Cost-effectiveness of strategies preventing late-onset infection in preterm infants

OBJECTIVE: Developing a model to analyse the cost-effectiveness of interventions preventing late-onset infection (LOI) in preterm infants and applying it to the evaluation of anti-microbial impregnated peripherally inserted central catheters (AM-PICCs) compared with standard PICCs (S-PICCs). DESIGN: Model-based cost-effectiveness analysis, using data from the Preventing infection using Antimicrobial Impregnated Long Lines (PREVAIL) randomised controlled trial linked to routine healthcare data, supplemented with published literature. The model assumes that LOI increases the risk of neurodevelopmental impairment (NDI). SETTING: Neonatal intensive care units in the UK National Health Service (NHS). PATIENTS: Infants born ≤32 weeks gestational age, requiring a 1 French gauge PICC. INTERVENTIONS: AM-PICC and S-PICC. MAIN OUTCOME MEASURES: Life expectancy, quality-adjusted life years (QALYs) and healthcare costs over the infants' expected lifetime. RESULTS: Severe NDI reduces life expectancy by 14.79 (95% CI 4.43 to 26.68; undiscounted) years, 10.63 (95% CI 7.74 to 14.02; discounted) QALYs and costs £19 057 (95% CI £14 197; £24697; discounted) to the NHS. If LOI causes NDI, the maximum acquisition price of an intervention reducing LOI risk by 5% is £120. AM-PICCs increase costs (£54.85 (95% CI £25.95 to £89.12)) but have negligible impact on health outcomes (-0.01 (95% CI -0.09 to 0.04) QALYs), compared with S-PICCs. The NHS can invest up to £2.4 million in research to confirm that AM-PICCs are not cost-effective. CONCLUSIONS: The model quantifies health losses and additional healthcare costs caused by NDI and LOI during neonatal care. Given these consequences, interventions preventing LOI, even by a small extent, can be cost-effective. AM-PICCs, being less effective and more costly than S-PICC, are not likely to be cost-effective. TRIAL REGISTRATION NUMBER: NCT03260517

A Novel TRAF3IP2 Mutation Causing Chronic Mucocutaneous Candidiasis

Inborn errors of the IL-17-mediated signaling have been associated with chronic mucocutaneous candidiasis (CMC). We describe a patient with CMC, atopic dermatitis, enamel dysplasia, and recurrent parotitis harboring a novel compound heterozygous mutation of TRAF3IP2, leading to autosomal recessive ACT1 deficiency and deficient IL-17 signaling.info:eu-repo/semantics/publishedVersio

Chromosome and DNA methylation dynamics during meiosis in autotetraploid Arabidopsis arenosa

Variation in chromosome number due to polyploidy can seriously compromise meiotic stability. In autopolyploids, the presence of more than two homologous chromosomes may result in complex pairing patterns and subsequent anomalous chromosome segregation. In this context, chromocenter, centromeric, telomeric and ribosomal DNA locus topology and DNA methylation patterns were investigated in the natural autotetraploid, Arabidopsis arenosa. The data show that homologous chromosome recognition and association initiates at telomeric domains in premeiotic interphase, followed by quadrivalent pairing of ribosomal 45S RNA gene loci (known as NORs) at leptotene. On the other hand, centromeric regions at early leptotene show pairwise associations rather than associations in fours. These pairwise associations are maintained throughout prophase I, and therefore likely to be related to the diploid-like behavior of A. arenosa chromosomes at metaphase I, where only bivalents are observed. In anthers, both cells at somatic interphase as well as at premeiotic interphase show 5-methylcytosine (5-mC) dispersed throughout the nucleus, contrasting with a preferential co-localization with chromocenters observed in vegetative nuclei. These results show for the first time that nuclear distribution patterns of 5-mC are simultaneously reshuffled in meiocytes and anther somatic cells. During prophase I, 5-mC is detected in extended chromatin fibers and chromocenters but interestingly is excluded from the NORs what correlates with the pairing patter

The Prosensory Function of Sox2 in the Chicken Inner Ear Relies on the Direct Regulation of Atoh1

The proneural gene Atoh1 is crucial for the development of inner ear hair cells and it requires the function of the transcription factor Sox2 through yet unknown mechanisms. In the present work, we used the chicken embryo and HEK293T cells to explore the regulation of Atoh1 by Sox2. The results show that hair cells derive from Sox2-positive otic progenitors and that Sox2 directly activates Atoh1 through a transcriptional activator function that requires the integrity of Sox2 DNA binding domain. Atoh1 activation depends on Sox transcription factor binding sites (SoxTFBS) present in the Atoh1 3′ enhancer where Sox2 directly binds, as shown by site directed mutagenesis and chromatin immunoprecipitation (ChIP). In the inner ear, Atoh1 enhancer activity is detected in the neurosensory domain and it depends on Sox2. Dominant negative competition (Sox2HMG-Engrailed) and mutation of the SoxTFBS abolish the reporter activity in vivo. Moreover, ChIP assay in isolated otic vesicles shows that Sox2 is bound to the Atoh1 enhancer in vivo. However, besides activating Atoh1, Sox2 also promotes the expression of Atoh1 negative regulators and the temporal profile of Atoh1 activation by Sox2 is transient suggesting that Sox2 triggers an incoherent feed-forward loop. These results provide a mechanism for the prosensory function of Sox2 in the inner ear. We suggest that sensory competence is established early in otic development through the activation of Atoh1 by Sox2, however, hair cell differentiation is prevented until later stages by the parallel activation of negative regulators of Atoh1 function

Long Distance Dispersal and Connectivity in Amphi-Atlantic Corals at Regional and Basin Scales

Among Atlantic scleractinian corals, species diversity is highest in the Caribbean, but low diversity and high endemism are observed in various peripheral populations in central and eastern Atlantic islands and along the coasts of Brazil and West Africa. The degree of connectivity between these distantly separated populations is of interest because it provides insight into processes at both evolutionary and ecological time scales, such as speciation, recruitment dynamics and the persistence of coral populations. To assess connectivity in broadly distributed coral species of the Atlantic, DNA sequence data from two nuclear markers were obtained for six coral species spanning their distributional ranges. At basin-wide scales, significant differentiation was generally observed among populations in the Caribbean, Brazil and West Africa. Concordance of patterns in connectivity among co-distributed taxa indicates that extrinsic barriers, such as the Amazon freshwater plume or long stretches of open ocean, restrict dispersal of coral larvae from region to region. Within regions, dispersal ability appears to be influenced by aspects of reproduction and life history. Two broadcasting species, Siderastrea siderea and Montastraea cavernosa, were able to maintain gene flow among populations separated by as much as 1,200 km along the coast of Brazil. In contrast, brooding species, such as Favia gravida and Siderastrea radians, had more restricted gene flow along the Brazilian coast

Permeation through the Cell Membrane of a Boron-Based β-Lactamase Inhibitor

Bacteria express beta-lactamases to counteract the beneficial action of antibiotics. Benzo[b]-thiophene-2-boronic acid (BZB) derivatives are β-lactamase inhibitors and, as such, promising compounds to be associated with β-lactam antibacterial therapies. The uncharged form of BZB, in particular, is suggested to diffuse through the outer membrane of Gram negative bacteria. In this study, through the combination of electrophysiological experiments across reconstituted PC/n-decane bilayers and metadynamics-based free energy calculations, we investigate the permeation mechanism of boronic compounds. Our experimental data establish that BZB passes through the membrane, while computer simulations provide hints for the existence of an aqueous, water-filled monomolecular channel. These findings provide new perspectives for the design of boronic acid derivatives with high membrane permeability

Effect of venlafaxine on bone loss associated with ligature-induced periodontitis in Wistar rats

<p>Abstract</p> <p>Background</p> <p>The present study investigated the effects of venlafaxine, an antidepressant drug with immunoregulatory properties on the inflammatory response and bone loss associated with experimental periodontal disease (EPD).</p> <p>Materials and Methods</p> <p>Wistar rats were subjected to a ligature placement around the second upper left molar. The treated groups received orally venlafaxine (10 or 50 mg/kg) one hour before the experimental periodontal disease induction and daily for 10 days. Vehicle-treated experimental periodontal disease and a sham-operated (SO) controls were included. Bone loss was analyzed morphometrically and histopathological analysis was based on cell influx, alveolar bone, and cementum integrity. Lipid peroxidation quantification and immunohistochemistry to TNF-α and iNOS were performed.</p> <p>Results</p> <p>Experimental periodontal disease rats showed an intense bone loss compared to SO ones (SO = 1.61 ± 1.36; EPD = 4.47 ± 1.98 mm, p < 0.001) and evidenced increased cellular infiltration and immunoreactivity for TNF-α and iNOS. Venlafaxine treatment while at low dose (10 mg/kg) afforded no significant protection against bone loss (3.25 ± 1.26 mm), a high dose (50 mg/kg) caused significantly enhanced bone loss (6.81 ± 3.31 mm, p < 0.05). Venlafaxine effectively decreased the lipid peroxidation but showed no significant change in TNF-α or iNOS immunoreactivity.</p> <p>Conclusion</p> <p>The increased bone loss associated with high dose venlafaxine may possibly be a result of synaptic inhibition of serotonin uptake.</p

Out of Amazonia: late-Holocene climate change and the Tupi–Guarani trans-continental expansion

The late Holocene expansion of the Tupi-Guarani languages from southern Amazonia to SE South America constitutes one of the largest expansions of any linguistic family in the world, spanning ~ 4000 km between latitudes 0°S and 35°S at about 2500 yr B.P. However, the underlying reasons for this expansion are a matter of debate. Here, we compare continental-scale palaeoecological, palaeoclimate, and archaeological datasets, to examine the role of climate change in facilitating the expansion of this forestfarming culture. Because this expansion lies within the path of the South American Low-Level Jet, the key mechanism for moisture transport across lowland South America, we were able to explore the relationship between climate change, forest expansion, and the Tupi-Guarani. Our data synthesis shows broad synchrony between late Holocene increasing precipitation and southerly expansion of both tropical forest and Guarani archaeological sites – the southernmost branch of the Tupi-Guarani. We conclude that climate change likely facilitated the agricultural expansion of the Guarani forest-farming culture by increasing the area of forested landscape that they could exploit, showing a prime example of ecological opportunism