Optical coherence and spin population dynamics in 171^{171}Yb3+^{3+}:Y2_2SiO5_5 single crystals

$^{171}$Yb$^{3+}$-doped Y$_2$SiO$_5$ crystals are a promising platform for optical quantum memories in long-distance quantum communications. The relevance of this material lies in $^{171}$Yb long optical and spin coherence times, along with a large hyperfine splitting, enabling long quantum storage over large bandwidths. Mechanisms affecting the optical decoherence are however not precisely known, especially since low-temperature measurements have so far focused on the 2 to 4 K range. In this work, we performed two- and three-pulse photon echoes and spectral hole burning to determine optical homogeneous linewidths in two 171 Yb:YSO crystals doped at 2 and 10 ppm. Experiments were performed in the 40 mK to 18 K temperature range, leading to linewidths between 320 Hz, among the narrowest reported for rare-earth ions, and several MHz. Our results show that above 6 K the homogeneous linewidth is mainly due to an elastic two-phonon process which results in a slow broadening with temperature, the homogeneous linewidth reaching only 25 kHz at 10 K. At lower temperatures, interactions with $^{89}$Yb nuclear spin-flips, paramagnetic defects or impurities, and also Yb-Yb interactions for the higher concentrated crystal, are likely the main limiting factor to the homogeneous linewidth. In particular, we conclude that the direct effect of spin and optical excited state lifetime is a minor contribution to optical decoherence in the whole temperature range studied. Our results indicate possible paths and regimes for further decreasing the homogeneous linewidths or maintaining narrow lines at higher $^{171}$Yb concentration.Comment: 11 pages, 7 figure for the manuscrip

Patterning of educational attainment across inflammatory markers : Findings from a multi-cohort study

Background: Evidence suggests that the inflammatory reaction, an adaptive response triggered by a variety of harmful stimuli and conditions involved in the risk and development of many chronic diseases, is a potential pathway through which the socioeconomic environment is biologically embedded. Difficulty in interpreting the role of the inflammatory system in the embodiment dynamic arises because of heterogeneity across studies that use a limited but varied number of inflammatory markers. There is no consensus in the literature as to which inflammatory markers beyond the C-reactive protein and to a lesser extent interleukin 6 are related to the social environment. Accordingly, we aimed to investigate the association between educational attainment, and several markers of inflammation - C-reactive protein, fibrinogen, interleukin 6, interleukin 1 beta and tumor necrosis factor alpha- in 6 European cohort studies. Methods: Up to 17,470 participants from six European cohort studies with data on educational attainment, health behaviors and lifestyle factors, and at least two different inflammatory markers. Four sub-datasets were drawn with varying numbers of participants to allow pairwise comparison of the social patterning of C-reactive protein and any other inflammatory markers. To evaluate within each sub-dataset the importance of the context and cohort specificities, linear regression-based analyses were performed separately for each cohort and combined in a random effect meta-analysis to determine the relationship between educational attainment and inflammation. Results: We found that the magnitude of the relationship between educational attainment and five inflammatory biomarkers (C-reactive protein, fibrinogen, interleukin 6 and 1 beta and tumor necrosis factor alpha) was variable. By far the most socially patterned biomarker was C-reactive protein, followed by fibrinogen and to lesser extent interleukin 6, where a low educational attainment was associated with higher inflammation even after adjusting for health behaviours and body mass index. No association was found with interleukin 1 beta and tumor necrosis factor alpha. Conclusions: Our study suggests different educational patterning of inflammatory biomarkers. Further large-scale research is needed to explore social differences in the inflammatory cascade in greater detail and the extent to which these differences contribute to social inequalities in health.Peer reviewe

Multi-cohort study identifies social determinants of systemic inflammation over the life course

Chronic inflammation has been proposed as having a prominent role in the construction of social inequalities in health. Disentangling the effects of early life and adulthood social disadvantage on inflammation is key in elucidating biological mechanisms underlying socioeconomic disparities. Here we explore the relationship between socioeconomic position (SEP) across the life course and inflammation (as measured by CRP levels) in up to 23,008 participants from six European cohort studies from three countries conducted between 1958 and 2013. We find a consistent inverse association between SEP and CRP across cohorts, where participants with a less advantaged SEP have higher levels of inflammation. Educational attainment is most strongly related to inflammation, after adjusting for health behaviours, body mass index and later-in-life SEP. These findings suggest socioeconomic disadvantage in young adulthood is independently associated with later life inflammation calling for further studies of the pathways operating through educational processes.Peer reviewe

RNA reference materials with defined viral RNA loads of SARS-CoV-2—A useful tool towards a better PCR assay harmonization

SARS-CoV-2, the cause of COVID-19, requires reliable diagnostic methods to track the circulation of this virus. Following the development of RT-qPCR methods to meet this diagnostic need in January 2020, it became clear from interlaboratory studies that the reported Ct values obtained for the different laboratories showed high variability. Despite this the Ct values were explored as a quantitative cut off to aid clinical decisions based on viral load. Consequently, there was a need to introduce standards to support estimation of SARS-CoV-2 viral load in diagnostic specimens. In a collaborative study, INSTAND established two reference materials (RMs) containing heat-inactivated SARS-CoV-2 with SARS-CoV-2 RNA loads of ~107 copies/mL (RM 1) and ~106 copies/mL (RM 2), respectively. Quantification was performed by RT-qPCR using synthetic SARS-CoV-2 RNA standards and digital PCR. Between November 2020 and February 2021, German laboratories were invited to use the two RMs to anchor their Ct values measured in routine diagnostic specimens, with the Ct values of the two RMs. A total of 305 laboratories in Germany were supplied with RM 1 and RM 2. The laboratories were requested to report their measured Ct values together with details on the PCR method they used to INSTAND. This resultant 1,109 data sets were differentiated by test system and targeted gene region. Our findings demonstrate that an indispensable prerequisite for linking Ct values to SARS-CoV-2 viral loads is that they are treated as being unique to an individual laboratory. For this reason, clinical guidance based on viral loads should not cite Ct values. The RMs described were a suitable tool to determine the specific laboratory Ct for a given viral load. Furthermore, as Ct values can also vary between runs when using the same instrument, such RMs could be used as run controls to ensure reproducibility of the quantitative measurements.Peer Reviewe

Cohesin complex-associated holoprosencephaly

Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80–90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly

Primeira consulta em âmbito hospitalar ao neonato com fissura labiopalatal: proposta de protocolo e fluxograma interdisciplinar / First hospital visit to the newborn with cleft lip and palate: proposal of a protocol and interdisciplinary flowchart

Frente à relevância de propostas de ações que abordem o universo do crescimento e desenvolvimento da criança, sob a ótica interdisciplinar e compreendendo o planejamento e a organização dos serviços de saúde como medida indispensável para a gestão do cuidado, desenvolveu-se o presente trabalho. O objetivo é apresentar a elaboração de um protocolo de organização e um fluxograma do primeiro atendimento em âmbito hospitalar ao neonato com fissura labiopalatal, proposto por diferentes categorias profissionais que integram a equipe pedagógica e de assistência em um hospital escola. O material foi elaborado por profissionais residentes atuantes na prática clínica sob a ótica do aprendizado interprofissional, após a assistência de um neonato com fissura labiopalatal. Como ponto de apoio, foi realizada uma revisão nas principais bases de dados científicas em saúde e reuniões para discussões. Os dados resultantes foram sistematizados e embasaram o desenvolvimento de um protocolo de organização interdisciplinar e um fluxograma, norteadores da atenção à saúde infantil em situações de fissura labiopalatal. Conclui-se que a atividade oportunizou a integração do conhecimento, do aprendizado e da relação de prática clínica colaborativa entre os profissionais e permitiu padronizar as condutas assistenciais referentes ao cuidado aos recém-nascidos fissurados

De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5 splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide

Construction of social inequalities in breast cancer : mechanisms involved in the incidence and initial presentation of the disease

Des inégalités sociales de mortalité par cancer du sein ont été mises en évidence dans la littérature. Le cancer du sein est un cancer relativement fréquent, bien documenté, pour lequel un nombre important de déterminants a été identifié. Au fil des années de plus en plus d'études se sont intéressées à l'impact de ces déterminants sur le gradient social d'incidence de cancer du sein. Cependant, ces déterminants ne suffisent pas à eux seuls à expliquer les inégalités d'incidence observées suggérant que d'autres mécanismes sont en jeu. Nous faisons l'hypothèse que les inégalités sociales observées dans la mortalité par cancer du sein sont la conséquence d'une distribution socialement différenciée de l'incidence de la maladie mais aussi de ses caractéristiques initiales, et de l'accès au système de soin. Cette thèse propose d'étudier le lien entre la position socio-économique (PSE) et l'incidence du cancer du sein ainsi que ses caractéristiques cliniques en considérant un large ensemble de variables de médiation potentielles. L'étude du lien entre la PSE et le fonctionnement biologique a fait l'objet de mon premier travail de thèse. Ce travail a mis en évidence un lien entre un faible niveau d'éducation et une inflammation plus élevée, indépendamment de la PSE au début de la vie ou à l'âge adulte, ainsi que des facteurs comportementaux et de l'indice de masse corporel. J'ai ensuite étudié le lien qui pouvait exister entre PSE, inflammation et risque de cancer. J'ai approfondi cette exploration dans le champ des cancers à travers trois travaux menés au sein de la cohorte prospective française E3N (N = 98 995 femmes dont 7 877 cas de cancer du sein), dans lesquels j'ai cherché à étudier la façon dont les facteurs sociaux, biologiques, comportementaux, anthropométriques et reproductifs interagissent à différents moments de la vie pour favoriser la survenue des cancers du sein et influencer leurs caractéristiques au moment du diagnostic. Dans un travail qui s'est intéressé à l'incidence de la maladie, mes résultats ont mis en évidence un risque de cancer du sein plus élevé chez les femmes éduquées, largement expliqué par un âge plus tardif à la première grossesse. Cependant, cette association n'était pas totalement expliquée par la prise en compte d'un nombre important de facteurs de risque, suggérant que d'autres déterminants ou mécanismes sont en jeu. Parmi ces mécanismes, nous avons étudié le lien entre le niveau d'éducation et des biomarqueurs. Un second travail a ainsi permis de mettre en évidence que certains biomarqueurs [la protéine C-réactive, les lipoprotéines de haute densité, l'œstradiol, la testostérone et les protéines de liaison des hormones sexuelles] étaient associés au risque de cancer du sein, indépendamment des facteurs comportementaux, anthropométriques et reproductifs, et que ces biomarqueurs étaient socialement distribués. Le lien entre l'éducation et ces biomarqueurs était en partie expliqué par les facteurs de risque considérés sauf en ce qui concerne la testostérone, suggérant que la relation entre l'éducation et cette hormone sexuelle pourrait constituer un mécanisme nouveau impliqué dans le gradient d'incidence. Concernant les caractéristiques des cancers, un troisième travail nous a permis de montrer que les femmes moins éduquées, bien que moins à risque de développer un cancer du sein, sont plus à risque de développer des tumeurs agressives et un sous type de moins bon pronostic. Ce travail doctoral souligne l'importance des facteurs reproductifs sur le risque de cancer du sein mais met également en évidence que d'autres mécanismes d'incorporation biologique de l'environnement social, en plus des facteurs de risque classiques, pourraient être impliqués dans les inégalités sociales d'incidence et de profils de tumeurs. D'autres travaux sont nécessaires pour mieux caractériser le rôle de l'incorporation biologique, notamment le recours à des analyses de médiation, et analyser les effets sur la survie.Social inequalities in breast cancer mortality have been identified in the literature. Breast cancer is a relatively common, well-documented cancer for which a large number of determinants have been identified. A growing number of studies have focused on the impact of these determinants on the social gradient of breast cancer incidence. However, these determinants are not sufficient to explain the observed inequalities of incidence, suggesting that other mechanisms are at play. We hypothesise that the observed social inequalities in breast cancer mortality are the consequence of a socially differentiated distribution of the incidence of the disease but also of its initial characteristics, and of access to the health care system. This thesis proposes to investigate the link between socioeconomic position (SEP) and breast cancer incidence and clinical characteristics by considering a broad set of potential mediating variables. The study of the link between SEP and biological functioning was the subject of my first thesis work. This work showed a link between low education and higher inflammation, independent of SEP in early life or in adulthood, as well as behavioural factors and body mass index. I then investigated the relationship between SEP, inflammation and cancer risk. I extended this exploration into the field of cancer through three studies conducted within the French prospective cohort E3N (N = 98,995 women, including 7,877 breast cancer cases), in which I sought to study the way in which social, biological, behavioural, anthropometric and reproductive factors interact at different times of life to promote the occurrence of breast cancers and influence their characteristics at the time of diagnosis. In a work that looked at the incidence of the disease, my results showed a higher risk of breast cancer in educated women, largely explained by a later age at first childbirth. However, this association was not fully explained by taking into account a large number of risk factors, suggesting that other determinants or mechanisms are at play. Among these mechanisms, we studied the link between the educational attainment and some biomarkers. A second study showed that some biomarkers [C-reactive protein, high-density lipoprotein, estradiol, testosterone and sex hormone binding globulin] were associated with breast cancer risk, independently of behavioural, anthropometric and reproductive factors, and that these biomarkers were socially distributed. The relationship between education and these biomarkers was partly explained by the considered risk factors except for testosterone, suggesting that the relationship between education and this sex hormone may be a novel mechanism involved in the incidence gradient. Regarding cancer characteristics, a third work allowed us to show that less educated women, although less likely to develop breast cancer, were more likely to develop aggressive tumours and a subtype with a poorer prognosis. This doctoral work highlights the importance of reproductive factors on breast cancer risk but also suggests that other mechanisms of biological embodiment of the social environment, in addition to classical risk factors, may be involved in social inequalities in tumour incidence and profiles. Further works are needed to better characterise the role of biological embodiment, including the use of mediation analyses, and to analyse the effects on survival

Construction des inégalités sociales de cancer du sein : mécanismes impliqués dans l'incidence et la présentation initiale de la maladie

Social inequalities in breast cancer mortality have been identified in the literature. Breast cancer is a relatively common, well-documented cancer for which a large number of determinants have been identified. A growing number of studies have focused on the impact of these determinants on the social gradient of breast cancer incidence. However, these determinants are not sufficient to explain the observed inequalities of incidence, suggesting that other mechanisms are at play. We hypothesise that the observed social inequalities in breast cancer mortality are the consequence of a socially differentiated distribution of the incidence of the disease but also of its initial characteristics, and of access to the health care system. This thesis proposes to investigate the link between socioeconomic position (SEP) and breast cancer incidence and clinical characteristics by considering a broad set of potential mediating variables. The study of the link between SEP and biological functioning was the subject of my first thesis work. This work showed a link between low education and higher inflammation, independent of SEP in early life or in adulthood, as well as behavioural factors and body mass index. I then investigated the relationship between SEP, inflammation and cancer risk. I extended this exploration into the field of cancer through three studies conducted within the French prospective cohort E3N (N = 98,995 women, including 7,877 breast cancer cases), in which I sought to study the way in which social, biological, behavioural, anthropometric and reproductive factors interact at different times of life to promote the occurrence of breast cancers and influence their characteristics at the time of diagnosis. In a work that looked at the incidence of the disease, my results showed a higher risk of breast cancer in educated women, largely explained by a later age at first childbirth. However, this association was not fully explained by taking into account a large number of risk factors, suggesting that other determinants or mechanisms are at play. Among these mechanisms, we studied the link between the educational attainment and some biomarkers. A second study showed that some biomarkers [C-reactive protein, high-density lipoprotein, estradiol, testosterone and sex hormone binding globulin] were associated with breast cancer risk, independently of behavioural, anthropometric and reproductive factors, and that these biomarkers were socially distributed. The relationship between education and these biomarkers was partly explained by the considered risk factors except for testosterone, suggesting that the relationship between education and this sex hormone may be a novel mechanism involved in the incidence gradient. Regarding cancer characteristics, a third work allowed us to show that less educated women, although less likely to develop breast cancer, were more likely to develop aggressive tumours and a subtype with a poorer prognosis. This doctoral work highlights the importance of reproductive factors on breast cancer risk but also suggests that other mechanisms of biological embodiment of the social environment, in addition to classical risk factors, may be involved in social inequalities in tumour incidence and profiles. Further works are needed to better characterise the role of biological embodiment, including the use of mediation analyses, and to analyse the effects on survival.Des inégalités sociales de mortalité par cancer du sein ont été mises en évidence dans la littérature. Le cancer du sein est un cancer relativement fréquent, bien documenté, pour lequel un nombre important de déterminants a été identifié. Au fil des années de plus en plus d'études se sont intéressées à l'impact de ces déterminants sur le gradient social d'incidence de cancer du sein. Cependant, ces déterminants ne suffisent pas à eux seuls à expliquer les inégalités d'incidence observées suggérant que d'autres mécanismes sont en jeu. Nous faisons l'hypothèse que les inégalités sociales observées dans la mortalité par cancer du sein sont la conséquence d'une distribution socialement différenciée de l'incidence de la maladie mais aussi de ses caractéristiques initiales, et de l'accès au système de soin. Cette thèse propose d'étudier le lien entre la position socio-économique (PSE) et l'incidence du cancer du sein ainsi que ses caractéristiques cliniques en considérant un large ensemble de variables de médiation potentielles. L'étude du lien entre la PSE et le fonctionnement biologique a fait l'objet de mon premier travail de thèse. Ce travail a mis en évidence un lien entre un faible niveau d'éducation et une inflammation plus élevée, indépendamment de la PSE au début de la vie ou à l'âge adulte, ainsi que des facteurs comportementaux et de l'indice de masse corporel. J'ai ensuite étudié le lien qui pouvait exister entre PSE, inflammation et risque de cancer. J'ai approfondi cette exploration dans le champ des cancers à travers trois travaux menés au sein de la cohorte prospective française E3N (N = 98 995 femmes dont 7 877 cas de cancer du sein), dans lesquels j'ai cherché à étudier la façon dont les facteurs sociaux, biologiques, comportementaux, anthropométriques et reproductifs interagissent à différents moments de la vie pour favoriser la survenue des cancers du sein et influencer leurs caractéristiques au moment du diagnostic. Dans un travail qui s'est intéressé à l'incidence de la maladie, mes résultats ont mis en évidence un risque de cancer du sein plus élevé chez les femmes éduquées, largement expliqué par un âge plus tardif à la première grossesse. Cependant, cette association n'était pas totalement expliquée par la prise en compte d'un nombre important de facteurs de risque, suggérant que d'autres déterminants ou mécanismes sont en jeu. Parmi ces mécanismes, nous avons étudié le lien entre le niveau d'éducation et des biomarqueurs. Un second travail a ainsi permis de mettre en évidence que certains biomarqueurs [la protéine C-réactive, les lipoprotéines de haute densité, l'œstradiol, la testostérone et les protéines de liaison des hormones sexuelles] étaient associés au risque de cancer du sein, indépendamment des facteurs comportementaux, anthropométriques et reproductifs, et que ces biomarqueurs étaient socialement distribués. Le lien entre l'éducation et ces biomarqueurs était en partie expliqué par les facteurs de risque considérés sauf en ce qui concerne la testostérone, suggérant que la relation entre l'éducation et cette hormone sexuelle pourrait constituer un mécanisme nouveau impliqué dans le gradient d'incidence. Concernant les caractéristiques des cancers, un troisième travail nous a permis de montrer que les femmes moins éduquées, bien que moins à risque de développer un cancer du sein, sont plus à risque de développer des tumeurs agressives et un sous type de moins bon pronostic. Ce travail doctoral souligne l'importance des facteurs reproductifs sur le risque de cancer du sein mais met également en évidence que d'autres mécanismes d'incorporation biologique de l'environnement social, en plus des facteurs de risque classiques, pourraient être impliqués dans les inégalités sociales d'incidence et de profils de tumeurs. D'autres travaux sont nécessaires pour mieux caractériser le rôle de l'incorporation biologique, notamment le recours à des analyses de médiation, et analyser les effets sur la survie

Association between low-grade inflammation and Breast cancer and B-cell Myeloma and Non-Hodgkin Lymphoma : findings from two prospective cohorts

Chronic inflammation may be involved in cancer development and progression. Using 28 inflammatory-related proteins collected from prospective blood samples from two case-control studies nested in the Italian component of the European Prospective Investigation into Cancer and nutrition (n = 261) and in the Northern Sweden Health and Disease Study (n = 402), we tested the hypothesis that an inflammatory score is associated with breast cancer (BC) and.-cell Non-Hodgkin Lymphoma (B-cell NHL, including 68 multiple myeloma cases) onset. We modelled the relationship between this inflammatory score and the two cancers studied: (BC and B-cell NHL) using generalised linear models, and assessed, through adjustments the role of behaviours and lifestyle factors. Analyses were performed by cancer types pooling both populations, and stratified by cohorts, and time to diagnosis. Our results suggested a lower inflammatory score in B-cell NHL cases (β = -1.28, p = 0.012), and, to lesser, extent with BC (β= -0.96, p = 0.33) compared to controls, mainly driven by cancer cases diagnosed less than 6 years after enrolment. These associations were not affected by subsequent adjustments for potential intermediate confounders, notably behaviours. Sensitivity analyses indicated that our findings were not affected by the way the inflammatory score was calculated. These observations call for further studies involving larger populations, larger variety of cancer types and repeated measures of larger panel of inflammatory markers