European Paediatric Formulation Initiative workshop report: Improving the administration of oral liquid medicines in paediatrics using dosing syringes and enteral accessories

Accurate dosing of the right medicine to the right patient is a key element of safe and efficacious pharmacotherapy, yet prone to technical challenges and human error when dosing involves the administration of small volumes of liquid medicines. For this reason, the topic has gained increased attention over the last decade from multiple stakeholder parties e.g. academia, hospital pharmacy, the medical device and pharmaceutical industry, and regulatory agencies. It is now well acknowledged that spoons and cups are not suitable for the measurement of small volumes of oral liquid medicines and that syringes are a better alternative, but syringes for parenteral use should not be used for oral dosing in order to avoid accidental parenteral delivery of oral products. However, dosing accuracy of very small volumes of liquid medicines to young children, and especially pre-term neonates, is still not sufficiently ensured. A workshop was organised in 2018 by the European Paediatric Formulation Initiative to reflect on current status and challenges (first part) and possible strategies to improve the present situation (second part). A voting system (n = 24) was used to consider the most favourable solutions. The harmonisation and/or standardisation of the technical design of oral syringes (including e.g. female/male connection) was considered a key priority

A Compendium of AR Splice Variants in Metastatic Castration-Resistant Prostate Cancer

Treatment-induced AR alterations, including AR alternative splice variants (AR-Vs), have been extensively linked to harboring roles in primary and acquired resistance to conventional and next-generation hormonal therapies in prostate cancer and therefore have gained momentum. Our aim was to uniformly determine recurrent AR-Vs in metastatic castration-resistant prostate cancer (mCRPC) using whole transcriptome sequencing in order to assess which AR-Vs might hold potential diagnostic or prognostic relevance in future research. This study reports that in addition to the promising AR-V7 as a biomarker, AR45 and AR-V3 were also seen as recurrent AR-Vs and that the presence of any AR-V could be associated with higher AR expression. With future research, these AR-Vs may therefore harbor similar or complementary roles to AR-V7 as predictive and prognostic biomarkers in mCRPC or as proxies for abundant AR expression.</p

The costs of peripheral blood progenitor cell reinfusion mobilised by granulocyte colony-stimulating factor following high dose melphalan as compared with conventional therapy in multiple myeloma

In a retrospective study, we calculated the treatment costs of 26 patients, who received either high dose melphalan combined with granulocyte colony-stimulating factor (G-CSF; filgrastim)(n=7) or without G-CSF (n=11) or alternatively, peripheral blood progenitor cell reinfusion (PBPC) mobilised by G-CSF following high dose melphalan. In comparison with the control group, a shortening of the pancytopenic period and platelet recovery was noticed in the PBPC group. This resulted in a reduction in hospital costs, diagnostics, laboratory services, total parenteral nutrition and transfusions. The average costs per treatment in the PBPC group amounted to about US$179 08 as compared to US$ 32 223 in the control group, implying a cost reduction of 44% when changing to PBPC reinfusion

Scaling Cosmologies of N=8 Gauged Supergravity

We construct exact cosmological scaling solutions in N=8 gauged supergravity. We restrict to solutions for which the scalar fields trace out geodesic curves on the scalar manifold. Under these restrictions it is shown that the axionic scalars are necessarily constant. The potential is then a sum of exponentials and has a very specific form that allows for scaling solutions. The scaling solutions describe eternal accelerating and decelerating power-law universes, which are all unstable. An uplift of the solutions to 11-dimensional supergravity is carried out and the resulting timedependent geometries are discussed. In the discussion we briefly comment on the fact that N=2 gauged supergravity allows stable scaling solutions.Comment: 17 pages; referenced added, reportnr changed and some corrections in section

Supra- and Infra-Renal Aortic Neck Diameter Increase after Endovascular Repair of a Ruptured Abdominal Aortic Aneurysm

Hypovolemia-induced hypotension may lead to an aortic diameter decrease in patients with a ruptured abdominal aortic aneurysm (rAAA). This study investigates the changes in supra- and infra-renal aortic neck diameters before and after endovascular aortic aneurysm repair (EVAR) for rAAA and the possible association with endograft apposition. A retrospective cohort study was conducted including 74 patients treated between 2010 and 2019 in two large European vascular centers. Outer-to-outer wall diameters were measured at +40, +10, 0, −10, and −20 mm relative to the lowest renal artery baseline on the last pre- and first post-EVAR computed tomography angiography (CTA) scan in a vascular workstation. Endograft apposition was determined on the first post-EVAR CTA scan. The post-operative diameter was significantly (p < 0.001) larger than the preoperative diameter at all aortic levels. The aortic diameter at +40 mm (supra-renal) and −10 mm (infra-renal) increased by 6.2 ± 7.3% and 12.6 ± 9.8%, respectively. The aortic diameter at +40 mm increased significantly more in patients with low preoperative systolic blood pressure (<90 mmHg; p = 0.005). A shorter apposition length was associated with a higher aortic diameter increase (R = −0.255; p = 0.032). Hypovolemic-induced hypotension results in a significant decrease in the aortic diameter in patients with an rAAA, which should be taken into account when oversizing the endograft

Modulation of airway epithelial innate immunity and wound repair by M(GM-CSF) and M(M-CSF) macrophages

Airway epithelial cells and macrophages participate in inflammatory responses to external noxious stimuli, which can cause epithelial injury. Upon injury, epithelial cells and macrophages act in concert to ensure rapid restoration of epithelial integrity. The nature of the interactions between these cell types during epithelial repair is incompletely understood. We used an in vitro human coculture model of primary bronchial epithelial cells cultured at the air-liquid interface (ALI-PBEC) and polarized primary monocyte-derived macrophages. Using this coculture, we studied the contribution of macrophages to epithelial innate immunity, wound healing capacity, and epithelial exposure to whole cigarette smoke (WCS). Coculture of ALI-PBEC with lipopolysaccharide (LPS)-activated M(GM-CSF) macrophages increased the expression ofDEFB4A,CXCL8, andIL6at 24 h in the ALI-PBEC, whereas LPS-activated M(M-CSF) macrophages only increased epithelialIL6expression. Furthermore, wound repair was accelerated by coculture with both activated M(GM-CSF) and M(M-CSF) macrophages, also following WCS exposure. Coculture of ALI-PBEC and M(GM-CSF) macrophages resulted in increasedCAMPexpression in M(GM-CSF) macrophages, which was absent in M(M-CSF) macrophages.CAMPencodes LL-37, an antimicrobial peptide with immune-modulating and repair-enhancing activities. In conclusion, dynamic crosstalk between ALI-PBEC and macrophages enhances epithelial innate immunity and wound repair, even upon concomitant cigarette smoke exposure.Pathogenesis and treatment of chronic pulmonary disease

Universal de Sitter solutions at tree-level

Type IIA string theory compactified on SU(3)-structure manifolds with orientifolds allows for classical de Sitter solutions in four dimensions. In this paper we investigate these solutions from a ten-dimensional point of view. In particular, we demonstrate that there exists an attractive class of de Sitter solutions, whose geometry, fluxes and source terms can be entirely written in terms of the universal forms that are defined on all SU(3)-structure manifolds. These are the forms J and Omega, defining the SU(3)-structure itself, and the torsion classes. The existence of such universal de Sitter solutions is governed by easy-to-verify conditions on the SU(3)-structure, rendering the problem of finding dS solutions purely geometrical. We point out that the known (unstable) solution coming from the compactification on SU(2)x SU(2) is of this kind.Comment: 20 pages, 3 figures, v2: added reference

Chemokine receptor CCR2 is expressed by human multiple myeloma cells and mediates migration to bone marrow stromal cell-produced monocyte chemotactic proteins MCP-1, -2 and -3

The restricted bone marrow (BM) localisation of multiple myeloma (MM) cells most likely results from a specific homing influenced by chemotactic factors, combined with the proper signals for growth and survival provided by the BM microenvironment. In analogy to the migration and homing of normal lymphocytes, one can hypothesise that the BM homing of MM cells is mediated by a multistep process, involving the concerted action of adhesion molecules and chemokines. In this study, we report that primary MM cells and myeloma derived cell lines (Karpas, LP-1 and MM5.1) express the chemokine receptor CCR2. In addition, we found that the monocyte chemotactic proteins (MCPs) MCP-1, -2 and -3, three chemokines acting as prominent ligands for CCR2, are produced by stromal cells, cultured from normal and MM BM samples. Conditioned medium (CM) from BM stromal cells, as well as MCP-1, -2 and -3, act as chemoattractants for human MM cells. Moreover, a blocking antibody against CCR2, as well as a combination of neutralizing antibodies against MCP-1, -2 and -3, significantly reduced the migration of human MM cells to BM stromal cell CM. The results obtained in this study indicate the involvement of CCR2 and the MCPs in the BM homing of human MM cells. (C) 2003 Cancer Research UK