Modeling the impact of patient treatment preference on health outcomes in relapsing-remitting multiple sclerosis.

Aims: Model how moving from current disease-modifying drug (DMD) prescribing patterns for relapsing-remitting multiple sclerosis (RRMS) observed in the United Kingdom (UK) to prescribing patterns based on patient preferences would impact health outcomes over time. Materials and methods: A cohort-based Markov model was used to measure the effect of DMDs on long-term health outcomes for individuals with RRMS. Data from a discrete choice experiment were used to estimate the market shares of DMDs based on patient preferences (i.e. preference shares). These preference shares and real-world UK market shares were used to calculate the effect of prescribing behavior on relapses, disability progression, and quality-adjusted life-years (QALYs). The incremental benefit of patient-centered prescribing over current practices for the UK RRMS population was then estimated; scenario and sensitivity analyses were also conducted. Results: Compared to current prescribing practices, when UK patients with RRMS were treated following patient preferences, health outcomes were improved. This population was expected to experience 501,690 relapses and gain 1,003,263 discounted QALYs over 50 years under patient-centered prescribing practices compared to 538,417 relapses and 958,792 discounted QALYs under current practices (−6.8% and +4.6%, respectively). Additionally, less disability progression was observed when prescribed treatment was based on patient preferences. In a scenario analysis where only oral treatments were considered, the results were similar, although the magnitude of benefit was smaller. Number of relapses was most sensitive to how the annualized relapse rate was modeled; disability progression was most sensitive to mortality rate assumptions. Limitations: Treatment efficacy estimates applied to various models in this study were based on data derived from clinical trials, rather than real-world data; the impact of patient-centered prescribing on treatment adherence and/or switching was not modeled. Conclusions: The population of UK RRMS patients may experience overall health gains if patient preferences are better incorporated into prescribing practices

Dilated cardiomyopathy in a cat with congenital hyposomatotropism.

Case summary A 7-month-old domestic shorthair cat was presented for evaluation of stunted growth, recurrent hypoglycaemia during the first months of its life and altered mentation. Complete blood count and biochemistry were unremarkable, except for mildly elevated serum creatinine concentration (despite low muscle mass) and concurrent isosthenuria. Hyposomatotropism was diagnosed based on persistent low circulating insulin-like growth factor 1 concentrations and a lack of response of circulating growth hormone (GH) concentration after the administration of GH-releasing hormone. Other endocrinopathies such as hypothyroidism and hypoadrenocorticism were excluded. MRI of the brain revealed a fluid-filled empty sella tursica, consistent with a pituitary cyst and atrophy/hypoplasia of the pituitary. Echocardiography was unremarkable at the time of diagnosis of hyposomatotropism. Three months later, ovariohysterectomy revealed immature ovaries, raising the suspicion of luteinising and follicle-stimulating hormone deficiency. At 1 year of age, the cat developed congestive heart failure secondarily to dilated cardiomyopathy (DCM) with severely reduced left ventricular systolic function and died a few days later. Pathology showed atrophy of the adenohypophysis, epithelial delineation of the pituitary cysts, mild cardiomegaly, multifocal fibrosis of the left ventricle and a mild, multifocal, chronic epicarditis. Relevance and novel information GH deficiency is a very rare endocrinopathy in cats. This is the first case to describe the development of DCM with concurrent hyposomatotropism, which has previously been reported in human medicine. Other notable abnormalities that could be related to GH deficiency are juvenile self-limiting hypoglycaemia, behavioural changes and possible nephropathy

Division-induced DNA double strand breaks in the chromosome terminus region of Escherichia coli lacking RecBCD DNA repair enzyme

Marker frequency analysis of the Escherichia coli recB mutant chromosome has revealed a deficit of DNA in a specific zone of the terminus, centred on the dif/TerC region. Using fluorescence microscopy of a marked chromosomal site, we show that the dif region is lost after replication completion, at the time of cell division, in one daughter cell only, and that the phenomenon is transmitted to progeny. Analysis by marker frequency and microscopy shows that the position of DNA loss is not defined by the replication fork merging point since it still occurs in the dif/TerC region when the replication fork trap is displaced in strains harbouring ectopic Ter sites. Terminus DNA loss in the recB mutant is also independent of dimer resolution by XerCD at dif and of Topo IV action close to dif. It occurs in the terminus region, at the point of inversion of the GC skew, which is also the point of convergence of specific sequence motifs like KOPS and Chi sites, regardless of whether the convergence of GC skew is at dif (wild-type) or a newly created sequence. In the absence of FtsK-driven DNA translocation, terminus DNA loss is less precisely targeted to the KOPS convergence sequence, but occurs at a similar frequency and follows the same pattern as in FtsK+ cells. Importantly, using ftsIts, ftsAts division mutants and cephalexin treated cells, we show that DNA loss of the dif region in the recB mutant is decreased by the inactivation of cell division. We propose that it results from septum-induced chromosome breakage, and largely contributes to the low viability of the recB mutant

Overview and progress of consortium research related to the biology, ecology and aquaculture of rabbitfish

editorial reviewedCoastal habitats support global fisheries by ensuring the survival of juvenile fishes. These habitats constitute one of the fishing areas targeted by small-scale fishermen in the least developed countries, including Madagascar. The accessibility of these habitats at low tides makes it an ideal fishing area for mosquito seine nets as observed for instance in SW Madagascar and beach seining in Kenya. However, this practice negatively impacts fisheries production due to catches of high numbers of juveniles, in Madagascar and Kenya mostly composed of shoemaker spinefoot rabbitfish (Siganus sutor). Despite Malagasy laws that forbid the deployment of mosquito seine nets, fishermen continue with their use. In Kenya, the beach seines have been outlawed but enforcement remains a challenge. This context highlights the need for management measures and alternative sources of income for a sustainable use of marine resources and for improving the fishermen livelihood. The ongoing consortium research entitled “Fish juvenile recruitment in coastal habitats of western Indian Ocean” was funded by MASMA program administered by WIOMSA. It is an interdisciplinary research program intending to understand recruitment patterns of shoemaker spinefoot rabbitfish (Siganus sutor) in coastal habitats of Kenya and Madagascar. It explores evidence-based solutions for improving the welfare of coastal communities and sustainable use of marine resources. Research activities were divided into four work packages. In WP1, Siganus sutor recruitment patterns in coastal habitats were targeted to identify the nursery ground and recruitment periods. It is based on juvenile fish sampling at four coastal habitats (mangroves, seagrass meadows, intermediate areas and seagrass associated with the coral reef) in Madagascar during twelve months. In WP2, sampling for the analysis of the population connectivity of S. sutor for detecting the sources of juveniles in the coastal habitats at five sites along the western coast of Madagascar was completed. In WP3, ecological models for predicting the arrival of newly settled S. sutor will be based on historical and newly collected data (WP1) using the random forests algorithm. Predictors are composed of remotely sensed oceanic conditions and a post-larval supply index calculated from post-larval sampling in the coastal habitats using light-traps. Like juvenile sampling, post-larval sampling was performed three nights per month which will cover all the juvenile sampling periods. In WP4, fish feeding behavior is studied and experiments on capture-based juvenile fish grow-out are ongoing at the Belaza aquaculture facilities (Toliara, Madagascar). Eight fish grow-out treatments focusing on three stocking densities, three fish diets, and pond dimensions are being tested. In WP1, about 5,720 juvenile individuals were obtained from 120 juvenile fish samples. The standard length of each of these individuals were measured for analyzing the spatial distribution of S. sutor. The nursery ground and recruitment seasons for S. sutor emerged from our research. The findings will be presented orally by PhD student Helga Berjulie Ravelohasina during the symposium. In addition, about 360 epifaunal community samples were obtained between July 2021 and April 2022. The spatial distribution of abundance, diversity and richness of epifauna associated with seagrass will be presented in a poster by MSc student Mory Justino. In WP2, at each location, 45 individuals were sampled, for a total of 225 adults for Madagascar and 180 from Kenya. Genotyping is in progress. In WP3, monitoring of the newly settled fish, in parallel with post-larval sampling, is in progress and should be completed by June 2022. In meantime, the extraction of remotely sensed oceanic conditions covering the sampling periods is being processed with R programming for the period. In WP4, preliminary results on fish grow-out identified the best fish diet and the most optimal stocking density at the smallest size (about 2 cm of standard length). More details related to these findings will be presented in a poster by master student Nandrianina Maminantenaina. In addition, the gut content and stage isotopes of three ontogenetic stages (i.e. post-larvae, juvenile, and adult) of S. sutor were analysed the natural trophodynamics. The findings are based on 1160 gut contents and muscle tissue samples collected during the warm (October 2021 to February 2022) and cool season (May to August 2022). The potential nursery areas and the main recruitment seasons of Siganus sutor were identified. The oral presentation entitled “The potential nursery areas and recruitment season of S. sutor in Madagascar” by Helga Berjulie Ravelohasina will provide further details of our findings. The variability of food availability related to epifauna concentration will be known in the poster on Mory Justino. The most optimal fish diet as well as the optimal stocking density will be presented in a separate poster entitled “Density and fish diet effect on rabbitfish growth in controlled systems” presented by Nandrianina Maminantenaina.Biology, ecology and aquaculture of rabbitfish14. Life below water2. Zero hunger11. Sustainable cities and communitie

Broken replication forks trigger heritable DNA breaks in the terminus of a circular chromosome

<p><u>(A) Circular map of the <i>E</i>. <i>coli</i> chromosome</u>: <i>oriC</i>, <i>dif</i> and <i>terD</i> to <i>terB</i> sites are indicated. Numbers refer to the chromosome coordinates (in kb) of MG1655. (<u>B) Linear map of the terminus region:</u> chromosome coordinates are shown increasing from left to right, as in the marker frequency panels (see Figure 1C for example), therefore in the opposite direction to the circular map. In addition to <i>dif</i> and <i>ter</i> sites, the positions of the <i>parS</i>_pMT1 sites used for microscopy experiments are indicated. (<u>C) MFA analysis of terminus DNA loss in the <i>recB</i> mutant</u>: sequence read frequencies of exponential phase cells normalized to the total number of reads were calculated for each strain. Ratios of normalized reads in isogenic wild-type and <i>recB</i> mutant are plotted against chromosomal coordinates (in kb). The profile ratio of the terminus region is enlarged and the profile of the corresponding entire chromosomes is shown in inset. Original normalized profiles used to calculate ratios are shown in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007256#pgen.1007256.s005" target="_blank">S1 Fig</a>. The position of <i>dif</i> is indicated by a red arrow. The <i>ter</i> sites that arrest clockwise forks (<i>terC</i>, <i>terB</i>, green arrow) and counter-clockwise forks (<i>terA</i>, <i>terD</i>, blue arrow) are shown. <u>(D) Schematic representation of focus loss in the <i>recB</i> mutant:</u> Time-lapse microscopy experiments showed that loss of a focus in the <i>recB</i> mutant occurs concomitantly with cell division in one of two daughter cells, and that the cell that keeps the focus then generates a focus-less cell at each generation. The percentage of initial events was calculated as the percentage of cell divisions that generate a focus-less cell, not counting the following generations. In this schematic representation, two initial events occurred (generations #2 and #7) out of 9 generations, and focus loss at generation #2 is heritable. Panels shown in this figure were previously published in [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007256#pgen.1007256.ref019" target="_blank">19</a>] and are reproduced here to introduce the phenomenon.</p

Kenya in Motion 2000-2020

This edited volume offers a broad understanding and particular visions of Kenya in the first quarter of the twenty-first century. By bringing together rigorous yet accessible contributions, it shows how, since the 2002 transition, Kenya has been striving for change through economic modernisation and political liberalisation. The planned transformations are coming to fruition, even if the legacies of the past and political habits are slowing down the process. The various chapters take us from developmental capitalism to extreme poverty and enduring inequalities, from reforms on paper to mixed results in multiple sectors: decentralised governance, natural resources, land, and education. They also explore Kenya’s ancient and colonial history and the diversity of its population. Thus, the book helps understand contemporary political, religious and community cleavages, the asymmetries between towns and the countryside, between Nairobi and the coast, in a country open to the world, as much through trade and finance as through art networks.Cet ouvrage offre une saisie synthétique et des visions particulières du Kenya en ce premier quart du XXIe siècle. Il rassemble des contributions rigoureuses et accessibles pour montrer comment, depuis l’alternance de 2002, le Kenya s’efforce de changer par la modernisation économique et la libéralisation politique. Les transformations annoncées voient le jour, même si les legs du passé et les habitus politiques en ralentissent la marche. Les différents chapitres nous mènent du capitalisme développemental kényan à la grande pauvreté et aux inégalités vivaces, des réformes sur le papier aux mises en œuvre en demi-teinte dans de multiples secteurs : gouvernance décentralisée, ressources naturelles, foncier, éducation. L’histoire ancienne et coloniale, la diversité du peuplement au Kenya permettent de mieux comprendre les clivages politiques, religieux et communautaires, les asymétries entre villes et campagnes, entre Nairobi et la côte, dans un Kenya ouvert sur le monde, autant par le commerce et la finance que par les réseaux de l’art

Le Kenya en marche, 2000-2020

Cet ouvrage offre une saisie synthétique et des visions particulières du Kenya en ce premier quart du XXIe siècle. Il rassemble des contributions rigoureuses et accessibles pour montrer comment, depuis l’alternance de 2002, le Kenya s’efforce de changer par la modernisation économique et la libéralisation politique. Les transformations annoncées voient le jour, même si les legs du passé et les habitus politiques en ralentissent la marche. Les différents chapitres nous mènent du capitalisme développemental kényan à la grande pauvreté et aux inégalités vivaces, des réformes sur le papier aux mises en œuvre en demi-teinte dans de multiples secteurs : gouvernance décentralisée, ressources naturelles, foncier, éducation. L’histoire ancienne et coloniale, la diversité du peuplement au Kenya permettent de mieux comprendre les clivages politiques, religieux et communautaires, les asymétries entre villes et campagnes, entre Nairobi et la côte, dans un Kenya ouvert sur le monde, autant par le commerce et la finance que par les réseaux de l’art.This edited volume offers a broad understanding and particular visions of Kenya in the first quarter of the twenty-first century. By bringing together rigorous yet accessible contributions, it shows how, since the 2002 transition, Kenya has been striving for change through economic modernisation and political liberalisation. The planned transformations are coming to fruition, even if the legacies of the past and political habits are slowing down the process. The various chapters take us from developmental capitalism to extreme poverty and enduring inequalities, from reforms on paper to mixed results in multiple sectors: decentralised governance, natural resources, land, and education. They also explore Kenya’s ancient and colonial history and the diversity of its population. Thus, the book helps understand contemporary political, religious and community cleavages, the asymmetries between towns and the countryside, between Nairobi and the coast, in a country open to the world, as much through trade and finance as through art networks

Synthesis of oligonucleotide analogues for use in DNA nanostructures

Thanks to its ability to form duplexes through selective base-pair recognition, DNA is aunique material for orderly self-assembled construction at the nanoscale. To develop ananotechnology platform on a grid of addressable molecular building blocks using DNAnode structures, DNA complexes need to be fixed onto surfaces. To fulfil thisrequirement on lipid membranes, phosphoramidites monomers modified with acholesterol moiety and a spacer unit were synthesised. The hydrophobic spacer providesseparation between the hydrophobic cholesterol moiety and the phosphate backbone ofthe DNA strand. For better anchorage of the network to a lipid surface, a hydrophilicspacer was also used to link the cholesterol to the nucleoside. Solution studies demonstrated that the melting temperature (Tm) of the duplex withadjacent cholesterols on each strand is much higher than that of the unmodified duplex.The reliable and highly selective copper(I)-catalysed azide-alkyne 1,3-dipolarcycloadition (CuAAC), the best known example of click chemistry, has proven to be ofremarkably broad utility in synthetic chemistry and in nucleic acid chemistry inparticular. CuAAC was exploited for the synthesis of a very stable double strandedcatenane duplex. The catenane was formed from a single stranded cyclic template andits linear complement, using a third short oligonucleotide (ODN) as a helper for thecircularisation of the second ODN. The copper(I)-catalysed cyclisation ofoligonucleotides occurred by reaction between their terminal azide and their oppositeterminal alkyne, to produce a 1,2,3-triazole linkage between the two reactants. Thecatenane was characterised by denaturing polyacrylamide gel electrophoresis, UVmelting studies and enzyme digestion