Meyer, Alison M. Meynert, Vanina Meysonnier, Mehdi Mezidi, Céline Michelanglei, Isabelle Michelet, Efstathia Mihelis, Vladislav Mihnovit, Duha Milad Abdullah, Jennene Miller, Hugo Miranda-Maldonado, Nor Arisah Misnan, Nik Nur Eliza Mohamed, Nouralsabah Mohamed, Tahira Jamal Mohamed, Alaa Mohamed Ads, Ahmed Reda Mohamed Elsayed Abdelhalim, Libya Mohammed, Shrouk Fawze Mohammed Mostafa, Manahil Omer Abdelrahman Mohammedahmed, Omer Abdullah Mohammedelhassan, Asma Moin, Walaa Mokhtar, Elena Molinos, Brenda Molloy, Mary Mone, Agostinho Monteiro, Claudia Montes, Giorgia Montrucchio, Sarah Moore, Shona C. Moore, Lina Morales Cely, Marwa Morgom, Lucia Moro, Catherine Motherway, Ana Motos, Hugo Mouquet, Clara Mouton Perrot, Julien Moyet, Suleiman Haitham Mualla, Mohamed Muftah, Aisha Kalsoom Mufti, Ng Yong Muh, Mo'nes Muhaisen, Dzawani Muhamad, Jimmy Mullaert, Fredrik Müller, Karl Erik Müller, Daniel Munblit, Syed Muneeb Ali, Nadeem Munir, Laveena Munshi, Aisling Murphy, Patrick Murray, Marlène Murris, Srinivas Murthy, Himed Musaab, Alamin Mustafa, Mus'ab Mustafa, Dana Mustafa, Himasha Muvindi, Dimitra Melia Myrodia, Farah Nadia Mohd-Hanafiah, Behzad Nadjm, Dave Nagpal, Alex Nagrebetsky, Blanka Nagybányai-Nagy, Herwin Nanda Boudoin, Mangala Narasimhan, Nageswaran Narayanan, Prashant Nasa, Rashid Nasim Khan, Ahmad Nasrallah, Adel Gerges Nassif Metri, Alasdair Nazerali-Maitland, Nadège Neant, Holger Neb, Nikita Nekliudov, Matthew Nelder, Erni Nelwan, Raul Neto, Emily Neumann, Wing Yiu Ng, Pauline Yeung Ng, Anthony Nghi, Duc Nguyen, Orna Ni Choileain, Niamh Ni Leathlobhair, Nerissa Niba, Alistair D. Nichol, Prompak Nitayavardhana, Stephanie Nonas, Nurul Amani Mohd Noordin, Nurul Faten Izzati Norharizam, Anita North, Alessandra Notari, Mahdad Noursadeghi, Adam Nowinski, Saad Nseir, Leonard Numfor, Nurnaningsih Nurnaningsih, Dwi Utomo Nusantara, Elsa Nyamankolly, Anders Benteson Nygaard, Fionnuala O. Brien, Annmarie O. Callaghan, Annmarie O'Callaghan, Giovanna Occhipinti, Derbrenn OConnor, Max O'Donnell, Lawrence Ofori-Boadu, Tawnya Ogston, Takayuki Ogura, Tak-Hyuk Oh, Sophie O'Halloran, Katie O'Hearn, Sally-Ann Ohene, João Oliveira, Larissa Oliveira, Piero L. Olliaro, Cinderella Omar Rageh Elnaggar, Alsarrah Ali Mohammed Omer, Pierre Ondobo, David S.Y. Ong, Jee Yan Ong, Wilna Oosthuyzen, Anne Opavsky, Peter Openshaw, Saijad Orakzai, Claudia Milena Orozco-Chamorro, Jamel Ortoleva, Mohamed Osama Elsayed Soliman, Javier Osatnik, Linda O'Shea, Miriam O'Sullivan, Eman Othman, Siti Zubaidah Othman, Nadia Ouamara, Rachida Ouissa, Micheal Owusu, Ama Akyampomaa Owusu-Asare, Eric Oziol, Maïder Pagadoy, Justine Pages, Amanda Palacios, Massimo Palmarini, Giovanna Panarello, Hem Paneru, Lai Hui Pang, Mauro Panigada, Nathalie Pansu, Aurélie Papadopoulos, Rachael Parke, Melissa Parker, Jérémie Pasquier, Bruno Pastene, Fabian Patauner, Drashti Patel, Mohan Dass Pathmanathan, Luís Patrão, Patricia Patricio, Lisa Patterson, Rajyabardhan Pattnaik, Christelle Paul, Mical Paul, Jorge Paulos, William A. Paxton, Jean-François Payen, Sandra L. Peake, Kalaiarasu Peariasamy, Giles J. Peek, Florent Peelman, Nathan Peiffer-Smadja, Vincent Peigne, Mare Pejkovska, Paolo Pelosi, Ithan D. Peltan, Rui Pereira, Daniel Perez, Thomas Perpoint, Antonio Pesenti, Vincent Pestre, Lenka Petrou, Michele Petrovic, Ventzislava Petrov-Sanchez, Frank Olav Pettersen, Gilles Peytavin, Richard Odame Philips, Ooyanong Phonemixay, Soulichanya Phoutthavong, Michael Piagnerelli, Walter Picard, Olivier Picone, Maria de Piero, Djura Piersma, Carlos Pimentel, Raquel Pinto, Catarina Pires, Lionel Piroth, Ayodhia Pitaloka, Chiara Piubelli, Riinu Pius, Simone Piva, Laurent Plantier, Hon Shen Png, Julien Poissy, Ryadh Pokeerbux, Sergio Poli, Georgios Pollakis, Diane Ponscarme, Diego Bastos Porto, Andra-Maris Post, Douwe F. Postma, Pedro Povoa, Diana Póvoas, Jeff Powis, Sofia Prapa, Viladeth Praphasiri, Sébastien Preau, Christian Prebensen, Jean-Charles Preiser, Anton Prinssen, Gamage Dona Dilanthi Priyadarshani, Lucia Proença, Sravya Pudota, Bambang Pujo Semedi, Mathew Pulicken, Peter Puplampu, Gregory Purcell, Luisa Quesada, Vilmaris Quinones-Cardona, Else Quist-Paulsen, Mohammed Quraishi, Fadi Qutishat, Maia Rabaa, Christian Rabaud, Ebenezer Rabindrarajan, Aldo Rafael, Marie Rafiq, Abdelrahman Ragab, Mutia Rahardjani, Arslan Rahat Ullah, Ahmad Kashfi Haji Ab Rahman, Rozanah Abd Rahman, Fernando Rainieri, Giri Shan Rajahram, Pratheema Ramachandran, Nagarajan Ramakrishnan, José Ramalho, Ahmad Afiq Ramli, Blandine Rammaert, Grazielle Viana Ramos, Asim Rana, Rajavardhan Rangappa, Ritika Ranjan, Christophe Rapp, Aasiyah Rashan, Thalha Rashan, Ghulam Rasheed, Menaldi Rasmin, Indrek Rätsep, Cornelius Rau, Tharmini Ravi, Ali Raza, Andre Real, Stanislas Rebaudet, Sarah Redl, Brenda Reeve, Attaur Rehman, Muhammad Osama Rehman Khalid, Dag Henrik Reikvam, Renato Reis, Jonathan Remppis, Martine Remy, Hongru Ren, Hanna Renk, Anne-Sophie Resseguier, Matthieu Revest, Oleksa Rewa, Maria Ines Ribeiro, Antonia Ricchiuto, David Richardson, Denise Richardson, Laurent Richier, Siti Nurul Atikah Ahmad Ridzuan, Ana L. Rios, Asgar Rishu, Patrick Rispal, Karine Risso, Maria Angelica Rivera Nuñez, Chiara Robba, André Roberto, Stephanie Roberts, Charles Roberts, David L. Robertson, Olivier Robineau, Anna Roca, Ferran Roche-Campo, Paola Rodari, Simão Rodeia, Bernhard Roessler, Claire Roger, Pierre-Marie Roger, Roberto Roncon-Albuquerque, Jr., Mélanie Roriz, Manuel Rosa-Calatrava, Michael Rose, Dorothea Rosenberger, Andrea Rossanese, Matteo Rossetti, Patrick Rossignol, Carine Roy, Benoît Roze, Desy Rusmawatiningtyas, Clark D. Russell, Maeve Ryan, Steffi Ryckaert, Aleksander Rygh Holten, Isabela Saba, Sairah Sadaf, Musharaf Sadat, Valla Sahraei, Abdurraouf Said, Nadia Saidani, Pranya Sakiyalak, Fodé Bangaly Sako, Moamen Salah, Ali Alaa Salah Eldin Mohamed Abbas, Nawal Salahuddin, Leonardo Salazar, Jodat Saleem, Mohammed Saleh Alyasiri, Talat Ahmed Abu Salem, Gabriele Sales, Charlotte Salmon Gandonniere, Hélène Salvator, Dana Samardali, Shaden Samardali, Yehia Samir Shaaban Aly Orabi, Emely Sanchez, Olivier Sanchez, Kizy Sanchez de Oliveira, Angel Sanchez-Miralles, Vanessa Sancho-Shimizu, Gyan Sandhu, Zulfiqar Sandhu, Pierre-François Sandrine, Oana Săndulescu, Marlene Santos, Shirley Sarfo-Mensah, Bruno Sarmento Banheiro, Iam Claire E. Sarmiento, Benjamine Sarton, Ankana Satya, Sree Satyapriya, Rumaisah Satyawati, Egle Saviciute, Yen Tsen Saw, Justin Schaffer, Tjard Schermer, Arnaud Scherpereel, Marion Schneider, János Schnur, Stephan Schroll, Michael Schwameis, Gary Schwartz, Janet T. Scott, James Scott-Brown, Nicholas Sedillot, Tamara Seitz, Jaganathan Selvanayagam, Mageswari Selvarajoo, Malcolm G. Semple, Rasidah Bt Senian, Eric Senneville, Claudia Sepulveda, Filipa Sequeira, Tânia Sequeira, Ary Serpa Neto, Ellen Shadowitz, Syamin Asyraf Shahidan, Hamza Shahla, Laila Shalabi, Haitam Shames, Anuraj Shankar, Shaikh Sharjeel, Pratima Sharma, Catherine A. Shaw, Victoria Shaw, John Robert Sheenan, Dr. Rajesh Mohan Shetty, Rohan Shetty, Mohiuddin Shiekh, Nobuaki Shime, Keiki Shimizu, Sally Shrapnel, Shubha Kalyan Shrestha, Pramesh Sundar Shrestha, Hoi Ping Shum, Nassima Si Mohammed, Ng Yong Siang, Moses Siaw-Frimpong, Jeanne Sibiude, Bountoy Sibounheuang, Nidhal Siddig, Atif Siddiqui, Maqsood Ahmed Siddiqui, Louise Sigfrid, Fatoumata Sillah, Piret Sillaots, Catarina Silva, Maria Joao Silva, Rogério Silva, Benedict Sim Lim Heng, Wai Ching Sin, Dario Sinatti, Mahendra Singh, Punam Singh, Pompini Agustina Sitompul, Karisha Sivam, Vegard Skogen, Sue Smith, Benjamin Smood, Coilin Smyth, Morgane Snacken, Dominic So, Tze Vee Soh, Lene Bergendal Solberg, Joshua Solomon, Tom Solomon, Emily Somers, Agnès Sommet, Myung Jin Song, Rima Song, Tae Song, Jack Song Chia, Arne Søraas, Albert Sotto, Edouard Soum, Ana Chora Sousa, Marta Sousa, Maria Sousa Uva, Vicente Souza-Dantas, Mamadou Saliou Sow, Alexandra Sperry, Elisabetta Spinuzza, B. P. Sanka Ruwan Sri Darshana, Shiranee Sriskandan, Sarah Stabler, Thomas Staudinger, Stephanie-Susanne Stecher, Trude Steinsvik, Ymkje Stienstra, Birgitte Stiksrud, Eva Stolz, Amy Stone, Anca Streinu-Cercel, Adrian Streinu-Cercel, Geoff Strong, Ami Stuart, David Stuart, Richa Su, Decy Subekti, Gabriel Suen, Jacky Y. Suen, Prasanth Sukumar, Asfia Sultana, Charlotte Summers, Dubravka Supic, Deepashankari Suppiah, Magdalena Surovcová, Atie Suwarti, Andrey Svistunov, Sarah Syahrin, Augustina Sylverken, Konstantinos Syrigos, Jaques Sztajnbok, Konstanty Szuldrzynski, Shirin Tabrizi, Fabio S. Taccone, Lysa Tagherset, Shahdattul Mawarni Taib, Sara Taleb, Cheikh Talla, Jelmer Talsma, Renaud Tamisier, Maria Lawrensia Tampubolon, Kim Keat Tan, Yan Chyi Tan, Hiroyuki Tanaka, Taku Tanaka, Hayato Taniguchi, Huda Taqdees, Arshad Taqi, Coralie Tardivon, Yousef Tarek Kamal Mostafa, Ali Tarhabat, Pierre Tattevin, M Azhari Taufik, Hassan Tawfik, Tze Yuan Tee, João Teixeira, Sofia Tejada, Marie-Capucine Tellier, Sze Kye Teoh, Vanessa Teotonio, François Téoulé, Olivier Terrier, Nicolas Terzi, Hubert Tessier-Grenier, Adrian Tey, Alif Adlan Mohd Thabit, Anand Thakur, Zhang Duan Tham, Suvintheran Thangavelu, Elmi Theron, Vincent Thibault, Simon-Djamel Thiberville, Benoît Thill, Jananee Thirumanickam, Niamh Thompson, Shaun Thompson, Emma C. Thomson, David Thomson, Mathew Thorpe, Surain Raaj Thanga Thurai, Ryan S. Thwaites, Paul Tierney, Vadim Tieroshyn, Peter S. Timashev, Jean-François Timsit, Noémie Tissot, Fiona Toal, Jordan Zhien Yang Toh, Maria Toki, Kristian Tonby, Sia Loong Tonnii, Marta Torre, Antoni Torres, Margarida Torres, Rosario Maria Torres Santos-Olmo, Hernando Torres-Zevallos, Aboubacar Tounkara, Michael Towers, Fodé Amara Traoré, Tony Trapani, Cécile Tromeur, Ioannis Trontzas, Tiffany Trouillon, Jeanne Truong, Christelle Tual, Sarah Tubiana, Helen Tuite, Alexis F. Turgeon, Jean-Marie Turmel, Lance C.W. Turtle, Anders Tveita, Pawel Twardowski, Makoto Uchiyama, PG Ishara Udayanga, Andrew Udy, Roman Ullrich, Alberto Uribe, Asad Usman, Effua Usuf, Timothy M. Uyeki, Cristinava Vajdovics, Piero Valentini, Luís Val-Flores, Stijn Van de Velde, Marcel van den Berge, Machteld van der Feltz, Job van der Palen, Paul van der Valk, Nicky Van Der Vekens, Peter Van der Voort, Sylvie Van Der Werf, Laura van Gulik, Jarne Van Hattem, Carolien van Netten, Ilonka van Veen, Noémie Vanel, Henk Vanoverschelde, Michael Varrone, Shoban Raj Vasudayan, Charline Vauchy, Pavan Kumar Vecham, Shaminee Veeran, Aurélie Veislinger, Sebastian Vencken, Sara Ventura, Annelies Verbon, José Ernesto Vidal, César Vieira, Deepak Vijayan, Judit Villar, Pierre-Marc Villeneuve, Andrea Villoldo, Gayatri Vishwanathan, Benoit Visseaux, Hannah Visser, Chiara Vitiello, Manivanh Vongsouvath, Harald Vonkeman, Fanny Vuotto, Suhaila Abdul Wahab, Noor Hidayu Wahab, Nadirah Abdul Wahid, Marina Wainstein, Laura Walsh, Wan Fadzlina Wan Muhd Shukeri, Chih-Hsien Wang, Steve Webb, Katharina Weil, Tan Pei Wen, Hassi Wesam, Sanne Wesselius, T. Eoin West, Murray Wham, Bryan Whelan, Nicole White, Paul Henri Wicky, Aurélie Wiedemann, Surya Otto Wijaya, Keith Wille, Sue Willems, Bailey Williams, Patricia J. Williams, Virginie Williams, Jessica Wittman, Calvin Wong, Xin Ci Wong, Yew Sing Wong, Teck Fung Wong, Natalie Wright, Lim Saio Xian, Ioannis Xynogalas, Siti Rohani Binti Mohd Yakop, Masaki Yamazaki, Elizabeth Yarad, Yazdan Yazdanpanah, Nicholas Yee Liang Hing, Abdelrahman Yehia Mahmoud Abdelaal, Cécile Yelnik, Chian Hui Yeoh, Stephanie Yerkovich, Touxiong Yiaye, Toshiki Yokoyama, Hodane Yonis, Obada Yousif, Saptadi Yuliarto, Akram Zaaqoq, Marion Zabbe, Gustavo E. Zabert, Kai Zacharowski, Masliza Zahid, Maram Zahran, Nor Zaila Binti Zaidan, Maria Zambon, Miguel Zambrano, Alberto Zanella, Nurul Zaynah, Hiba Zayyad, Alexander Zoufaly, and David Zucman

Subjects
COVID-19, Non-respiratory symptoms, Respiratory symptoms, Risk factors, Mortality, Science (General), Q1-390, Social sciences (General), H1-99
Abstract

Background: COVID-19 is primarily known as a respiratory illness; however, many patients present to hospital without respiratory symptoms. The association between non-respiratory presentations of COVID-19 and outcomes remains unclear. We investigated risk factors and clinical outcomes in patients with no respiratory symptoms (NRS) and respiratory symptoms (RS) at hospital admission. Methods: This study describes clinical features, physiological parameters, and outcomes of hospitalised COVID-19 patients, stratified by the presence or absence of respiratory symptoms at hospital admission. RS patients had one or more of: cough, shortness of breath, sore throat, runny nose or wheezing; while NRS patients did not. Results: Of 178,640 patients in the study, 86.4 % presented with RS, while 13.6 % had NRS. NRS patients were older (median age: NRS: 74 vs RS: 65) and less likely to be admitted to the ICU (NRS: 36.7 % vs RS: 37.5 %). NRS patients had a higher crude in-hospital case-fatality ratio (NRS 41.1 % vs. RS 32.0 %), but a lower risk of death after adjusting for confounders (HR 0.88 [0.83–0.93]). Conclusion: Approximately one in seven COVID-19 patients presented at hospital admission without respiratory symptoms. These patients were older, had lower ICU admission rates, and had a lower risk of in-hospital mortality after adjusting for confounders.

Published
2024
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13. One size does not fit all: notable individual variation in brain activity correlates of antidepressant treatment response

Author

Gwen van der Wijk, Yaruuna Enkhbold, Kelsey Cnudde, Matt W. Szostakiwskyj, Pierre Blier, Verner Knott, Natalia Jaworska, and Andrea B. Protzner

Subjects
major depression, treatment response, EEG connectivity, EEG complexity, individual variability, Psychiatry, RC435-571
Abstract

IntroductionTo date, no robust electroencephalography (EEG) markers of antidepressant treatment response have been identified. Variable findings may arise from the use of group analyses, which neglect individual variation. Using a combination of group and single-participant analyses, we explored individual variability in EEG characteristics of treatment response.MethodsResting-state EEG data and Montgomery-Åsberg Depression Rating Scale (MADRS) symptom scores were collected from 43 patients with depression before, at 1 and 12 weeks of pharmacotherapy. Partial least squares (PLS) was used to: 1) identify group differences in EEG connectivity (weighted phase lag index) and complexity (multiscale entropy) between eventual medication responders and non-responders, and 2) determine whether group patterns could be identified in individual patients.ResultsResponders showed decreased alpha and increased beta connectivity, and early, widespread decreases in complexity over treatment. Non-responders showed an opposite connectivity pattern, and later, spatially confined decreases in complexity. Thus, as in previous studies, our group analyses identified significant differences between groups of patients with different treatment outcomes. These group-level EEG characteristics were only identified in ~40-60% of individual patients, as assessed quantitatively by correlating the spatiotemporal brain patterns between groups and individual results, and by independent raters through visualization.DiscussionOur single-participant analyses suggest that substantial individual variation exists, and needs to be considered when investigating characteristics of antidepressant treatment response for potential clinical applicability.Clinical trial registrationhttps://clinicaltrials.gov, identifier NCT00519428.

Published
2024
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14. A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials

Author

Sforzini, Luca, Worrell, Courtney, Kose, Melisa, Anderson, Ian M, Aouizerate, Bruno, Arolt, Volker, Bauer, Michael, Baune, Bernhard T, Blier, Pierre, Cleare, Anthony J, Cowen, Philip J, Dinan, Timothy G, Fagiolini, Andrea, Ferrier, I Nicol, Hegerl, Ulrich, Krystal, Andrew D, Leboyer, Marion, McAllister-Williams, R Hamish, McIntyre, Roger S, Meyer-Lindenberg, Andreas, Miller, Andrew H, Nemeroff, Charles B, Normann, Claus, Nutt, David, Pallanti, Stefano, Pani, Luca, Penninx, Brenda WJH, Schatzberg, Alan F, Shelton, Richard C, Yatham, Lakshmi N, Young, Allan H, Zahn, Roland, Aislaitner, Georgios, Butlen-Ducuing, Florence, Fletcher, Christine, Haberkamp, Marion, Laughren, Thomas, Mäntylä, Fanni-Laura, Schruers, Koen, Thomson, Andrew, Arteaga-Henríquez, Gara, Benedetti, Francesco, Cash-Gibson, Lucinda, Chae, Woo Ri, De Smedt, Heidi, Gold, Stefan M, Hoogendijk, Witte JG, Mondragón, Valeria Jordán, Maron, Eduard, Martynowicz, Jadwiga, Melloni, Elisa, Otte, Christian, Perez-Fuentes, Gabriela, Poletti, Sara, Schmidt, Mark E, van de Ketterij, Edwin, Woo, Katherine, Flossbach, Yanina, Ramos-Quiroga, J Antoni, Savitz, Adam J, and Pariante, Carmine M

Subjects
Clinical Trials and Supportive Activities, Depression, Clinical Research, Mental Health, Brain Disorders, Serious Mental Illness, Major Depressive Disorder, Good Health and Well Being, Depressive Disorder, Major, Depressive Disorder, Treatment-Resistant, Humans, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD.

Published
2022

15. Unbiased Methods for Multi-Goal Reinforcement Learning

Author

Blier, Léonard and Ollivier, Yann

Subjects
Computer Science - Machine Learning
Abstract

In multi-goal reinforcement learning (RL) settings, the reward for each goal is sparse, and located in a small neighborhood of the goal. In large dimension, the probability of reaching a reward vanishes and the agent receives little learning signal. Methods such as Hindsight Experience Replay (HER) tackle this issue by also learning from realized but unplanned-for goals. But HER is known to introduce bias, and can converge to low-return policies by overestimating chancy outcomes. First, we vindicate HER by proving that it is actually unbiased in deterministic environments, such as many optimal control settings. Next, for stochastic environments in continuous spaces, we tackle sparse rewards by directly taking the infinitely sparse reward limit. We fully formalize the problem of multi-goal RL with infinitely sparse Dirac rewards at each goal. We introduce unbiased deep Q-learning and actor-critic algorithms that can handle such infinitely sparse rewards, and test them in toy environments., Comment: 9 pages

Published
2021

16. Geographic ratemaking with spatial embeddings

Author

Blier-Wong, Christopher, Cossette, Hélène, Lamontagne, Luc, and Marceau, Etienne

Subjects
Statistics - Applications, Statistics - Machine Learning
Abstract

Spatial data is a rich source of information for actuarial applications: knowledge of a risk's location could improve an insurance company's ratemaking, reserving or risk management processes. Insurance companies with high exposures in a territory typically have a competitive advantage since they may use historical losses in a region to model spatial risk non-parametrically. Relying on geographic losses is problematic for areas where past loss data is unavailable. This paper presents a method based on data (instead of smoothing historical insurance claim losses) to construct a geographic ratemaking model. In particular, we construct spatial features within a complex representation model, then use the features as inputs to a simpler predictive model (like a generalized linear model). Our approach generates predictions with smaller bias and smaller variance than other spatial interpolation models such as bivariate splines in most situations. This method also enables us to generate rates in territories with no historical experience.

Published
2021
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17. Rethinking Representations in P&C Actuarial Science with Deep Neural Networks

Author

Blier-Wong, Christopher, Baillargeon, Jean-Thomas, Cossette, Hélène, Lamontagne, Luc, and Marceau, Etienne

Subjects
Statistics - Applications
Abstract

Insurance companies gather a growing variety of data for use in the insurance process, but most traditional ratemaking models are not designed to support them. In particular, many emerging data sources (text, images, sensors) may complement traditional data to provide better insights to predict the future losses in an insurance contract. This paper presents some of these emerging data sources and presents a unified framework for actuaries to incorporate these in existing ratemaking models. Our approach stems from representation learning, whose goal is to create representations of raw data. A useful representation will transform the original data into a dense vector space where the ultimate predictive task is simpler to model. Our paper presents methods to transform non-vectorial data into vectorial representations and provides examples for actuarial science., Comment: 27 pages, 16 figures

Published
2021

18. Learning Successor States and Goal-Dependent Values: A Mathematical Viewpoint

Author

Blier, Léonard, Tallec, Corentin, and Ollivier, Yann

Subjects
Computer Science - Machine Learning
Abstract

In reinforcement learning, temporal difference-based algorithms can be sample-inefficient: for instance, with sparse rewards, no learning occurs until a reward is observed. This can be remedied by learning richer objects, such as a model of the environment, or successor states. Successor states model the expected future state occupancy from any given state for a given policy and are related to goal-dependent value functions, which learn how to reach arbitrary states. We formally derive the temporal difference algorithm for successor state and goal-dependent value function learning, either for discrete or for continuous environments with function approximation. Especially, we provide finite-variance estimators even in continuous environments, where the reward for exactly reaching a goal state becomes infinitely sparse. Successor states satisfy more than just the Bellman equation: a backward Bellman operator and a Bellman-Newton (BN) operator encode path compositionality in the environment. The BN operator is akin to second-order gradient descent methods and provides the true update of the value function when acquiring more observations, with explicit tabular bounds. In the tabular case and with infinitesimal learning rates, mixing the usual and backward Bellman operators provably improves eigenvalues for asymptotic convergence, and the asymptotic convergence of the BN operator is provably better than TD, with a rate independent from the environment. However, the BN method is more complex and less robust to sampling noise. Finally, a forward-backward (FB) finite-rank parameterization of successor states enjoys reduced variance and improved samplability, provides a direct model of the value function, has fully understood fixed points corresponding to long-range dependencies, approximates the BN method, and provides two canonical representations of states as a byproduct.

Published
2021

19. Does chronic exposure to moderate hypoxia affect growth, physiological and oxidative stress biomarkers in adult spotted wolffish (Anarhichas minor) and the hybrid A. minor × A. lupus?

Author

N. R. Le François, C. Drouin‐Johnson, F. Larouche, D. Chabot, and P. U. Blier

Subjects
hypoxia, growth rate, metabolic organization, oxidative stress, hybrid, spotted wolffish, Aquaculture. Fisheries. Angling, SH1-691
Abstract

Abstract Both in their natural habitat (estuaries, marine coastal environment, ocean depths and freshwater lakes) or in captivity conditions (land‐based, open‐sea aquaculture and aquariums), exposure to hypoxia can have direct detrimental effects on fish growth, reproduction, behaviour and health. The objective of this study was to investigate the effects of chronic exposure of spotted wolffish (Anarhichas minor) (∼1.4 kg) and the interspecific hybrid (A. minor × A. lupus) (∼600 g) to moderate hypoxia levels (dissolved oxygen [DO]: 40%, 50% and 60% saturation) in comparison to a normoxia group (control 100%) over a period of 14 weeks at ∼7.5°C. The trials were conducted as a common‐garden experiment (both fish groups reared together) in quadruplicate (4 tanks per DO level = 16 tanks). Fish performance (specific growth rate, feed intake [FI]) and physiological status (condition factor [K] and hepatosomatic index, haematocrit) were monitored at different intervals. The metabolic enzyme activity of citrate synthase (CS), lactate dehydrogenase (LDH) and pyruvate kinase (PK) was measured as well as antioxidant enzymes glutathione reductase and catalase. Oxidative stress indices were assessed by the quantification of thiobarbituric acid reactive substances (TBARS) and the measurement of the enzymatic activity level of aconitase. Significant reduction in growth rate occurred at DO 40%. DO was identified as a major driver of FI. Our results indicate a very strong adaptation to hypoxia as (1) exposures to DO 40% were not severe enough to affect aerobic or anaerobic metabolism capacity or to significantly induce oxidative stress and (2) metabolic organization of the muscle tissue, as expressed by LDH, CS and PK is not affected by DO levels down to 40%. However, at the lowest DO levels (40% and 50%), hybrid fish displayed significantly better growth than the spotted wolffish.

Published
2024
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20. Under pressure—exploring partner changes, physiological responses and telomere dynamics in northern gannets across varying breeding conditions

Author

David Pelletier, Pierre U. Blier, François Vézina, France Dufresne, Frédérique Paquin, Felix Christen, and Magella Guillemette

Subjects
Inflammation, Individual quality, Life history theory, Nutritional status, Oxidative stress, Physiological costs of reproduction, Medicine, Biology (General), QH301-705.5
Abstract

Background Life history theory predicts trade-offs between reproduction and survival in species like the northern gannet (Morus bassanus). During breeding, demanding foraging conditions lead them to expand their foraging range and diversify their diet, increasing the risk of reproductive failure. Changing partners may enhance breeding success but lead to more physiological costs. Methods To investigate the physiological costs of reproduction upon partner changes, we measured and compared 21 biomarkers related to telomere dynamics, oxidative stress, inflammation, hematology, nutritional status, and muscle damage. We used a longitudinal approach with gannets (n = 38) over three contrasting years (2017, 2018 and 2019). Results Our results suggest that annual breeding conditions exert a greater influence on physiological changes than partnership status. Individuals that changed partner experienced greater short-term stress than retained partners. This transient increase in stress was marked by short-term increases in oxidative lipid damage, lower antioxidant capacity, signs of inflammation, and greater weight loss than individuals that retained partners. During favorable conditions, individuals that changed mates had stabilized telomere length, decreased antioxidant capacity, glucose concentration, and muscle damage, along with increased oxygen transport capacity. Conversely, unfavorable breeding conditions led to increased telomere attrition, stabilized antioxidant capacity, decreased inflammation susceptibility, diminished oxygen transport capacity, and increased muscle damage. In the cases where partners were retained, distinct physiological changes were observed depending on the year’s conditions, yet the telomere dynamics remained consistent across both partnership status categories. During the favorable year, there was an increase in unsaturated fatty acids and oxygen transport capacity in the blood, coupled with a reduction in inflammation potential and protein catabolism. In contrast, during the unfavorable year in the retained mates, we observed an increase in oxidative DNA damage, antioxidant capacity, weight loss, but a decrease in inflammation susceptibility as observed in changed mates. Discussion Our study shows that behavioral flexibility such as mate switching can help seabirds cope with the challenges of food scarcity during reproduction, but these coping strategies may have a negative impact on physiological status at the individual level. In addition, the marked reduction in telomere length observed during harsh conditions, coupled with the stabilization of telomere length in favorable conditions, highlights the long-term physiological impact of annual breeding conditions on seabirds. These findings underscore the effect on their potential survival and fitness, emphasizing that the influence of annual breeding conditions is greater than that of partnership status.

Published
2023
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21. Sustaining the benefits of intravenous ketamine with behavioural activation therapy for depression: A case series

Author

Jennifer L. Phillips, Pierre Blier, and Jeanne Talbot

Subjects
Behavioural activation therapy, Ketamine, Treatment-resistant depression, Major depressive disorder, Relapse prevention, Mental healing, RZ400-408
Abstract

Background: Despite advances in treatments for depression, approximately one third of patients do not benefit from available therapies. Intravenous ketamine is a novel intervention that can yield rapid yet transient antidepressant effects. Behavioural activation (BA) therapy for depression has been shown to be effective in preventing relapse of major depressive episodes. In this pilot study, we examined whether antidepressant response achieved through repeated ketamine infusions could be maintained with BA. Methods: In this case series, patients with treatment-resistant depression who met antidepressant response criteria in a clinical trial of repeated ketamine infusions subsequently completed 12–17 sessions of BA. Depressive symptoms were measured at each session with the Beck Depression Inventory-II (BDI-II). Secondary outcomes included changes in work and social adjustment, suicidal ideation, and anxiety. Results: Ten of the 13 participants who initiated BA completed the full course of psychotherapy. These participants showed significant improvement in self-reported depressive symptoms (p = 0.007) and work and social adjustment scores (p

Published
2023
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22. New Approach Methods to Assess the Enteropathogenic Potential of Strains of the Bacillus cereus Group, including Bacillus thuringiensis

Author

Arnaud Fichant, Rachelle Lanceleur, Salma Hachfi, Alexandra Brun-Barale, Anne-Louise Blier, Olivier Firmesse, Armel Gallet, Valérie Fessard, and Mathilde Bonis

Subjects
Bacillus cereus, Bacillus thuringiensis, enteropathogenicity, Caco-2 cells, Drosophila melanogaster, new approach methods, Chemical technology, TP1-1185
Abstract

Bacillus cereus (Bc) is a wide group of Gram-positive and spore-forming bacteria, known to be the etiological agents of various human infections, primarily food poisoning. The Bc group includes enteropathogenic strains able to germinate in the digestive tract and to produce enterotoxins such as Nhe, Hbl, and CytK. One species of the group, Bacillus thuringiensis (Bt), has the unique feature of producing insecticidal crystals during sporulation, making it an important alternative to chemical pesticides to protect crops from insect pest larvae. Nevertheless, several studies have suggested a link between the ingestion of pesticide strains and human cases of food poisoning, calling their safety into question. Consequently, reliable tools for virulence assessment are worth developing to aid decision making in pesticide regulation. Here, we propose complementary approaches based on two biological models, the human intestinal Caco-2 cell line and the insect Drosophila melanogaster, to assess and rank the enteric virulence potency of Bt strains in comparison with other Bc group members. Using a dataset of 48 Bacillus spp. strains, we showed that some Bc group strains, including Bt, were able to induce cytotoxicity in Caco-2 cells with concomitant release of IL-8 cytokine, a landmark of pro-inflammatory response. In the D. melanogaster model, we were able to sort a panel of 39 strains into four different classes of virulence, ranging from no virulence to strong virulence. Importantly, for the most virulent strains, mortality was associated with a loss of intestinal barrier integrity. Interestingly, although strains can share a common toxinotype, they display different degrees of virulence, suggesting the existence of specific mechanisms of virulence expression in vivo in the intestine.

Published
2024
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23. Ketamine promptly normalizes excess norepinephrine and enhances dopamine neuronal activity in Wistar Kyoto rats

Author

Stephen Daniels, Mostafa El Mansari, Rami Hamoudeh, and Pierre Blier

Subjects
Wistar Kyoto, ketamine, serotonin, norepinephrine, dopamine, electrophysiology, Therapeutics. Pharmacology, RM1-950
Abstract

Ketamine acts primarily by blocking the N-methyl-D-aspartate (NMDA) receptor at the phencyclidine site. The rapid antidepressant properties of ketamine were demonstrated in the clinic and several behavioral models of depression in rodents. We hypothesized that the normalization of abnormal activity of monoamine neurons in Wistar Kyoto (WKY) rats contributes to the rapid antidepressant effects of ketamine. A single administration of ketamine (10 mg/kg, i. p) or saline was administered to anesthetized WKY rats before in vivo electrophysiological recordings of dorsal raphe nucleus (DRN) serotonin (5-HT), locus coeruleus (LC) norepinephrine (NE) and ventral tegmental area (VTA) dopamine (DA) neuronal activity. Pyramidal neurons from the medial prefrontal cortex (mPFC) were also recorded before and after a ketamine injection. In the VTA, ketamine elicited a significant increase in the population activity of DA neurons. This enhancement was consistent with findings in other depression-like models in which such a decreased population activity was observed. In the LC, ketamine normalized increased NE neuron burst activity found in WKY rats. In the DRN, ketamine did not significantly reverse 5-HT neuronal activity in WKY rats, which is dampened compared to Wistar rats. Ketamine did not significantly alter the neuronal activity of mPFC pyramidal neurons. These findings demonstrate that ketamine normalized NE neuronal activity and enhanced DA neuronal activity in WKY rats, which may contribute to its rapid antidepressant effect.

Published
2023
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24. Making Deep Q-learning methods robust to time discretization

Author

Tallec, Corentin, Blier, Léonard, and Ollivier, Yann

Subjects
Computer Science - Machine Learning, Statistics - Machine Learning
Abstract

Despite remarkable successes, Deep Reinforcement Learning (DRL) is not robust to hyperparameterization, implementation details, or small environment changes (Henderson et al. 2017, Zhang et al. 2018). Overcoming such sensitivity is key to making DRL applicable to real world problems. In this paper, we identify sensitivity to time discretization in near continuous-time environments as a critical factor; this covers, e.g., changing the number of frames per second, or the action frequency of the controller. Empirically, we find that Q-learning-based approaches such as Deep Q- learning (Mnih et al., 2015) and Deep Deterministic Policy Gradient (Lillicrap et al., 2015) collapse with small time steps. Formally, we prove that Q-learning does not exist in continuous time. We detail a principled way to build an off-policy RL algorithm that yields similar performances over a wide range of time discretizations, and confirm this robustness empirically.

Published
2019

25. Effects of CYP2C19 and CYP2D6 gene variants on escitalopram and aripiprazole treatment outcome and serum levels: results from the CAN-BIND 1 study

Author

Farhana Islam, Victoria S. Marshe, Leen Magarbeh, Benicio N. Frey, Roumen V. Milev, Claudio N. Soares, Sagar V. Parikh, Franca Placenza, Stephen C. Strother, Stefanie Hassel, Valerie H. Taylor, Francesco Leri, Pierre Blier, Rudolf Uher, Faranak Farzan, Raymond W. Lam, Gustavo Turecki, Jane A. Foster, Susan Rotzinger, Sidney H. Kennedy, and Daniel J. Müller

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Cytochrome P450 drug-metabolizing enzymes may contribute to interindividual differences in antidepressant outcomes. We investigated the effects of CYP2C19 and CYP2D6 gene variants on response, tolerability, and serum concentrations. Patients (N = 178) were treated with escitalopram (ESC) from weeks 0–8 (Phase I), and at week 8, either continued ESC if they were responders or were augmented with aripiprazole (ARI) if they were non-responders (

Published
2022
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26. SNORD90 induces glutamatergic signaling following treatment with monoaminergic antidepressants

Author

Rixing Lin, Aron Kos, Juan Pablo Lopez, Julien Dine, Laura M Fiori, Jennie Yang, Yair Ben-Efraim, Zahia Aouabed, Pascal Ibrahim, Haruka Mitsuhashi, Tak Pan Wong, El Cherif Ibrahim, Catherine Belzung, Pierre Blier, Faranak Farzan, Benicio N Frey, Raymond W Lam, Roumen Milev, Daniel J Muller, Sagar V Parikh, Claudio Soares, Rudolf Uher, Corina Nagy, Naguib Mechawar, Jane A Foster, Sidney H Kennedy, Alon Chen, and Gustavo Turecki

Subjects
major depressive disorder, Antidepressant, snoRNA, m6A, Medicine, Science, Biology (General), QH301-705.5
Abstract

Pharmacotherapies for the treatment of major depressive disorder were serendipitously discovered almost seven decades ago. From this discovery, scientists pinpointed the monoaminergic system as the primary target associated with symptom alleviation. As a result, most antidepressants have been engineered to act on the monoaminergic system more selectively, primarily on serotonin, in an effort to increase treatment response and reduce unfavorable side effects. However, slow and inconsistent clinical responses continue to be observed with these available treatments. Recent findings point to the glutamatergic system as a target for rapid acting antidepressants. Investigating different cohorts of depressed individuals treated with serotonergic and other monoaminergic antidepressants, we found that the expression of a small nucleolar RNA, SNORD90, was elevated following treatment response. When we increased Snord90 levels in the mouse anterior cingulate cortex (ACC), a brain region regulating mood responses, we observed antidepressive-like behaviors. We identified neuregulin 3 (NRG3) as one of the targets of SNORD90, which we show is regulated through the accumulation of N6-methyladenosine modifications leading to YTHDF2-mediated RNA decay. We further demonstrate that a decrease in NRG3 expression resulted in increased glutamatergic release in the mouse ACC. These findings support a molecular link between monoaminergic antidepressant treatment and glutamatergic neurotransmission.

Published
2023
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27. Learning with Random Learning Rates

Author

Blier, Léonard, Wolinski, Pierre, and Ollivier, Yann

Subjects
Computer Science - Machine Learning, Computer Science - Neural and Evolutionary Computing, Statistics - Machine Learning
Abstract

Hyperparameter tuning is a bothersome step in the training of deep learning models. One of the most sensitive hyperparameters is the learning rate of the gradient descent. We present the 'All Learning Rates At Once' (Alrao) optimization method for neural networks: each unit or feature in the network gets its own learning rate sampled from a random distribution spanning several orders of magnitude. This comes at practically no computational cost. Perhaps surprisingly, stochastic gradient descent (SGD) with Alrao performs close to SGD with an optimally tuned learning rate, for various architectures and problems. Alrao could save time when testing deep learning models: a range of models could be quickly assessed with Alrao, and the most promising models could then be trained more extensively. This text comes with a PyTorch implementation of the method, which can be plugged on an existing PyTorch model: https://github.com/leonardblier/alrao ., Comment: 20 pages, 8 figures, code available on GitHub

Published
2018

28. The Description Length of Deep Learning Models

Author

Blier, Léonard and Ollivier, Yann

Subjects
Computer Science - Machine Learning
Abstract

Solomonoff's general theory of inference and the Minimum Description Length principle formalize Occam's razor, and hold that a good model of data is a model that is good at losslessly compressing the data, including the cost of describing the model itself. Deep neural networks might seem to go against this principle given the large number of parameters to be encoded. We demonstrate experimentally the ability of deep neural networks to compress the training data even when accounting for parameter encoding. The compression viewpoint originally motivated the use of variational methods in neural networks. Unexpectedly, we found that these variational methods provide surprisingly poor compression bounds, despite being explicitly built to minimize such bounds. This might explain the relatively poor practical performance of variational methods in deep learning. On the other hand, simple incremental encoding methods yield excellent compression values on deep networks, vindicating Solomonoff's approach., Comment: NIPS 2018

Published
2018

29. Safety of Cefazolin Test Dose in Patients With Penicillin Allergy Just Prior to Cardiac Device Implantation: A Single-Centre Experience

Author

Jean-François Sarrazin, MD, Jamal Laaouaj, MD, François Philippon, MD, Marina Sanchez, PhD, Philippe Gervais, MD, Jean Champagne, MD, Christian Steinberg, MD, Isabelle Nault, MD, Karine Roy, MD, Benoît Plourde, MD, Louis Blier, MD, and Gilles O’Hara, MD

Subjects
Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background: Cephalosporins are the cornerstone of cardiac device infection prophylaxis. Owing to fears of cross-reactivity, penicillin-allergic patients are exposed to potentially more-toxic drugs, with decreased efficacy. We evaluated the safety of a cefazolin test dose (CTD) in self-reported penicillin-allergic patients. Methods: In this single-centre study, we evaluated consecutive patients with chart documentation of penicillin allergy undergoing cardiac device implantation, over a 2-year period. A CTD was performed if no cephalosporin allergy or severe anaphylactic reaction to penicillin had been documented. Patients were given 2 doses of 100 mg IV cefazolin, and if no allergic reaction occurred after 5 minutes, the full dose (1800 mg) was administered in the electrophysiology laboratory just before the implantation procedure. Results: A total of 2200 patients were included. The frequency of reported penicillin allergy was 9.3% (n = 204). In 80% of cases, the type of allergic reaction was not reported in medical notes or was unknown by the patient. A CTD was performed in 67.6% of patients with a penicillin allergy (n = 138). A total of 5 adverse events occurred (3.6% of patients [95% confidence interval, 1.1%-6.1%]) — 4 skin rashes and 1 tongue edema. These 5 patients became asymptomatic after antihistaminic and corticosteroid IV treatment. Even if the test dose was negative, 79% of patients also were administered vancomycin before the procedure, as it requires a 1-hour infusion prior to the CTD in the implantation procedure room. Conclusion: A CTD in most penicillin-allergic patients appears to be safe and allows its use per recommended guidelines. Résumé: Contexte: Les céphalosporines sont la pierre angulaire de la prophylaxie des infections des dispositifs cardiaques. En raison du risque appréhendé de réactivité croisée, les patients allergiques à la pénicilline se trouvent exposés à des médicaments potentiellement plus toxiques, qui s’avèrent aussi moins efficaces. Nous avons évalué l’innocuité d’une dose d’essai de céfazoline chez des patients qui s’étaient dits allergiques à la pénicilline. Méthodologie: Dans cette étude monocentrique, nous avons suivi pendant deux ans des patients consécutifs dont le dossier médical faisait état d’une allergie à la pénicilline et chez qui un dispositif cardiaque devait être implanté. Une dose d’essai de céfazoline a été administrée aux patients sans antécédents documentés d’allergie aux céphalosporines ou de réaction anaphylactique sévère à la pénicilline. Deux doses de 100 mg de céfazoline ont été administrées par voie intraveineuse. En l’absence de réaction allergique après cinq minutes, les patients recevaient la dose complète (1 800 mg) au laboratoire d’électrophysiologie juste avant l’implantation du dispositif cardiaque. Résultats: Au total, 2 200 patients ont été inscrits à l’étude. Le taux de signalement de l’allergie à la pénicilline était de 9,3 % (n = 204). Dans 80 % des cas, le type de réaction allergique n’a pas été précisé dans les notes médicales ou était inconnu du patient. Une dose d’essai de céfazoline a été administrée à 67,6 % des patients allergiques à la pénicilline (n = 138). Au total, cinq événements indésirables se sont produits (3,6 % des patients [intervalle de confiance à 95 % : 1,1-6,1 %]) – quatre éruptions cutanées et un œdème de la langue. Les cinq patients touchés par ces événements sont devenus asymptomatiques après avoir reçu un antihistaminique et un corticostéroïde par voie intraveineuse. Même en l’absence de réaction allergique à la dose d’essai, 79 % des patients ont reçu de la vancomycine avant l’intervention, cet agent devant être administré par perfusion durant une heure avant la dose d’essai de céfazoline dans la salle d’intervention. Conclusion: Chez la plupart des patients allergiques à la pénicilline, une dose d’essai de céfazoline semble sans danger et permet d’avoir recours à ce médicament conformément aux lignes directrices.

Published
2022
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30. Good times bad times — Unfavorable breeding conditions, more than divorce, lead to increased parental effort and reduced physiological condition of northern gannets

Author

David Pelletier, Pierre Blier, François Vézina, and Magella Guillemette

Subjects
parental effort, behavioral flexibility, oxidative stress, nutritional status, seabirds, physical condition, Evolution, QH359-425, Ecology, QH540-549.5
Abstract

Decreased productivity in long-lived bird species is linked to prey depletion in marine ecosystems. Seabirds, however, exhibit behavioral flexibility at individual level to prevent this outcome. One such strategy to alleviate any impact on fitness would be to divorce from their partners. Although changing mates and increasing foraging effort have been shown to increase or maintain reproductive success, how the behavioral flexibility affects fundamental physiological parameters remains to be elucidated. Here, we compared physiological components (nutritional status, muscle damage and oxidative stress) of northern gannets (Morus bassanus) in relation to their partnership status and foraging effort. Specifically, we used a cross-sectional data set (at the population level) of three contrasted years to compare retained and changed mates. We predicted that mate change is a stressful event with impacts on health condition and those effects are higher during unfavorable years with food depletion. Our study showed that gannets changing mate increase parental effort only during years of low food abundance, with consequences on health condition (increased body mass loss, higher protein catabolism and higher oxidative damage during chick rearing period). Ultimately, our study suggests that partnership decision is not likely to reduce the long-term quality and the fitness of parents. Reproduction during harsh conditions would however likely be one of the primary causes of individual quality loss and fitness decline in this long-lived bird species.

Published
2023
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31. Effects of CYP2C19 and CYP2D6 gene variants on escitalopram and aripiprazole treatment outcome and serum levels: results from the CAN-BIND 1 study

Author

Islam, Farhana, Marshe, Victoria S., Magarbeh, Leen, Frey, Benicio N., Milev, Roumen V., Soares, Claudio N., Parikh, Sagar V., Placenza, Franca, Strother, Stephen C., Hassel, Stefanie, Taylor, Valerie H., Leri, Francesco, Blier, Pierre, Uher, Rudolf, Farzan, Faranak, Lam, Raymond W., Turecki, Gustavo, Foster, Jane A., Rotzinger, Susan, Kennedy, Sidney H., and Müller, Daniel J.

Published
2022
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32. A randomized, crossover comparison of ketamine and electroconvulsive therapy for treatment of major depressive episodes: a Canadian biomarker integration network in depression (CAN-BIND) study protocol

Author

Jennifer L. Phillips, Natalia Jaworska, Elizabeth Kamler, Venkat Bhat, Jean Blier, Jane A. Foster, Stefanie Hassel, Keith Ho, Lisa McMurray, Roumen Milev, Zahra Moazamigoudarzi, Franca M. Placenza, Stéphane Richard-Devantoy, Susan Rotzinger, Gustavo Turecki, Gustavo H. Vazquez, Sidney H. Kennedy, Pierre Blier, and on behalf of the CAN-BIND Investigator Team

Subjects
Major depressive disorder, Bipolar disorder, Depression, Intravenous ketamine, Electroconvulsive therapy, Biomarkers, Psychiatry, RC435-571
Abstract

Abstract Background Recent evidence underscores the utility of rapid-acting antidepressant interventions, such as ketamine, in alleviating symptoms of major depressive episodes (MDE). However, to date, there have been limited head-to-head comparisons of intravenous (IV) ketamine infusions with other antidepressant treatment strategies in large randomized trials. This study protocol describes an ongoing multi-centre, prospective, randomized, crossover, non-inferiority trial comparing acute treatment of individuals meeting diagnostic criteria for a major depressive episode (MDE) with ketamine and electroconvulsive therapy (ECT) on efficacy, speed of therapeutic effects, side effects, and health care resource utilization. A secondary aim is to compare a 6-month maintenance strategy for ketamine responders to standard of care ECT maintenance. Finally, through the measurement of clinical, cognitive, neuroimaging, and molecular markers we aim to establish predictors and moderators of treatment response as well as treatment-elicited effects on these outcomes. Methods Across four participating Canadian institutions, 240 patients with major depressive disorder or bipolar disorder experiencing a MDE are randomized (1:1) to a course of ECT or racemic IV ketamine (0.5 mg/kg) administered 3 times/week for 3 or 4 weeks. Non-responders (

Published
2020
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33. Childhood Arthritis and Rheumatology Research Alliance Biologic Disease‐Modifying Antirheumatic Drug Consensus Treatment Plans for Refractory Moderately Severe Juvenile Dermatomyositis

Author

Tarvin, Stacey E., Sherman, Matthew A., Kim, Hanna, Balmuri, Nayimisha, Brown, Amanda G., Chow, Albert, Gewanter, Harry L., Guzman, Marietta M., Huber, Adam M., Kim, Susan, Klein‐Gitelman, Marisa S, Perron, Megan M., Robinson, Angela Byun, Sabbagh, Sara E., Savani, Sonia, Shenoi, Susan, Spitznagle, Jacob, Stingl, Cory, Syverson, Grant, Tory, Heather, Spencer, Charles, Aguiar Lapsia, Cassyanne L., Ardalan, Kaveh, Blier, Peter, Chang, Johanna, Chhabra, Amieleena, Cook, Kathryn, Curran, Megan, Fuller, Julie, Hui‐Yuen, Joyce, Lang, Bianca, Orandi, Amir B., Schmeling, Heinrike, and Turnier, Jessica

Abstract

The objective was to develop consensus treatment plans (CTPs) for patients with refractory moderately severe juvenile dermatomyositis (JDM) treated with biologic disease‐modifying antirheumatic drugs (bDMARDs). The Biologics Workgroup of the Childhood Arthritis and Rheumatology Research Alliance JDM Research Committee used case‐based surveys, consensus framework, and nominal group technique to produce bDMARD CTPs for patients with refractory moderately severe JDM. Four bDMARD CTPs were proposed: tumor necrosis factor α (TNFα) inhibitor (adalimumab or infliximab), abatacept, rituximab, and tocilizumab. Each CTP has different options for dosing and/or route. Among 76 respondents, consensus was achieved for the proposed CTPs (93% [67 of 72]) as well as for patient characteristics, assessments, outcome measures, and follow‐up. By weighted average, respondents indicated that they would most likely administer rituximab, followed by abatacept, TNFα inhibitor, and tocilizumab. CTPs for the administration of bDMARDs in refractory moderately severe JDM were developed using consensus methodology. The implementation of the bDMARD CTPs will lay the groundwork for registry‐based prospective comparative effectiveness studies.

Published
2024
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34. Proceedings of the 2016 Childhood Arthritis and Rheumatology Research Alliance (CARRA) Scientific Meeting : Toronto, Canada. 14-17 April 2016.

Author

Fotis, Lampros, Shaikh, Nur, Baszis, Kevin, French, Anthony, Tarr, Phillip, Grevich, Sriharsha, Lee, Peggy, Ringold, Sarah, Leroux, Brian, Leahey, Hannah, Yuasa, Megan, Foster, Jessica, Sokolove, Jeremy, Lahey, Lauren, Robinson, William, Newsom, Joshua, Stevens, Anne, Karasawa, Rie, Tamaki, Mayumi, Tanaka, Megumi, Sato, Toshiko, Yudoh, Kazuo, Jarvis, James N, Moncrieffe, Halima, Bennett, Mark F, Tsoras, Monica, Luyrink, Lorie, Xu, Huan, Prahalad, Sampath, Morris, Paula, Dare, Jason, Nigrovic, Peter A, Rosenkranz, Margalit, Becker, Mara, O’Neil, Kathleen M, Griffin, Thomas, Lovell, Daniel J, Grom, Alexei A, Medvedovic, Mario, Thompson, Susan D, Zhu, Lisha, Jiang, Kaiyu, Wong, Laiping, Buck, Michael J, Chen, Yanmin, Brungs, Laura, Liu, Tao, Wang, Ting, Alsaeid, Khaled, Alfailakawi, Jasim, Alenezi, Hamid, Alsaeed, Hazim, Beukelman, Tim, Natter, Marc, Ilowite, Norm, Mieszkalski, Kelly, Burrell, Grendel, Best, Brian, Bristow, Helen, Carr, Shannon, Dennos, Anne, Kaufmann, Rachel, Kimura, Yukiko, Schanberg, Laura, Blier, Peter R, Boneparth, Alexis, Wenderfer, Scott E, Moorthy, L Nandini, Radhakrishna, Suhas M, Sagcal-Gironella, Anna Carmela P, von Scheven, Emily, Gedik, Kader Cetin, Siddique, Salma, Aguiar, Cassyanne L, Erkan, Doruk, Cohen, Ezra, Lee, Yvonne, Dossett, Michelle, Mehta, Darshan, Davis, Roger, Gilbert, Mileka, Goilav, Beatrice, Meidan, Esra, Hsu, Joyce, Chua, Anabelle, Ardoin, Stacy, Von Scheven, Emily, Ruth, Natasha M, Hui-Yuen, Joyce, Bermudez, Liza, Cook, Ashlea, Imundo, Lisa, Starr, Amy, Eichenfield, Andrew, and Askanase, Anca

Subjects
Arthritis & Rheumatology, Clinical Sciences, Paediatrics and Reproductive Medicine
Published
2016

36. Linseed oil as a substitute for fish oil in the diet of Arctic charr (Salvelinus alpinus), brook charr (S. fontinalis) and their reciprocal hybrids.

Author

Bernard-Antonin Dupont-Cyr, Nathalie R. Le François, Felix Christen, Véronique Desrosiers, Arianne Savoie, Grant W. Vandenberg, France Dufresne, and Pierre U. Blier

Subjects
Charr, Salvelinus, Growth, Hybridization, Proteolytic enzymes, Aquafeed, Aquaculture. Fisheries. Angling, SH1-691
Abstract

This study examines the potential effects of linseed oil as a total replacement for fish oil in the formulated diet of Arctic charr, brook charr and their reciprocal hybrids. Muscle fatty acid composition, growth performance and feed utilization were evaluated on four experimental groups submitted to two different dietary lipid sources (100% linseed oil or 100% fish oil). Growth performance, feed utilization, muscle lipids and protein content were not affected by dietary linseed oil. Lipid source significantly affected muscle fatty acid profile. The replacement of fish oil by linseed led to an average reduction in 20:5n3 and 22:6 n3 (25.5% and 18.4% respectively) and an increase in 18:3n3 (177%) (mean values calculated for the four experimental groups). Muscle fatty acid profile was primarily influenced by feed content. Hybridization between the closely related species did not appear to affect the expression of key enzymes for HUFA biosynthesis. Our results show that linseed can be used as a fish oil replacement in charr without any significant impact on growth, feed utilization or muscle lipid and protein content.

Published
2022
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37. Common Data Elements to Facilitate Sharing and Re-use of Participant-Level Data: Assessment of Psychiatric Comorbidity Across Brain Disorders

Author

Anthony L. Vaccarino, Derek Beaton, Sandra E. Black, Pierre Blier, Farnak Farzan, Elizabeth Finger, Jane A. Foster, Morris Freedman, Benicio N. Frey, Susan Gilbert Evans, Keith Ho, Mojib Javadi, Sidney H. Kennedy, Raymond W. Lam, Anthony E. Lang, Bianca Lasalandra, Sara Latour, Mario Masellis, Roumen V. Milev, Daniel J. Müller, Douglas P. Munoz, Sagar V. Parikh, Franca Placenza, Susan Rotzinger, Claudio N. Soares, Alana Sparks, Stephen C. Strother, Richard H. Swartz, Brian Tan, Maria Carmela Tartaglia, Valerie H. Taylor, Elizabeth Theriault, Gustavo Turecki, Rudolf Uher, Lorne Zinman, and Kenneth R. Evans

Subjects
common data elements, psychiatric comorbidity, major depressive disorder, neurological disorders, data sharing, pooled participant data, Psychiatry, RC435-571
Abstract

The Ontario Brain Institute's “Brain-CODE” is a large-scale informatics platform designed to support the collection, storage and integration of diverse types of data across several brain disorders as a means to understand underlying causes of brain dysfunction and developing novel approaches to treatment. By providing access to aggregated datasets on participants with and without different brain disorders, Brain-CODE will facilitate analyses both within and across diseases and cover multiple brain disorders and a wide array of data, including clinical, neuroimaging, and molecular. To help achieve these goals, consensus methodology was used to identify a set of core demographic and clinical variables that should be routinely collected across all participating programs. Establishment of Common Data Elements within Brain-CODE is critical to enable a high degree of consistency in data collection across studies and thus optimize the ability of investigators to analyze pooled participant-level data within and across brain disorders. Results are also presented using selected common data elements pooled across three studies to better understand psychiatric comorbidity in neurological disease (Alzheimer's disease/amnesic mild cognitive impairment, amyotrophic lateral sclerosis, cerebrovascular disease, frontotemporal dementia, and Parkinson's disease).

Published
2022
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40. Investigation of the Genotoxic Potential of the Marine Toxin C17-SAMT Using the In Vivo Comet and Micronucleus Assays

Author

Zeineb Marzougui, Sylvie Huet, Anne-Louise Blier, Ludovic Le Hégarat, Haïfa Tounsi-Kettiti, Riadh Kharrat, Riadh Marrouchi, and Valérie Fessard

Subjects
marine biotoxins, C17-SAMT, genotoxicity, comet assay, micronucleus assay, Biology (General), QH301-705.5
Abstract

The contaminant responsible for the atypical toxicity reported in mussels from Bizerte Lagoon (Northern Tunisia) during the last decade has been characterized as C17-sphinganine analog mycotoxin (C17-SAMT). This neurotoxin showed common mouse toxic symptoms, including flaccid paralysis and severe dyspnea, followed by rapid death. For hazard assessment on human health, in this work we aimed to evaluate the in vivo genotoxic effects of this marine biotoxin using the classical alkaline and modified Fpg comet assays performed to detect DNA breaks and alkali-labile sites as well as oxidized bases. The micronucleus assay was used on bone marrow to detect chromosome and genome damage. C17-SAMT induces a statistically insignificant increase in DNA tail intensity at all doses in the duodenum, and in the spleen contrary to the liver, the percentage of tail DNA increased significantly at the mid dose of 300 µg/kg b.w/d. C17-SAMT did not affect the number of micronuclei in the bone marrow. Microscopic observations of the liver showed an increase in the number of mitosis and hepatocytes’ cytoplasm clarification. At this level of study, we confirm that C17-SAMT induced DNA damage in the liver but there was no evidence of effects causing DNA oxidation or chromosome and genome damage.

Published
2022
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41. A quantum characterization of NP

Author

Blier, Hugue and Tapp, Alain

Subjects
Quantum Physics
Abstract

In this article we introduce a new complexity class called PQMA_log(2). Informally, this is the class of languages for which membership has a logarithmic-size quantum proof with perfect completeness and soundness which is polynomially close to 1 in a context where the verifier is provided a proof with two unentangled parts. We then show that PQMA_log(2) = NP. For this to be possible, it is important, when defining the class, not to give too much power to the verifier. This result, when compared to the fact that QMA_log = BQP, gives us new insight on the power of quantum information and the impact of entanglement., Comment: The class QMA_Log(2) have been replace by PQMA_log(2) where the power of the verifier is slightly weaker

Published
2007

42. Long-Lived Species of Bivalves Exhibit Low MT-DNA Substitution Rates

Author

Mathieu Mortz, Aurore Levivier, Nicolas Lartillot, France Dufresne, and Pierre U. Blier

Subjects
life-history evolution, longevity, mitochondrial genome, synonymous substitution rates, Markov chain Monte Carlo, bayesian statistics, Biology (General), QH301-705.5
Abstract

Bivalves represent valuable taxonomic group for aging studies given their wide variation in longevity (from 1–2 to >500 years). It is well known that aging is associated to the maintenance of Reactive Oxygen Species homeostasis and that mitochondria phenotype and genotype dysfunctions accumulation is a hallmark of these processes. Previous studies have shown that mitochondrial DNA mutation rates are linked to lifespan in vertebrate species, but no study has explored this in invertebrates. To this end, we performed a Bayesian Phylogenetic Covariance model of evolution analysis using 12 mitochondrial protein-coding genes of 76 bivalve species. Three life history traits (maximum longevity, generation time and mean temperature tolerance) were tested against 1) synonymous substitution rates (dS), 2) conservative amino acid replacement rates (Kc) and 3) ratios of radical over conservative amino acid replacement rates (Kr/Kc). Our results confirm the already known correlation between longevity and generation time and show, for the first time in an invertebrate class, a significant negative correlation between dS and longevity. This correlation was not as strong when generation time and mean temperature tolerance variations were also considered in our model (marginal correlation), suggesting a confounding effect of these traits on the relationship between longevity and mtDNA substitution rate. By confirming the negative correlation between dS and longevity previously documented in birds and mammals, our results provide support for a general pattern in substitution rates.

Published
2021
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43. Twiddler Syndrome without Lead Dislodgment Discovered by Remote Monitoring

Author

Catherine Champagne, Nicolas Dognin, Franck Molin, Christian Steinberg, François Philippon, Jean-François Sarrazin, Gilles O'hara, Isabelle Nault, Karine Roy, Benoit Plourde, Louis Blier, and Jean Champagne

Subjects
Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Twiddler syndrome is an uncommon yet dangerous phenomenon usually resulting in lead displacement with loss of capture of cardiac implantable electronic devices. In this case report, we present an interesting case of Twiddler syndrome without lead dislodgment which was detected by an alert triggered by an increase in impedance on remote monitoring.

Published
2021
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44. Exploring Thermal Sensitivities and Adaptations of Oxidative Phosphorylation Pathways

Author

Hélène Lemieux and Pierre U. Blier

Subjects
mitochondrial function, thermal sensitivity, NADH pathway, succinate pathway, electron-transferring flavoprotein, glycerophosphate dehydrogenase, Microbiology, QR1-502
Abstract

Temperature shifts are a major challenge to animals; they drive adaptations in organisms and species, and affect all physiological functions in ectothermic organisms. Understanding the origin and mechanisms of these adaptations is critical for determining whether ectothermic organisms will be able to survive when faced with global climate change. Mitochondrial oxidative phosphorylation is thought to be an important metabolic player in this regard, since the capacity of the mitochondria to produce energy greatly varies according to temperature. However, organism survival and fitness depend not only on how much energy is produced, but, more precisely, on how oxidative phosphorylation is affected and which step of the process dictates thermal sensitivity. These questions need to be addressed from a new perspective involving a complex view of mitochondrial oxidative phosphorylation and its related pathways. In this review, we examine the effect of temperature on the commonly measured pathways, but mainly focus on the potential impact of lesser-studied pathways and related steps, including the electron-transferring flavoprotein pathway, glycerophosphate dehydrogenase, dihydroorotate dehydrogenase, choline dehydrogenase, proline dehydrogenase, and sulfide:quinone oxidoreductase. Our objective is to reveal new avenues of research that can address the impact of temperature on oxidative phosphorylation in all its complexity to better portray the limitations and the potential adaptations of aerobic metabolism.

Published
2022
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45. Ventricular Arrhythmia in Septal and Apical Hypertrophic Cardiomyopathy: The French-Canadian Experience

Author

Christian Steinberg, Charles Nadeau-Routhier, Philippe André, François Philippon, Jean-François Sarrazin, Isabelle Nault, Gilles O'Hara, Louis Blier, Franck Molin, Benoit Plourde, Karine Roy, Eric Larose, Marie Arsenault, and Jean Champagne

Subjects
hypertrophic cardiomyopathy, apical hypertrophic cardiomyopathy, ventricular arrhythmia, septal hypertrophic cardiomyopathy, French-Canadian, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background: Apical hypertrophic cardiomyopathy (aHCM) is thought to have a more benign clinical course compared to septal HCM (sHCM), but most data have been derived from Asian cohorts. Comparative data on clinical outcome in Caucasian aHCM cohorts are scarce, and the results are conflicting. The aim of this study was to estimate the prevalence and outcome of aHCM in French-Canadians of Caucasian descent.Methods and results: We conducted a retrospective, single-center cohort study. The primary endpoint was a composite of documented sustained ventricular arrhythmia (VA), appropriate ICD therapy, arrhythmogenic syncope, cardiac arrest, or all-cause mortality. A total of 301 HCM patients (65% males) were enrolled including 80/301 (27%) with aHCM and 221/301 (73%) with sHCM. Maximal wall thickness was similar in both groups. Left ventricular apical aneurysm was significantly more common in aHCM (10 vs. 0.5%; p < 0.001). The proportion of patients with myocardial fibrosis ≥ 15% of the left ventricular mass was similar between aHCM and sHCM (21 vs. 24%; p = 0.68). Secondary prevention ICDs were more often implanted in aHCM patients (16 vs. 7%; p = 0.02). The primary endpoint occurred in 26% of aHCM and 10.4% of sHCM patients (p = 0.001) and was driven by an increased incidence of sustained VA (10 vs. 2.3%; p = 0.01). Multivariate analysis identified apical aneurysm and a phenotype of aHCM as independent predictors of the primary endpoint and the occurrence of sustained ventricular tachycardia. Unexplained syncope and a family history of sudden cardiac death were additional predictors for sustained VA. Apical HCM was associated with an increased risk of ventricular arrhythmia even when excluding patients with apical aneurysm.Conclusions: The phenotype of apical HCM is much more common in French-Canadians (27%) of Caucasian descent compared to other Caucasian HCM populations. Apical HCM in French-Canadians is associated with an increased risk for ventricular arrhythmia.

Published
2020
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47. Optimized regimens of combined medications for the treatment of major depressive disorder: a double-blind, randomized-controlled trial

Author

Zuilhof Z, Norris S, Blondeau C, Tessier P, and Blier P

Subjects
antidepressant, escitalopram, bupropion, action onset, augmentation, prolongation, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Zoë Zuilhof, Sandhaya Norris, Claude Blondeau, Pierre Tessier, Pierre Blier Department of Psychiatry, University of Ottawa, The Royal Ottawa Institute of Mental Health Research, Ottawa, ON, Canada Introduction: This study investigated if optimized dose regimens of escitalopram and bupropion combination from treatment initiation can be superior to either drug alone in speed of onset, remission rate, and maintenance of therapeutic efficacy.Methods: Patients from a single site (N=85) within a larger double-blind 12-week trial (N=245) showed a lower dropout rate (14% vs 40%) and used higher doses; therefore, this cohort was analyzed separately. Uniquely at this single site, after 12 weeks, non-remitters on a single drug received the other one in addition and combination non-remitters underwent a switch of escitalopram for duloxetine for a 6-week period. Escitalopram could be given up to 40 mg/day and bupropion up to 450 mg/day. A 6-month prolongation was then implemented in remitters, maintaining the double-blind design throughout. Remission was defined as ≤7 on the 17-item Hamilton Rating Scale for Depression, as in the initial publication.Results: At week 2, combination treatment was superior in remission rate (5/28) compared with both bupropion (0/26) and escitalopram monotherapies (0/31; P=0.03 and P=0.02, respectively). The week 12 remission rate of combination treatment showed a higher rate (15/28) relative to bupropion monotherapy (7/26; P=0.04), but not statistically different from escitalopram monotherapy (11/31; P=0.13). The 6-week augmentation produced remission in 7/21 monotherapy non-remitters and 0/6 in the switch group (P=0.13). Remission was sustained in 28/31 patients enrolled in the 6-month maintenance.Conclusion: These results suggest that combination of escitalopram and bupropion from treatment initiation is superior to either monotherapy in speed of onset. The addition of a second drug in non-remitters can lead to additional remissions, as shown with other combinations of medications. Treatment prolongation using optimized regimens leads to low relapse rates. Keywords: antidepressant, escitalopram, bupropion, action onset, augmentation, prolongation

Published
2018

48. Pre-treatment EEG signal variability is associated with treatment success in depression

Author

Natalia Jaworska, Hongye Wang, Dylan M. Smith, Pierre Blier, Verner Knott, and Andrea B. Protzner

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

Background: Previous work suggests that major depressive disorder (MDD) is associated with disturbances in global connectivity among brain regions, as well as local connectivity within regions. However, the relative importance of these global versus local changes for successful antidepressant treatment is unknown. We used multiscale entropy (MSE), a measure of brain signal variability, to examine how the propensity for local (fine scale MSE) versus global (coarse scale MSE) neural processing measured prior to antidepressant treatment is related to subsequent treatment response. Methods: We collected resting-state EEG activity during eyes-open and closed conditions from unmedicated individuals with MDD prior to antidepressant pharmacotherapy (N=36) as well as from non-depressed controls (N=36). Treatment response was assessed after 12weeks of treatment using the Montgomery-Åsberg Depression Rating Scale (MADRS), at which time participants with MDD were characterized as either responders (≥50% MADRS decrease) or non-responders. MSE was calculated from baseline EEG, and compared between controls, future treatment responders and non-responders. Putative interactions with the well-documented age effect on signal variability (increased reliance on local neural communication with increasing age, indexed by greater finer-scale variability) were assessed. Results: Only in responders, we found that reduced MSE at fine temporal scales (especially fronto-centrally) and increased MSE diffusely at coarser temporal scales was related to the magnitude of the antidepressant response. In controls and MDD non-responders, but not MDD responders, there was an increase in MSE with age at fine temporal scales and a decrease in MSE with age at coarse temporal scales. Conclusion: Our results suggest that an increased propensity toward global processing, indexed by greater MSE at coarser timescales, at baseline appears to facilitate eventual antidepressant treatment response. Keywords: Depression, Treatment, Response, Multi-scale entropy (MSE), Electroencephalography (EEG), Signal variability, Spectral power density (SPD)

Published
2018
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49. Influence of CYP2C19, CYP2D6, and ABCB1Gene Variants and Serum Levels of Escitalopram and Aripiprazole on Treatment-Emergent Sexual Dysfunction: A Canadian Biomarker Integration Network in Depression 1 (CAN-BIND 1) Study

Author

Islam, Farhana, Magarbeh, Leen, Elsheikh, Samar S. M., Kloiber, Stefan, Espinola, Caroline W., Bhat, Venkat, Frey, Benicio N., Milev, Roumen, Soares, Claudio N., Parikh, Sagar V., Placenza, Franca, Hassel, Stefanie, Taylor, Valerie H., Leri, Francesco, Blier, Pierre, Uher, Rudolf, Farzan, Faranak, Lam, Raymond W., Turecki, Gustavo, Foster, Jane A., Rotzinger, Susan, Kennedy, Sidney H., and Müller, Daniel J.

Abstract

Objectives Treatment-emergent sexual dysfunction is frequently reported by individuals with major depressive disorder (MDD) on antidepressants, which negatively impacts treatment adherence and efficacy. We investigated the association of polymorphisms in pharmacokinetic genes encoding cytochrome-P450 drug-metabolizing enzymes, CYP2C19and CYP2D6, and the transmembrane efflux pump, P-glycoprotein (i.e., ABCB1), on treatment-emergent changes in sexual function (SF) and sexual satisfaction (SS) in the Canadian Biomarker Integration Network in Depression 1 (CAN-BIND-1) sample.Methods A total of 178 adults with MDD received treatment with escitalopram (ESC) from weeks 0–8 (Phase I). At week 8, nonresponders were augmented with aripiprazole (ARI) (i.e., ESC + ARI, n= 91), while responders continued ESC (i.e., ESC-Only, n= 80) from weeks 8–16 (Phase II). SF and SS were evaluated using the sex effects (SexFX) scale at weeks 0, 8, and 16. We assessed the primary outcomes, SF and SS change for weeks 0–8 and 8–16, using repeated measures mixed-effects models.Results In ESC-Only, CYP2C19intermediate metabolizer (IM) + poor metabolizers (PMs) showed treatment-related improvements in sexual arousal, a subdomain of SF, from weeks 8–16, relative to CYP2C19normal metabolizers (NMs) who showed a decline, F(2,54) = 8.00, p < 0.001, q = 0.048. Specifically, CYP2C19IM + PMs reported less difficulty with having and sustaining vaginal lubrication in females and erection in males, compared to NMs. Furthermore, ESC-Only females with higher concentrations of ESC metabolite, S-desmethylcitalopram (S-DCT), and S-DCT/ESC ratio in serum demonstrated more decline in SF (r= −0.42, p = 0.004, q = 0.034) and SS (r= −0.43, p = 0.003, q = 0.034), respectively, which was not observed in males. ESC-Only females also demonstrated a trend for a correlation between S-DCT and sexual arousal change in the same direction (r= −0.39, p = 0.009, q = 0.052).Conclusions CYP2C19metabolizer phenotypes may be influencing changes in sexual arousal related to ESC monotherapy. Thus, preemptive genotyping of CYP2C19may help to guide selection of treatment that circumvents selective serotonin reuptake inhibitor-related sexual dysfunction thereby improving outcomes for patients. Additionally, further research is warranted to clarify the role of S-DCT in the mechanisms underlying ESC-related changes in SF and SS. This CAN-BIND-1 study was registered on clinicaltrials.gov (Identifier: NCT01655706) on 27 July 2012.

Published
2024
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