Achievement of therapeutic antibiotic exposures using Bayesian dosing software in critically unwell children and adults with sepsis

PURPOSE: Early recognition and effective treatment of sepsis improves outcomes in critically ill patients. However, antibiotic exposures are frequently suboptimal in the intensive care unit (ICU) setting. We describe the feasibility of the Bayesian dosing software Individually Designed Optimum Dosing Strategies (ID-ODS™), to reduce time to effective antibiotic exposure in children and adults with sepsis in ICU. METHODS: A multi-centre prospective, non-randomised interventional trial in three adult ICUs and one paediatric ICU. In a pre-intervention Phase 1, we measured the time to target antibiotic exposure in participants. In Phase 2, antibiotic dosing recommendations were made using ID-ODS™, and time to target antibiotic concentrations were compared to patients in Phase 1 (a pre-post-design). RESULTS: 175 antibiotic courses (Phase 1 = 123, Phase 2 = 52) were analysed from 156 participants. Across all patients, there was no difference in the time to achieve target exposures (8.7 h vs 14.3 h in Phase 1 and Phase 2, respectively, p = 0.45). Sixty-one courses in 54 participants failed to achieve target exposures within 24 h of antibiotic commencement (n = 36 in Phase 1, n = 18 in Phase 2). In these participants, ID-ODS™ was associated with a reduction in time to target antibiotic exposure (96 vs 36.4 h in Phase 1 and Phase 2, respectively, p < 0.01). These patients were less likely to exhibit subtherapeutic antibiotic exposures at 96 h (hazard ratio (HR) 0.02, 95% confidence interval (CI) 0.01-0.05, p < 0.01). There was no difference observed in in-hospital mortality. CONCLUSIONS: Dosing software may reduce the time to achieve target antibiotic exposures. It should be evaluated further in trials to establish its impact on clinical outcomes

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

A Full Suite of Histone and Histone Modifying Genes Are Transcribed in the Dinoflagellate Lingulodinium

BACKGROUND: Dinoflagellates typically lack histones and nucleosomes are not observed in DNA spreads. However, recent studies have shown the presence of core histone mRNA sequences scattered among different dinoflagellate species. To date, the presence of all components required for manufacturing and modifying nucleosomes in a single dinoflagellate species has not been confirmed. METHODOLOGY AND RESULTS: Analysis of a Lingulodinium transcriptome obtained by Illumina sequencing of mRNA shows several different copies of each of the four core histones as well as a suite of histone modifying enzymes and histone chaperone proteins. Phylogenetic analysis shows one of each Lingulodinium histone copies belongs to the dinoflagellate clade while the second is more divergent and does not share a common ancestor. All histone mRNAs are in low abundance (roughly 25 times lower than higher plants) and transcript levels do not vary over the cell cycle. We also tested Lingulodinium extracts for histone proteins using immunoblotting and LC-MS/MS, but were unable to confirm histone expression at the protein level. CONCLUSION: We show that all core histone sequences are present in the Lingulodinium transcriptome. The conservation of these sequences, even though histone protein accumulation remains below currently detectable levels, strongly suggests dinoflagellates possess histones

Apoptotic cell-based therapies against transplant rejection: role of recipient’s dendritic cells

One of the ultimate goals in transplantation is to develop novel therapeutic methods for induction of donor-specific tolerance to reduce the side effects caused by the generalized immunosuppression associated to the currently used pharmacologic regimens. Interaction or phagocytosis of cells in early apoptosis exerts potent anti-inflammatory and immunosuppressive effects on antigen (Ag)-presenting cells (APC) like dendritic cells (DC) and macrophages. This observation led to the idea that apoptotic cell-based therapies could be employed to deliver donor-Ag in combination with regulatory signals to recipient’s APC as therapeutic approach to restrain the anti-donor response. This review describes the multiple mechanisms by which apoptotic cells down-modulate the immuno-stimulatory and pro-inflammatory functions of DC and macrophages, and the role of the interaction between apoptotic cells and APC in self-tolerance and in apoptotic cell-based therapies to prevent/treat allograft rejection and graft-versus-host disease in murine experimental systems and in humans. It also explores the role that in vivo-generated apoptotic cells could have in the beneficial effects of extracorporeal photopheresis, donor-specific transfusion, and tolerogenic DC-based therapies in transplantation

High-Resolution Electron Microscopy of Semiconductor Heterostructures and Nanostructures

This chapter briefly describes the fundamentals of high-resolution electron microscopy techniques. In particular, the Peak Pairs approach for strain mapping with atomic column resolution, and a quantitative procedure to extract atomic column compositional information from Z-contrast high-resolution images are presented. It also reviews the structural, compositional, and strain results obtained by conventional and advanced transmission electron microscopy methods on a number of III–V semiconductor nanostructures and heterostructures

Structural Analysis of a Metazoan Nuclear Pore Complex Reveals of Fused Concentric Ring Architecture

The sole gateway for molecular exchange between the cytoplasm and the nucleus is the nuclear pore complex (NPC). This large supramolecular assembly mediates transport of cargo into and out of the nucleus and fuse the inner and outer nuclear membranes to form an aqueous translocation channel. The NPC is composed of eight proteinaceous asymmetric units forming a pseudo-8-fold symmetric passage. Due to its shear size, complexity, and plastic nature, dissecting the high-resolution three-dimensional structure of the NPC in its hydrated state is a formidable challenge. Toward this goal, we applied cryo-electron tomography to spread nuclear envelopes from Xenopus oocytes. To compensate for perturbations of the 8-fold symmetry of individual NPCs, we performed symmetry-independent asymmetric unit averaging of three-dimensional tomographic NPC volumes to eventually yield a refined model at 6.4 nm resolution. This approach revealed novel structural features, particularly in the spoke-ring complex and luminal domains. Fused concentric ring architecture of the spoke-ring complex was found along the translocation channel. Additionally, a comparison of the refined Xenopus model to that of its Dictyostelium homologue yielded similar pore diameters at the level of the three canonical rings, although the Xenopus NPC was found to be 30% taller than the Dictyostelium pore. This discrepancy is attributed primarily to the relatively low homology and different organization of some nucleoporins in the Dictyostelium genome as compared to that of vertebrates. Nevertheless, the experimental conditions impose a preferred axial orientation of the NPCs within spread Xenopus oocyte nuclear envelopes. This may at least in part explain the increased height of the reconstructed vertebrate NPCs compared to those obtained from tomographic reconstruction of intact Dictyostelium nuclei

Enhancement of coercivity and saturation magnetization of Al3+ substituted M-type Sr-hexaferrites

Hexagonal SrFe12-xAlxO19 (x = 0, 0.2, 1, 2, 4) powders were prepared via mechanochemical activation and subsequently calcined at different temperatures (between 900 °C and 1300 °C). Afterwards the powders were milled by high energy milling and annealed at 1000 °C in NaCl to obtain ultrafine nano-particles. The particle size, measured by scanning electron microscopy (SEM), varied between 50 nm and few micrometers depending on Al3+ substitution and calcination temperature. Average crystallite size, determined by X-ray diffraction (XRD), decreases from 330 nm ± 30 nm (x = 0) to 70 nm ± 10 nm (x = 4) by substitution of Fe3+ by Al3+ for optimized calcination temperature of 1100 °C. Furthermore coercivity measured by SQUID magnetometry increases from 420 kA/m (x = 0) to 970 kA/m (x = 4). A maximum saturation magnetization of 74 Am2/kg (x = 0) was observed. With substitution of Fe3+ by Al3+ saturation magnetization decreases monotonously to 28 Am2/kg (x = 4). Annealing in NaCl matrix at lower temperatures compared to calcination temperatures leads to a further increase of coercivity. At the same time saturation magnetization increases for SrFe12-xAlxO19 (x = 0, 1) by NaCl annealing treatment. Additionally, we discuss the initial magnetization curves of SrFe12O19 and SrFe8Al4O19 after different processing steps with respect to the specific reversal mechanism of hexaferrites. The here proposed processing route enables a simultaneous enhancement of coercivity and saturation magnetization as compared to conventional ceramic method [1] and [2]. The presented processing route can solve challenges of conventional manufacturing steps towards single domain grains in rare earth free SrFe12-xAlxO19 for higher coercivity and could enable an improved industrial production process

In-situ magnetic force microscopy analysis of magnetization and demagnetization behavior in Al 3+ substituted Sr-hexaferrite

The sintering temperature of an Al3+ substituted Sr-hexaferrite composite was systematically varied from 1180 °C to 1280 °C resulting in different microstructures. The grain size was found to range from a few hundred nanometers to several hundred micrometers depending on Al content and sintering temperature. Adding an Al substituted powder to a commercial powder increased the coercivity from 360 mT to 470 mT, at the same time, decreasing remanence from 350 mT to 305 mT. Magnetization and demagnetization processes from the thermally demagnetized state (TDS) and DC-demagnetized state (DCD) have been investigated systematically by in-situ magnetic force microscopy (MFM) under magnetic field. From the surface domain contrast a polarization was derived which quantitatively matches the global i.e. bulk polarization obtained by superconducting quantum interface device (SQUID) magnetometry. The shape of the initial polarization curve and the polarization from the DCD state were correlated with the in-situ MFM data revealing a distinctly different magnetization behavior depending on grain size. The presented results enable a better understanding of local nucleation mechanisms, global influences of pinning centers and further opportunities to improve rare earth (RE) free permanent magnets based on ferrites