Synthesis and Photophysical Evaluation of 3,3’‐Nitrogen Bis‐Substituted <i>fac</i>‐[Re(CO)₃(Diimine)Br] Complexes

The preparations, photophysical and electrochemical properties of a series of fac‐[Re(CO)$_{3}$(diimine)Br] complexes are presented. The bipyridine (bpy) based diimine ligands feature symmetrical and asymmetrical 3,3’‐diamino‐2,2’‐bipyridine substitution patterns. Photophysical and electrochemical properties of these complexes are tunable, depending on their organic diimine framework. Introduction of a distal urea bridge via the 3,3’‐substitution pattern led to prolonged phosphorescence lifetimes without a significant change in absorbance and phosphorescence emission wavelengths. Reversible electrochemical bipyridine reduction remained largely unchanged by this derivatization

Informed consent in critically ill adults participating to a randomized trial.

The 2014 update of the Swiss law on research increases patients' protection; it adds specific requirements for emergency situations, implying an active search for patients' wishes regarding research participation; the possibility of consent waivers is not clearly stated. We explored its practical impact in a RCT on critically ill adults. We considered prospectively collected consents of a multicenter trial addressing the impact of continuous EEG on survival. We assessed the proportions of consents obtained strictly according to the law, of specific waivers for this study obtained from the IRB (early death; relatives' unavailability despite repeated attempts), and the yield of retrieving statements on willingness to research participation. We compared the proportion of consent refusals with those of recent trials in similar environments, and estimated the potential impact on study results. Of 402 recruited patients, six had double inclusions, one died before intervention, and 27 (6.7%, alive on long-term) were excluded following consent refusal or withdrawal, leaving 368 analyzable patients. Specific waivers allowed inclusion of 134 (36.4%) patients, while informed consents were obtained for all others. A statement of willingness to research participation was found in only 14.1%. In recent trials, consent refusal oscillated between 0%-23%, according to different waiver policies. Consent waivers should be specifically foreseen to prevent losing a potentially relevant proportion of patients reaching endpoints, and ensure results generalizability. The yield of looking for willingness to research participation seems low; this questions its current usefulness and calls for a public awareness campaign

Safety and immunogenicity of a synthetic nanoparticle-based, T cell priming peptide vaccine against dengue in healthy adults in Switzerland: a double-blind, randomized, vehicle-controlled, phase 1 study.

Vaccines that minimize the risk of vaccine-induced antibody-dependent enhancement and severe dengue are needed to address the global health threat posed by dengue. This study assessed the safety and immunogenicity of a gold nanoparticle (GNP)-based, multi-valent, synthetic peptide dengue vaccine candidate (PepGNP-Dengue), designed to provide protective CD8+ T cell immunity, without inducing antibodies. In this randomized, double-blind, vehicle-controlled, phase 1 trial (NCT04935801), healthy naïve individuals aged 18-45 years recruited at the Centre for primary care and public health, Lausanne, Switzerland, were randomly assigned to receive PepGNP-Dengue or comparator (GNP without peptides [vehicle-GNP]). Randomization was stratified into four groups (low dose [LD] and high dose [HD]), allocation was double-blind from participants and investigators. Two doses were administered by intradermal microneedle injection 21 days apart. Primary outcome was safety, secondary outcome immunogenicity. Analysis was by intention-to-treat for safety, intention-to-treat and per protocol for immunogenicity. 26 participants were enrolled (August-September 2021) to receive PepGNP-Dengue (LD or HD, n = 10 each) or vehicle-GNP (LD or HD, n = 3 each). No vaccine-related serious adverse events occurred. Most (90%) related adverse events were mild; injection site pain and transient discoloration were most frequently reported. Injection site erythema occurred in 58% of participants. As expected, PepGNP-Dengue did not elicit anti-DENV antibodies of significance. Significant increases were observed in specific CD8+ T cells and dengue dextramer+ memory cell subsets in the LD PepGNP-Dengue but not in the HD PepGNP-Dengue or vehicle-GNP groups, specifically PepGNP-activated CD137+CD69+CD8+ T cells (day 90, +0.0318%, 95% CI: 0.0088-0.1723, p = 0.046), differentiated effector memory (TemRA) and central memory (Tcm) CD8+ T cells (day 35, +0.8/10 &lt;sup&gt;5&lt;/sup&gt; CD8+, 95% CI: 0.19-5.13, p = 0.014 and +1.34/10 &lt;sup&gt;5&lt;/sup&gt; CD8+, 95% CI: 0.1-7.34, p = 0.024, respectively). Results provide proof of concept that a synthetic nanoparticle-based peptide vaccine can successfully induce virus-specific CD8+ T cells. The favourable safety profile and cellular responses observed support further development of PepGNP-Dengue. Emergex Vaccines Holding Limited

Pervasive carbonation of peridotite to listvenite (Semail Ophiolite, Sultanate of Oman): clues from iron partitioning and chemical zoning

Earth's long-term cycling of carbon is regulated from mid-ocean ridges to convergent plate boundaries by mass transfers involving mantle rocks. Here we examine the conversion of peridotite to listvenite (magnesite + quartz rock) during CO2 metasomatism along the basal thrust of the Semail Ophiolite (Fanja, Sultanate of Oman). At the outcrop scale, this transformation defines reaction zones, from serpentinized peridotites to carbonated serpentinites and listvenites. Based on a detailed petrological and chemical study, we show that carbonation progressed through three main stages involving the development of replacive textures ascribed to early stages, whilst carbonate (± quartz) veining becomes predominant in the last stage. The pervasive replacement of serpentine by magnesite is characterized by the formation of spheroids, among which two types are identified based on the composition of their core regions: Fe-core and Mg-core spheroids. Fe zoning is a type feature of matrix and vein magnesite formed during the onset carbonation (Stage 1). While Fe-rich magnesite is predicted to form at low fluid XCO2 from a poorly to moderately oxidized protolith, our study evidences that the local non-redox destabilization of Fe oxides into Fe-rich magnesite is essential to the development of Fe-core spheroids. The formation of Fe-core spheroids is followed by the pervasive (over-)growth of Mg-rich spheroids and aggregates (Stage 2) at near-equilibrium conditions in response to increasing fluid XCO2. Furthermore, the compositions of carbonates indicate that most siderophile transition elements released by the dissolution of primary minerals are locally trapped in carbonate and oxides during matrix carbonation, while elements with a chalcophile affinity are the most likely to be leached out of reaction zones.</p

Safety and immunogenicity of a chimpanzee adenovirus-vectored Ebola vaccine in healthy adults: a randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a study.

BACKGROUND: The ongoing Ebola outbreak led to accelerated efforts to test vaccine candidates. On the basis of a request by WHO, we aimed to assess the safety and immunogenicity of the monovalent, recombinant, chimpanzee adenovirus type-3 vector-based Ebola Zaire vaccine (ChAd3-EBO-Z). METHODS: We did this randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a trial at the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. Participants (aged 18-65 years) were randomly assigned (2:2:1), via two computer-generated randomisation lists for individuals potentially deployed in endemic areas and those not deployed, to receive a single intramuscular dose of high-dose vaccine (5 × 10(10) viral particles), low-dose vaccine (2·5 × 10(10) viral particles), or placebo. Deployed participants were allocated to only the vaccine groups. Group allocation was concealed from non-deployed participants, investigators, and outcome assessors. The safety evaluation was not masked for potentially deployed participants, who were therefore not included in the safety analysis for comparison between the vaccine doses and placebo, but were pooled with the non-deployed group to compare immunogenicity. The main objectives were safety and immunogenicity of ChAd3-EBO-Z. We did analysis by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02289027. FINDINGS: Between Oct 24, 2014, and June 22, 2015, we randomly assigned 120 participants, of whom 18 (15%) were potentially deployed and 102 (85%) were non-deployed, to receive high-dose vaccine (n=49), low-dose vaccine (n=51), or placebo (n=20). Participants were followed up for 6 months. No vaccine-related serious adverse events were reported. We recorded local adverse events in 30 (75%) of 40 participants in the high-dose group, 33 (79%) of 42 participants in the low-dose group, and five (25%) of 20 participants in the placebo group. Fatigue or malaise was the most common systemic adverse event, reported in 25 (62%) participants in the high-dose group, 25 (60%) participants in the low-dose group, and five (25%) participants in the placebo group, followed by headache, reported in 23 (57%), 25 (60%), and three (15%) participants, respectively. Fever occurred 24 h after injection in 12 (30%) participants in the high-dose group and 11 (26%) participants in the low-dose group versus one (5%) participant in the placebo group. Geometric mean concentrations of IgG antibodies against Ebola glycoprotein peaked on day 28 at 51 μg/mL (95% CI 41·1-63·3) in the high-dose group, 44·9 μg/mL (25·8-56·3) in the low-dose group, and 5·2 μg/mL (3·5-7·6) in the placebo group, with respective response rates of 96% (95% CI 85·7-99·5), 96% (86·5-99·5), and 5% (0·1-24·9). Geometric mean concentrations decreased by day 180 to 25·5 μg/mL (95% CI 20·6-31·5) in the high-dose group, 22·1 μg/mL (19·3-28·6) in the low-dose group, and 3·2 μg/mL (2·4-4·9) in the placebo group. 28 (57%) participants given high-dose vaccine and 31 (61%) participants given low-dose vaccine developed glycoprotein-specific CD4 cell responses, and 33 (67%) and 35 (69%), respectively, developed CD8 responses. INTERPRETATION: ChAd3-EBO-Z was safe and well tolerated, although mild to moderate systemic adverse events were common. A single dose was immunogenic in almost all vaccine recipients. Antibody responses were still significantly present at 6 months. There was no significant difference between doses for safety and immunogenicity outcomes. This acceptable safety profile provides a reliable basis to proceed with phase 2 and phase 3 efficacy trials in Africa. FUNDING: Swiss State Secretariat for Education, Research and Innovation (SERI), through the EU Horizon 2020 Research and Innovation Programme

Intravaginal and subcutaneous immunization induced vaccine specific CD8 T cells and tumor regression in the bladder.

PURPOSE: Vaccines targeting tumor associated antigens are in development for bladder cancer. Most of these cancers are nonmuscle invasive at diagnosis and confined in the mucosa and submucosa. However, to our knowledge how vaccination may induce the regression of tumors at such mucosal sites has not been examined previously. We compared different immunization routes for the ability to induce vaccine specific antitumor CD8 T cells in the bladder and bladder tumor regression in mice. MATERIALS AND METHODS: In the absence of a murine bladder tumor model expressing a tumor antigen relevant for human use we established an orthotopic model expressing the HPV-16 tumor antigen E7 as a model. We used an adjuvant E7 polypeptide to induce CD8 T cell mediated tumor regression. RESULTS: Subcutaneous and intravaginal but not intranasal vaccination induced a high number of TetE7(+)CD8(+) T cells in the bladder as well as bladder tumor regression. The entry of vaccine specific T cells in the bladder was not the only key since persistent regression of established bladder tumors by intravaginal or subcutaneous immunization was associated with tumor infiltration of total CD4 and CD8 T cells. This resulted in an increase in TetE7(+)CD8(+) T cells and a decrease in T regulatory cells, leading to an increased number of effector interferon-γ secreting vaccine specific CD8 T cells in the regressing bladder tumor. CONCLUSIONS: These data show that immunization routes should be tailored to each mucosal tumor site. Subcutaneous or intravaginal vaccination may be of additional value to treat patients with bladder cancer

Etude des séries de listvénites au chevauchement basal de l'Ophiolite de Semail : compréhension du métasomatisme lié aux circulations de fluides riches en CO2 et des processus de carbonatation des péridotites

Mantle rocks exposed to subsurface conditions or hydrothermal fluids react in response to disequilibrium. In nature serpentinization and carbonation are the two prevalent fluid-rock reactions affecting mantle rocks. Listvenites form by the complete conversion of peridotites into Mg-carbonates-quartz rocks by interaction with reactive CO2-bearing fluids. The geochemical and mineralogical complexity of listvenites led to the establishment of different genetic models, however the processes and conditions favouring listvenite formation are poorly documented. Our study focusses on listvenite exposures along the base of the Semail ophiolite mantle in Oman, which have been the focus of drilling Oman Drilling Project Hole BT1B.The present PhD thesis benefited from high-resolution core sampling from Hole BT1B, further complemented by regional sampling. Aiming to better understand the processes of peridotite carbonation, our study combines a multi-scale and multi-technique approach including: fieldwork, microstructural characterization (optical and scanning electron microscopy, Raman spectroscopy, EBSD), whole rock (XRF, ICP-QMS) and mineral geochemistry (EPMA, LA-ICPMS), and isotopic studies (bulk C-Fe-Zn isotopes, C-O isotopes on carbonates).In the Fanja region, listvenites occur as kilometre-scale tabular sheets or smaller lenses interlayering the ophiolite mantle close to or along the basal thrust of the ophiolite. On field, peridotite carbonation defined reactions fronts from serpentinized peridotites, to intensively foliated and carbonated serpentinites at the transition with listvenite. The mantle section mainly consists of (Cpx-)harzburgites, lherzolites and rare dunites. Protoliths show selective enrichments in fluid-mobile Li, Rb, Sr, Cs, Ba and Pb. This compositional signature is typical of basal peridotites in Oman. Peridotite carbonation proceeded by the infiltration of fluids rich in As, Sr, Sb, Ba and Pb, as evidenced by bulk rock and mineral trace element compositions. Spatial disparity in the occurrence of magnesite-rich and dolomite-rich listvenites suggests their formation during different metasomatic events and/or from multiple sources of fluids.The petrological study of carbonated serpentinites and listvenites indicate that serpentinization underwent completion prior to the onset of carbonation. Carbonation progressed through distinctive stages of pervasive rock matrix replacement and veining. Incipient carbonation is texturally ascribed to pseudomorphic replacement of serpentine veins and the generation of antitaxial carbonate veins. The onset of pervasive carbonation is characterized by the formation of chemically zoned Fe-rich magnesite spheroids and aggregates in the vicinity of antitaxial Fe-rich magnesite veins. This transient stage was followed by extended matrix replacement by Mg-rich magnesite, prior to silicification of the remaining background serpentine. Variations in magnesite compositions indicate changes in fluid compositions, redox conditions and/or fluid access during carbonation.The bulk carbon isotopes compositions of carbonated peridotites in Hole BT1B indicate a strong inorganic component in reactive fluids. This is compatible with fluids sourced from the devolatilzation of clastic sediments underlying the ophiolite triggered by burial during regional convergence. The distribution of oxygen isotope signatures of carbonates across the well suggest carbonation at low temperature (<200 °C) by infiltration of repeated fluid batches at different structural levels over time. The bulk iron and zinc isotope compositions of BT1B listvenites series are among the most variable for mantle rocks considering a single lithological suite. Fe isotopes compositions remained relatively unaffected during successive serpentinization and carbonation. In contrast, a clear correlation between δ13CTC and δ66Zn indicate the preferential mobility and transport of Zn in reactive fluids.La serpentinisation et la carbonatation sont les deux réactions métasomatiques les plus fréquentes affectant les roches du manteau. Les listvénites résultent de l’interaction entre les péridotites et des fluides riches en CO2, pour former des roches à carbonates magnésiens et quartz. Différents modèles pétrogénétiques ont été établis pour expliquer leur complexité géochimique et minéralogique. Cependant, les processus et conditions favorisant leur formation sont peu documentés. Notre étude a été menée sur des listvénites affleurant le long de la base du manteau ophiolitique de Semail en Oman, qui a fait l'objet du forage du puits BT1B dans le cadre du projet Oman Drilling Project.Cette thèse a bénéficié d'un échantillonnage exhaustif de carottes provenant du puits, complété par un échantillonnage régional. Dans le but de mieux comprendre les processus de carbonatation des péridotites, notre étude a combiné une approche multi-échelle et multi-technique incluant : du travail de terrain, une caractérisation microstructurale des échantillons (SEM, Raman, EBSD), des analyses géochimiques en roche totale (XRF, ICP-QMS) et sur minéral (EPMA, LA-ICPMS), ainsi que des études isotopiques (isotopie du C-Fe-Zn en roche totale, isotopie du C-O sur carbonates).Dans la région de Fanja, les listvénites forment des corps tabulaires, kilométriques, ou de lentilles plus petites intercalant le manteau ophiolitique à proximité ou le long du chevauchement basal. La carbonatation des péridotites définit des fronts réactionnels à partir de péridotites serpentinisées et fracturées, pour des serpentinites intensément foliées et carbonatées à la transition avec les listvénites. La section du manteau étudiée est principalement constituée de (Cpx-)harzburgites, de lherzolites et de rares dunites. Les protolithes montrent des enrichissements en éléments mobiles dans les fluides (Li, Rb, Sr, Cs, Ba et Pb). Ces signatures sont typiques des péridotites basales en Oman. La carbonatation des péridotites s’est effectuée par infiltration de fluides riches en As, Sr, Sb, Ba et Pb. La disparité spatiale entre des listvénites riches en magnésite et en dolomite suggère que leur formation s’est déroulée lors de différents événements métasomatiques, et/ou la présence de sources de fluides multiples.L’étude pétrologique des péridotites carbonatées révèle une complète serpentinisation avant l’initiation de la carbonatation. Celle-ci s’est déroulée en étapes distinctes, initiée par le remplacement statique de veines de serpentine par des carbonates et par la génération de veines antitaxiales de carbonates. La carbonatation diffuse est caractérisée par la formation précoce de sphéroïdes et d'agrégats de magnésites riches en fer, à proximité de veines de magnésite antitaxiales riches en fer. Cette étape transitoire a été suivie par un remplacement plus étendu de la matrice par des magnésites riches en Mg, avant la silicification de la serpentine résiduelle. Les variations compositionnelles des magnésites témoignent d’un changement dans la composition des fluides, dans les conditions redox et/ou de l’accessibilité des fluides au cours de la carbonatation.L’isotopie en carbone des péridotites carbonatées révèle une composante inorganique prédominante dans les fluides, cohérente la dévolatilisation de sédiments clastiques lors de leur enfouissement en contexte de convergence. La distribution le long du puits des signatures isotopiques en oxygène des carbonates suggère une carbonatation à basse température (<200 ° C) par infiltration répétée de fluides à différents niveaux structurels au fil du temps. L’isotopie du fer et du zinc des listvénites sont parmi les plus variables pour des péridotites. Alors que les compositions isotopiques du Fe sont restées inchangées au cours de la serpentinisation et de la carbonatation, une corrélation entre les compositions en δ13CTC et δ66Zn indique la mobilité et le transport préférentiels du Zn dans les fluides réactifs