Digital Commons Network^™

The Biomechanics Of Fibrillin Microfibrils: Lessons From The Ciliary Zonule, Pooja Rathaur, Juan Rodriguez, John Kuchtey, Samuel Insignares, Wendell B Jones, Rachel W Kuchtey, Steven Bassnett

2020-Current year OA Pubs

Marfan syndrome is an inherited connective tissue disorder that affects the cardiovascular, musculoskeletal, and ocular systems. It is caused by pathogenic variants in the fibrillin-1 gene (

The C-Terminal Activating Domain Promotes Pannexin 1 Channel Opening, Erik Henze, Jacqueline J Ehrlich, Janice L Robertson, Eric Gelsleichter, Toshimitsu Kawate

2020-Current year OA Pubs

Pannexin 1 (Panx1) constitutes a large pore channel responsible for the release of adenosine triphosphate (ATP) from apoptotic cells. Strong evidence indicates that caspase-mediated cleavage of the C-terminus promotes the opening of the Panx1 channel by unplugging the pore. However, this simple pore-plugging mechanism alone cannot account for the observation that a Panx1 construct ending before the caspase cleavage site remains closed. Here, we show that a helical region located immediately before the caspase cleavage site, referred to as the "C-terminal activating domain (CAD)", plays a pivotal role in facilitating Panx1 activation. Electrophysiology and mutagenesis studies uncovered that two conserved …

Impact Of Site-Specific Conjugation Strategies On The Pharmacokinetics Of Antibody Conjugated Radiotherapeutics, Ábel Nagy, David Ulmert, Wahed Zedan, Claire M Storey, Julie Park, Susanne Geres, Katharina Lückerath, Kjell Sjöström, Hadis Westin, Norbert Peekhaus, Daniel Lj Thorek, Amelie Eriksson Karlström, Mohamed Altai

2020-Current year OA Pubs

Antibody radionuclide conjugates are an emerging modality for targeted imaging and potent therapy of disseminated disease. Coupling of radionuclides to monoclonal antibodies (mAbs) is typically achieved by applying non-site-specific labelling techniques. With the ambition of reducing variability, increasing labelling efficacy and stability, several site-specific conjugation strategies have been developed in recent years for toxin- and fluorophore-mAb conjugates. In this study, we studied two site-specific labelling strategies for the conjugation of the macrocyclic chelating agent, DOTA, to the anti-Leucine Rich Repeat Containing 15 (LRRC15) mAb DUNP19. Specifically, one approach utilized a DOTA-bearing peptide (FcIII) with a strong affinity for the fragment …

A Practical Clinical Approach To Navigate Pulmonary Embolism Management: A Primer And Narrative Review Of The Evolving Landscape, Kevin Benavente, Bradley Fujiuchi, Hafeez Ul Hassan Virk, Pavan K Kavali, Walter Ageno, Geoffrey D Barnes, Marc Righini, Mahboob Alam, Rachel P Rosovsky, Chayakrit Krittanawong

2020-Current year OA Pubs

Advances in imaging, pharmacological, and procedural technologies have rapidly expanded the care of pulmonary embolism. Earlier, more accurate identification and quantification has enhanced risk stratification across the spectrum of the disease process, with a number of clinical tools available to prognosticate outcomes and guide treatment. Direct oral anticoagulants have enabled a consistent and more convenient long-term therapeutic option, with a greater shift toward outpatient treatment for a select group of low-risk patients. The array of catheter-directed therapies now available has contributed to a more versatile and nuanced armamentarium of treatment options, including ultrasound-facilitated thrombolysis and mechanical thrombectomy. Research into supportive …

Transcriptomic Landscape Of Mammalian Ventral Pallidum At Single-Cell Resolution, Lite Yang, Lisa Z Fang, Michelle R Lynch, Chang S Xu, Hannah J Hahm, Yufen Zhang, Monique R Heitmeier, Vincent D Costa, Vijay K Samineni, Meaghan C Creed

2020-Current year OA Pubs

The ventral pallidum (VP) is critical for motivated behaviors. While contemporary work has begun to elucidate the functional diversity of VP neurons, the molecular heterogeneity underlying this functional diversity remains incompletely understood. We used single-nucleus RNA sequencing and in situ hybridization to define the transcriptional taxonomy of VP cell types in mice, macaques, and baboons. We found transcriptional conservation between all three species, within the broader neurochemical cell types. Unique dopaminoceptive and cholinergic subclusters were identified and conserved across both primate species but had no homolog in mice. This harmonized consensus VP cellular atlas will pave the way for understanding …

A Potent Pan-Sarbecovirus Neutralizing Antibody Resilient To Epitope Diversification, Laura E Rosen, Zhuoming Liu, Sean P J Whelan, Et Al.

2020-Current year OA Pubs

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has resulted in viral escape from clinically authorized monoclonal antibodies (mAbs), creating a need for mAbs that are resilient to epitope diversification. Broadly neutralizing coronavirus mAbs that are sufficiently potent for clinical development and retain activity despite viral evolution remain elusive. We identified a human mAb, designated VIR-7229, which targets the viral receptor-binding motif (RBM) with unprecedented cross-reactivity to all sarbecovirus clades, including non-ACE2-utilizing bat sarbecoviruses, while potently neutralizing SARS-CoV-2 variants since 2019, including the recent EG.5, BA.2.86, and JN.1. VIR-7229 tolerates extraordinary epitope variability, partly attributed to its high binding affinity, …

Out-Of-Focus Signal Rejection For In Vivo Po2 Measurements Using Two-Photon Phosphorescence Lifetime Microscopy, Qi Pian, Baoqiang Li, Ikbal Şencan-Eğilmez, Xiaojun Cheng, Jay Dubb, Xinyue Huang, Buyin Fu, Srinivasa Rao Allu, Mohammad Abbas Yaseen, Anna Devor, Sergei A Vinogradov, Sava Sakadžić

2020-Current year OA Pubs

Two-photon phosphorescence lifetime microscopy has been a key tool for studying cerebral oxygenation in mice. However, the accuracy of the partial pressure of oxygen (pO

Incidence, Healthcare And Out-Of-Pocket Costs, And Mortality Of Clostridioides Difficile Infection Among Us Adults Aged 18 To 64 Years, Holly Yu, Tamuno Alfred, Jingying Zhou, Jennifer Judy, Margaret A. Olsen

2020-Current year OA Pubs

No abstract provided.

Unraveling The Role Of Uils, A Urea-Induced Acyl-Homoserine Lactonase That Enhances Serratia Marcescens Fitness, Interbacterial Competition, And Urinary Tract Infection, Marisel R Tuttobene, Brayan S Arango Gil, Gisela Di Venanzio, Javier F Mariscotti, Rodrigo Sieira, Mario F Feldman, María Soledad Ramirez, Eleonora García Véscovi

2020-Current year OA Pubs

UNLABELLED:

IMPORTANCE: This work reveals the acyl-homoserine lactonase

Type I Interferon Signaling In Dendritic Cells Limits Direct Antigen Presentation And Cd8+ T Cell Responses Against An Arthritogenic Alphavirus, Christopher B Bullock, Leran Wang, Brian C Ware, Ngan Wagoner, Ray A Ohara, Tian-Tian Liu, Pritesh Desai, Bjoern Peters, Kenneth M Murphy, Scott A Handley, Thomas E Morrison, Michael S Diamond

2020-Current year OA Pubs

Ross River virus (RRV) and other alphaviruses cause chronic musculoskeletal syndromes that are associated with viral persistence, which suggests deficits in immune clearance mechanisms, including CD8

Effects Of Dietary Medium-Chain Triglyceride Supplementation On The Serum Metabolome Of Young Adult And Senior Canines, Yuanlong Pan, Miriam Sindelar, Ethan Stancliffe, Leah P Shriver, Rondo P Middleton, Gary J Patti

2020-Current year OA Pubs

In dogs, brain aging may lead to cognitive decline and cognitive dysfunction syndrome (CDS) [...].

A Trivalent Mucosal Vaccine Encoding Phylogenetically Inferred Ancestral Rbd Sequences Confers Pan-Sarbecovirus Protection In Mice, James Brett Case, Shilpa Sanapala, Suzanne M Scheaffer, Déborah Carolina Carvalho Dos Anjos, Lucas J Adams, Nadia Soudani, Chieh-Yu Liang, Baoling Ying, Adrianus C M Boon, Daved H Fremont, Sean P J Whelan, Michael S Diamond, Et Al.

2020-Current year OA Pubs

The continued emergence of SARS-CoV-2 variants and the threat of future Sarbecovirus zoonoses have spurred the design of vaccines that can induce broad immunity against multiple coronaviruses. Here, we use computational methods to infer ancestral phylogenetic reconstructions of receptor binding domain (RBD) sequences across multiple Sarbecovirus clades and incorporate them into a multivalent adenoviral-vectored vaccine. Mice immunized with this pan-Sarbecovirus vaccine are protected in the upper and lower respiratory tracts against infection by historical and contemporary SARS-CoV-2 variants, SARS-CoV, and pre-emergent SHC014 and Pangolin/GD coronavirus strains. Using genetic and immunological approaches, we demonstrate that vaccine-induced protection unexpectedly is conferred principally …

Type I Ifn-Mediated Net Release Promotes Mycobacterium Tuberculosis Replication And Is Associated With Granuloma Caseation, Chanchal Sur Chowdhury, Rachel L Kinsella, Michael E Mcnehlan, Sumanta K Naik, Daniel S Lane, Priyanka Talukdar, Asya Smirnov, Neha Dubey, Ananda N Rankin, Samuel R Mckee, Reilly Woodson, Abigail Hii, Sthefany M Chavez, Darren Kreamalmeyer, Wandy Beatty, Joshua T Mattila, Christina L Stallings

2020-Current year OA Pubs

Neutrophils are the most abundant cell type in the airways of tuberculosis patients. Mycobacterium tuberculosis (Mtb) infection induces the release of neutrophil extracellular traps (NETs); however, the molecular regulation and impact of NET release on Mtb pathogenesis are unknown. We find that during Mtb infection in neutrophils, PAD4 citrullinates histones to decondense chromatin that gets released as NETs in a manner that can maintain neutrophil viability and promote Mtb replication. Type I interferon promotes the formation of chromatin-containing vesicles that allow NET release without compromising plasma membrane integrity. Analysis of nonhuman primate granulomas supports a model where neutrophils are exposed …

Cellular Trafficking And Fate Mapping Of Cells Within The Nervous System After In Utero Hematopoietic Cell Transplantation, Matthew T Grant, Hemanth Ramesh Nelvagal, Maria Tecos, Amal Hamed, Kerry Swanson, Jonathan D Cooper, Jesse D Vrecenak

2020-Current year OA Pubs

In utero hematopoietic cell transplantation (IUHCT) utilizes fetal immune tolerance to achieve durable chimerism without conditioning or immunosuppression during a unique window in fetal development. Though donor cells have been observed within the nervous system following in utero injection, the timeline and distribution of cellular trafficking across the blood-brain barrier following IUHCT is not well understood. We injected 20 × 10

Alzheimer's Disease-Linked Risk Alleles Elevate Microglial Cgas-Associated Senescence And Neurodegeneration In A Tauopathy Model, Gillian K Carling, Xiaoying Chen, David M Holtzman, Et Al.

2020-Current year OA Pubs

The strongest risk factors for late-onset sporadic Alzheimer's disease (AD) include the ε4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2

Arousal Effects On Oscillatory Dynamics In The Non-Human Primate Brain, Shashank A Anand, Fatih Sogukpinar, Ilya E Monosov

2020-Current year OA Pubs

Arousal states are thought to influence many aspects of cognition and behavior by broadly modulating neural activity. Many studies have observed arousal-related modulations of alpha (~8 to 15 Hz) and gamma (~30 to 50 Hz) power and coherence in local field potentials across relatively small groups of brain regions. However, the global pattern of arousal-related oscillatory modulation in local field potentials is yet to be fully elucidated. We simultaneously recorded local field potentials in numerous cortical and subcortical regions in the primate brain and assessed oscillatory activity and inter-regional coherence associated with arousal state. In high arousal states, we found …

Redesigning The Hospital Environment To Improve Restfulness, Caellagh D Catley, Kayla Paynter, Kendall Jackson, Ashley Huggins, Jenny Ji, Sai Anusha Sanka, Michelle Simkins, Thomas M Maddox, Patrick G Lyons

2020-Current year OA Pubs

IMPORTANCE: Hospital wards are often not conducive to patient sleep, negatively affecting patient health and experience.

OBJECTIVES: To assess determinants of in-hospital restfulness and to design and test rest-promoting interventions on the wards in partnership with clinicians, staff, and patients.

DESIGN, SETTING, AND PARTICIPANTS: This rapid-sequential mixed-methods quality improvement study was performed at a large urban academic hospital in St Louis, Missouri, from May 1, 2021, to December 31, 2022, with follow-up through hospitalization. Mixed-methods activities involved purposively selected hospitalized adults on the wards, nurses, hospitalists, and hospital staff. Interventions included all adult hospitalizations on the study wards.

INTERVENTIONS: Sequential …

Heterozygous Btnl8 Variants In Individuals With Multisystem Inflammatory Syndrome In Children (Mis-C), Evangelos Bellos, Erica G Schmitt, Et Al.

2020-Current year OA Pubs

Multisystem inflammatory syndrome in children (MIS-C) is a rare condition following SARS-CoV-2 infection associated with intestinal manifestations. Genetic predisposition, including inborn errors of the OAS-RNAseL pathway, has been reported. We sequenced 154 MIS-C patients and utilized a novel statistical framework of gene burden analysis, "burdenMC," which identified an enrichment for rare predicted-deleterious variants in BTNL8 (OR = 4.2, 95% CI: 3.5-5.3, P < 10-6). BTNL8 encodes an intestinal epithelial regulator of Vγ4+γδ T cells implicated in regulating gut homeostasis. Enrichment was exclusive to MIS-C, being absent in patients with COVID-19 or bacterial disease. Using an available functional test for BTNL8, rare variants from a larger cohort of MIS-C patients (n = 835) were tested which identified eight variants in 18 patients (2.2%) with impaired engagement of Vγ4+γδ T cells. Most of these variants were in the B30.2 domain of BTNL8 implicated in sensing epithelial cell status. These findings were associated with altered intestinal permeability, suggesting a possible link between disrupted gut homeostasis and MIS-C-associated enteropathy triggered by SARS-CoV-2.

Vps13b Is Localized At The Interface Between Golgi Cisternae And Is A Functional Partner Of Fam177a1, Berrak Ugur, Florian Schueder, Jimann Shin, Michael G Hanna, Yumei Wu, Marianna Leonzino, Maohan Su, Anthony R Mcadow, Catherine Wilson, John Postlethwait, Lilianna Solnica-Krezel, Joerg Bewersdorf, Pietro De Camilli

2020-Current year OA Pubs

Mutations in VPS13B, a member of a protein family implicated in bulk lipid transport between adjacent membranes, cause Cohen syndrome. VPS13B is known to be concentrated in the Golgi complex, but its precise location within this organelle and thus the site(s) where it achieves lipid transport remains unclear. Here, we show that VPS13B is localized at the interface between proximal and distal Golgi subcompartments and that Golgi complex reformation after Brefeldin A (BFA)-induced disruption is delayed in VPS13B KO cells. This delay is phenocopied by the loss of FAM177A1, a Golgi complex protein of unknown function reported to be a …

Functional Role Of Myosin-Binding Protein H In Thick Filaments Of Developing Vertebrate Fast-Twitch Skeletal Muscle, Andrew F Mead, Marilyn J Cipolla, Aaron N Johnson, Christina A Gurnett, Et Al.

2020-Current year OA Pubs

Myosin-binding protein H (MyBP-H) is a component of the vertebrate skeletal muscle sarcomere with sequence and domain homology to myosin-binding protein C (MyBP-C). Whereas skeletal muscle isoforms of MyBP-C (fMyBP-C, sMyBP-C) modulate muscle contractility via interactions with actin thin filaments and myosin motors within the muscle sarcomere "C-zone," MyBP-H has no known function. This is in part due to MyBP-H having limited expression in adult fast-twitch muscle and no known involvement in muscle disease. Quantitative proteomics reported here reveal that MyBP-H is highly expressed in prenatal rat fast-twitch muscles and larval zebrafish, suggesting a conserved role in muscle development and …

Major Depressive Disorder And Driving Behavior Among Older Adults, Ganesh M Babulal, Ling Chen, Jean-Francois Trani, David C Brown, David B Carr, Beau M Ances, Eric J Lenze, Drives Project

2020-Current year OA Pubs

IMPORTANCE: Depression and antidepressant use are independently associated with crash risk among older drivers. However, it is unclear what factors impact daily driving that increase safety risk for drivers with depression.

OBJECTIVE: To examine differences in naturalistic driving behavior and safety between older adults with and without major depressive disorder (MDD).

DESIGN, SETTING, AND PARTICIPANTS: A prospective longitudinal cohort study was conducted among older adults (≥65 years) from the Driving Real-World In-Vehicle Evaluation System Project collected from July 1, 2021, to December 30, 2023. The sample included 85 participants with MDD and 310 participants without. Neurological, clinical, mood, and neuropsychological …

Molecular Imaging In Experimental Pulmonary Fibrosis Reveals That Nintedanib Unexpectedly Modulates Ccr2 Immune Cell Infiltration, Hasan Farooq, Hannah P Luehmann, Jeffrey R Koenitzer, Gyu Seong Heo, Deborah H Sultan, Devesha H Kulkarni, Sean P Gunsten, Rekha M Sashti, Tao Huang, Amanda R Keller, Kory J Lavine, Jeffrey J Atkinson, Laura M Wingler, Yongjian Liu, Steven L Brody

2020-Current year OA Pubs

BACKGROUND: Pulmonary fibrosis is a challenging clinical problem with lung pathology featuring immune cell infiltrates, fibroblast expansion, and matrix deposition. Molecular analysis of diseased lungs and preclinical models have uncovered C-C chemokine receptor type 2 (CCR2)+ monocyte egress from the bone marrow into the lung, where they acquire profibrotic activities. Current drug treatment is focused on fibroblast activity. Alternatively, therapeutic targeting and monitoring CCR2+ cells may be an effective patient management strategy.

METHODS: Inhibition of CCR2+ cells and, as a benchmark, the clinical antifibrotic agent, nintedanib, were used in mouse lung fibrosis models. Lungs were evaluated directly for CCR2+ cell …

Development And Validation Of A Prechiasmatic Mouse Model Of Subarachnoid Hemorrhage To Measure Long-Term Cognitive Deficits, Deepti Diwan, Jogender Mehla, James W Nelson, James D Quirk, Sheng-Kwei Song, Sarah Cao, Benjamin Meron, Aminah Mostofa, Gregory J Zipfel

2020-Current year OA Pubs

Controllable and reproducible animal models of aneurysmal subarachnoid hemorrhage (SAH) are crucial for the systematic study of the pathophysiology and treatment of this debilitating condition. However, current animal models have not been successful in replicating the pathology and disabilities seen in SAH patients, especially the long-term neurocognitive deficits that affect the survivor's quality of life. Therefore, there is an unmet need to develop experimental models that reliably replicate the long-term clinical ramifications of SAH - especially in mice where genetic manipulations are straightforward and readily available. To address this need, a standardized mouse SAH model is developed that reproducibly produced …

Fibrolytic Vaccination Against Adam12 Reduces Desmoplasia In Preclinical Pancreatic Adenocarcinomas, Jing Chen, David Denardo, Et Al.

2020-Current year OA Pubs

A hallmark feature of pancreatic ductal adenocarcinoma (PDAC) is massive intratumoral fibrosis, designated as desmoplasia. Desmoplasia is characterized by the expansion of cancer-associated fibroblasts (CAFs) and a massive increase in extracellular matrix (ECM). During fibrogenesis, distinct genes become reactivated specifically in fibroblasts, e.g., the disintegrin metalloprotease, ADAM12. Previous studies have shown that immunotherapeutic ablation of ADAM12

Tyk2 Regulates Tau Levels, Phosphorylation And Aggregation In A Tauopathy Mouse Model, Jiyoen Kim, Bakhos Tadros, Yan Hong Liang, Youngdoo Kim, Cristian Lasagna-Reeves, Jun Young Sonn, Dah-Eun Chloe Chung, Bradley Hyman, David M Holtzman, Huda Yahya Zoghbi

2020-Current year OA Pubs

Alzheimer's disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau. We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau …

Emergent Microenvironments Of Nucleoli, Matthew R King, Kiersten M Ruff, Rohit V Pappu

2020-Current year OA Pubs

In higher eukaryotes, the nucleolus harbors at least three sub-phases that facilitate multiple functionalities including ribosome biogenesis. The three prominent coexisting sub-phases are the fibrillar center (FC), the dense fibrillar component (DFC), and the granular component (GC). Here, we review recent efforts in profiling sub-phase compositions that shed light on the types of physicochemical properties that emerge from compositional biases and territorial organization of specific types of macromolecules. We highlight roles played by molecular grammars which refers to protein sequence features including the substrate binding domains, the sequence features of intrinsically disordered regions, and the multivalence of these distinct types …

Pathogenicity And Virulence Of Human Respiratory Syncytial Virus: Multifunctional Nonstructural Proteins Ns1 And Ns2, Trudy N Merritt, Jingjing Pei, Daisy W Leung

2020-Current year OA Pubs

Human respiratory syncytial virus (hRSV) is a major cause of lower respiratory tract infections in young children, the elderly, and immunocompromised. Despite its discovery over 60 years ago and the global impact on human health, limited effective prophylactic or therapeutic options have been available for hRSV infections. This has largely been attributed to the legacy of vaccine failure in the 1960s using a formalin-inactivated RSV , which led to enhancement of disease post exposure to hRSV infection and hampered subsequent development of vaccine candidates. Recent FDA approval of vaccines for older adults and pregnant individuals are major advancements but leaves …

The Sodium-Proton Exchangers Snhe And Nhe1 Control Plasma Membrane Hyperpolarization In Mouse Sperm, Analia G Novero, Celia M Santi, Et Al.

2020-Current year OA Pubs

Sperm capacitation is a complex process that takes place in the female reproductive tract and empowers mammalian sperm with the competence to fertilize an egg. It consists of an intricate cascade of events that can be mimicked in vitro through incubation in a medium containing essential components, such as bicarbonate, albumin, Ca

Cxcr3-Cxcl11 Signaling Restricts Angiogenesis And Promotes Pericyte Recruitment, Jihui Lee, Megan E. Goeckel, Allison Levitas, Sarah Colijn, Jimann Shin, Anna Hindes, Geonyoung Mun, Zarek Burton, Bharadwaj Chintalapati, Ying Yin, Javier Abello, Lilianna Solnica-Krezel, Amber N. Stratman

2020-Current year OA Pubs

BACKGROUND: Endothelial cell (EC)-pericyte interactions are known to remodel in response to hemodynamic forces; yet there is a lack of mechanistic understanding of the signaling pathways that underlie these events. Here, we have identified a novel signaling network regulated by blood flow in ECs-the chemokine receptor CXCR3 (CXC motif chemokine receptor 3) and one of its ligands, CXCL11 (CXC motif chemokine ligand 11)-that delimits EC angiogenic potential and promotes pericyte recruitment to ECs during development.

METHODS: We investigated the role of CXCR3 on vascular development using both 2- and 3-dimensional in vitro assays, to study EC-pericyte interactions and EC behavioral …

2024 European Heart Rhythm Association/Heart Rhythm Society/Asia Pacific Heart Rhythm Society/Latin American Heart Rhythm Society Expert Consensus Statement On Catheter And Surgical Ablation Of Atrial Fibrillation, Stylianos Tzeis, Ralph J Damiano, Et Al.

2020-Current year OA Pubs

In the last three decades, ablation of atrial fibrillation (AF) has become an evidence-based safe and efficacious treatment for managing the most common cardiac arrhythmia. In 2007, the first joint expert consensus document was issued, guiding healthcare professionals involved in catheter or surgical AF ablation. Mounting research evidence and technological advances have resulted in a rapidly changing landscape in the field of catheter and surgical AF ablation, thus stressing the need for regularly updated versions of this partnership which were issued in 2012 and 2017. Seven years after the last consensus, an updated document was considered necessary to define a …