Using pharmacokinetics for tailoring prophylaxis in people with hemophilia switching between clotting factor products: A scoping review

Abstract The objective of this scoping review is to summarize the current use of pharmacokinetics for tailoring prophylaxis in hemophilia patients switching between clotting factor products. Patients with hemophilia may require switching of clotting factor concentrates due to a variety of factors, but there have been perceived risks associated with switching, such as inhibitor development or suboptimal protection due to inadequate dosing while titrating treatment. Studies that look at patients switching from one clotting factor concentrate to another are categorized in terms of their primary and/or secondary objectives, notably biosimilarity and comparative pharmacokinetic studies and inhibitor development studies. Research on how best to switch concentrates with respect to dosing regimen are lacking, and currently a trial-and-error approach is used for dosing the new factor concentrate. In the future, studies looking at the predictability of pharmacokinetics (PK) of a new factor concentrate based on individual PK knowledge of the original factor concentrate may offer clinical benefit by providing a safer switching approach and protocol.Peer reviewe

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Using pharmacokinetics for tailoring prophylaxis in people with hemophilia switching between clotting factor products: A scoping review.

The objective of this scoping review is to summarize the current use of pharmacokinetics for tailoring prophylaxis in hemophilia patients switching between clotting factor products. Patients with hemophilia may require switching of clotting factor concentrates due to a variety of factors, but there have been perceived risks associated with switching, such as inhibitor development or suboptimal protection due to inadequate dosing while titrating treatment. Studies that look at patients switching from one clotting factor concentrate to another are categorized in terms of their primary and/or secondary objectives, notably biosimilarity and comparative pharmacokinetic studies and inhibitor development studies. Research on how best to switch concentrates with respect to dosing regimen are lacking, and currently a trial-and-error approach is used for dosing the new factor concentrate. In the future, studies looking at the predictability of pharmacokinetics (PK) of a new factor concentrate based on individual PK knowledge of the original factor concentrate may offer clinical benefit by providing a safer switching approach and protocol

Metal-Free Alkyne Polyhydrothiolation: Synthesis of Functional Poly(vinylenesulfide)s with High Stereoregularity by Regioselective Thioclick Polymerization

A new synthetic route to sulfur-rich polymers has been developed. The alkynepolyhydrothiolations of 4,4(-thiodibenzenethiol (1) and arylene dipropiolates(2–5) mediated by amines proceed at room temperature in a regioselectivefashion, furnishin g sole anti-Markovnikov products of poly(vinylenesulfide)s(P1/2–P1/5) with high molecular weights (Mwup to 32 300) and highstereoregularities (Z content up to 81.4%) in high yields (up to 98.2%).Polymers P1/2–P1/4 are soluble in common organic solve nts. They areoptically transparent, allowing almost all visible and IR light to transmitthrough. Thanks to the high sulfur contents of the polymers, their films showhigh refractive indic es (n ¼ 1.73–1.70) in the wavele ngth region of 500–1700 nm as well as high Abbe´numbers (nD' up to 539) and low opticaldispersions (D' down to 0.002) at wavelengths important fortelecommunications. Their refractivities can be further enhanced (n up to2.06) by metal complexation and their films can be crosslinked by UVirradiation, which enables ready fabrication of fluorescent photopatterns

Programmed cell death-1 is expressed in large retinal ganglion cells and is upregulated after optic nerve crush.

Programmed cell death-1 (PD-1) is a key negative receptor inducibly expressed on T cells, B cells and dendritic cells. It was discovered on T cells undergoing classical programmed cell death. Studies showed that PD-1 ligation promotes retinal ganglion cell (RGC) death during retinal development. The purpose of this present study is to characterize PD-1 regulation in the retina after optic nerve crush (ONC). C57BL/6 mice were subjected to ONC and RGC loss was monitored by immunolabelling with RNA-binding protein with multiple splicing (Rbpms). Time course of PD-1 mRNA expression was determined by real-time PCR. PD-1 expression was detected with anti-PD-1 antibody on whole mount retinas. PD-1 staining intensity was quantitated. Colocalization of PD-1 and cleaved-caspase-3 after ONC was analyzed. Real-time PCR results demonstrated that PD-1 gene expression was significantly upregulated at day 1, 3, 7, 10 and 14 after ONC. Immunofluorescent staining revealed a dramatic increase of PD-1 expression following ONC. In both control and injured retinas, PD-1 tended to be up-expressed in a subtype of RGCs, whose somata size were significantly larger than others. Compared to control, PD-1 intensity in large RGCs was increased by 82% in the injured retina. None of the large RGCs expressed cleaved-caspase-3 at day 5 after ONC. Our work presents the first evidence of PD-1 induction in RGCs after ONC. This observation supports further investigation into the role of PD-1 expression during RGC death or survival following injury

Differential Retinal Protein Expression in Primary and Secondary Retinal Ganglion Cell Degeneration Identified by Integrated SWATH and Target-Based Proteomics.

To investigate the retinal proteins associated with primary and secondary retinal ganglion cell (RGC) degeneration and explore their molecular pathways, SWATH label-free and target-based mass spectrometry was employed to identify the proteomes in various retinal locations in response to localized optic nerve injury. Unilateral partial optic nerve transection (pONT) was performed on adult Wistar rats and their retinas were harvested 2 weeks later. To confirm the separation of primary and secondary RGC degeneration, immunohistochemistry of RNA binding protein with multiple splicing (RBPMS) and glial fibrillary acidic protein (GFAP) was performed on retinal whole-mounts. Retinal proteomes in the temporal and nasal quadrants were evaluated with high resolution hybrid quadrupole time-of-flight mass spectrometry (QTOF-MS), and SWATH-based acquisition, and their expression was compared to the corresponding retinal quadrant in contralateral control eyes and further validated by multiple reaction monitoring mass spectrometry (MRM-MS). A total of 3641 proteins (FDR < 1%) were identified using QTOF-MS. The raw data are available via ProteomeXchange with the identifier PXD026783. Bioinformatics data analysis showed that there were 37 upregulated and 25 downregulated proteins in the temporal quadrant, whereas 20 and five proteins were upregulated and downregulated, respectively, in the nasal quadrant, respectively (n = 4, p < 0.05; fold change ≥ 1.4-fold or ≤0.7). Six proteins were regulated in both the temporal and the nasal quadrants, including CLU, GFAP, GNG5, IRF2BPL, L1CAM, and CPLX1. Linear regression analysis indicated a strong association between the data obtained by means of SWATH-MS and MRM-MS (temporal, R2 = 0.97; nasal, R2 = 0.96). Gene ontology analysis revealed statistically significant changes in the biological processes and cellular components of primary RGC degeneration. The majority of the significant changes in structural, signaling, and cell death proteins were associated with the loss of RGCs in the area of primary RGC degeneration. The combined use of SWATH-MS and MRM-MS methods detects and quantifies regional changes of retinal protein expressions after localized injury. Future investigation with this integrated approach will significantly increase the understanding of diverse processes of progressive RGC degeneration from a proteomic prospective

A Photostable AIEgen for Nucleolus and Mitochondria Imaging with Organelle-Specific Emission

Dynamic visualization of the morphology of membrane-bound organelles offers useful insights for studying various intracellular activities. Fluorescent probes with superior specificity and photostability are desirable for long-term tracking of these processes. In this work, we present the design and synthesis of an a-cyanostilbene derivative, abbreviated as ASCP, with the aggregation-induced emission (AIE) characteristic, and its application in cell imaging. ASCP can simultaneously label mitochondria and nucleolus in live cells with distinct fluorescence, which is demonstrative of a single molecule with dualcolour organelle imaging

Functional isocoumarin-containing polymers synthesized by rhodium-catalyzed oxidative polycoupling of aryl diacid and internal diyne

An atom-economical and straightforward polymerization method to generate functional isocoumarin-containing polymers was developed in this work. The oxidative polycoupling of 4,4'-(1,2-diphenyl-1,2-ethenylene)dibenzoic acid and 1,6-bis[4-(phenylethynyl)phenoxy]hexane proceeds efficiently in dimethylformamide under nitrogen or air in the presence of [Cp*RhCl2]2 and a catalytic amount of Cu(OAc)2·H2O at 120 °C for 24 h, generating a polymer with a high molecular weight of up to 42 900 in a high yield of up to 92.9%. An isocoumarin framework forms in situ during the polymerization from readily accessible and inexpensive monomers. The resulting polymer possesses good thermal stability, optical transparency and film-forming ability. Its thin film exhibits high and UV-tunable refractive indices (n =1.9697–1.6507) in a wide wavelength region of 390–890 nm. A two-dimensional fluorescent photopattern can be readily fabricated by irradiating its thin film under UV light through a copper mask. Due to the incorporation of tetraphenylethene units in the monomer, the polymer obtained is weakly emissive in solution but it emits intensely when aggregated, demonstrating a phenomenon of aggregation-induced emission