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This paper describes an investigation into the possible heat transfer benefits of conformal cooling channels using maraging steel MS1 inserts, which could result in a reduction of cycle times and cost per product, and improve part quality by eliminating defects such as warpage and heat sinks. A manufacturing cost and lead-time comparison showed that a conventionally manufactured insert reached its break-even point after fewer injection moulding cycles than an additive manufactured insert, due to its lower manufacturing costs. During high-volume production, the additive manufactured insert becomes more profitable to use, due to its shorter cycle times.

Existing techniques to manufacture conventional tool steel inserts for the plastic injection moulding process are expensive and time-consuming. Complex mould inserts, difficult to manufacture with conventional processes, can be produced using Direct Metal Laser Sintering (DMLS) with Maraging tool steel (MS1). MS1 is an additive manufacturing (AM) material made available by Electro Optical Systems (EOS) GmbH. Contrary to material removal processes, DMLS can produce MS1 tool steel inserts directly from Computer-Aided Design (CAD) files suitable for high volume plastic injection moulding. Through DMLS it is possible to create conformal cooling channels inside the MS1 inserts that have advantages in reducing heat rapidly and evenly. This can result in a reduction of cycle times, cost per product as well as improving part quality by eliminating defects such as warpage and heat sinks. This paper will present a comparison between Finite Element Analysis (FEA) simulations of the injection mould inserts with actual mould trails of AM and conventional manufactured inserts. It also includes the design and manufacturing of conventional and DMLS inserts and compares the manufacturing costs and lead times. Using FEA simulations, the design of conformal cooling channels is optimised by comparing the mould temperature of different cooling channel layouts.

This paper describes the possibility of using laser-sintered Alumide® as an alternative material for producing rapid tooling (RT) inserts. To determine the durability of Alumide® inserts for the injection moulding (IM) process, a product with geometrical features was developed, and Alumide® inserts were manufactured. Polypropylene (PP), acrylonitrile-butadiene-styrene (ABS), polycarbonate (PC), and polyamide 6 (PA 6) were used for IM trials with the Alumide® inserts. From these trials, it was concluded that polymer materials with a processing temperature of about 230 °C, similar to PP and ABS, can be used with Alumide® inserts as RT inserts for the IM process. [ABSTRACT FROM AUTHOR]

Young sub-Saharan African and developing-world patients with rheumatic heart valve diseases urgently require cost-effective prosthetic valves. To design cost-effective polyurethane heart valves, comprehend haemodynamic behaviour, expedite prototype development, and reduce the need for clinical testing for functional evaluation, the implementation of an experimental test digital twinning is essential. The use of computational fluid dynamics (CFD) and finite element analysis (FEA) to improve heart valve replacement designs rapidly, in order to comply with the minimum requirements of Food and Drug Administration (FDA) and International Organization for Standardization (ISO) regulations and specifications, forms the core of this study. This approach is presented, and the results are discussed. A conclusion is drawn about the valve geometric orifice area (GOA) compared with experimental tests. When the valve was fully opened, there was only an 11% difference between the computed experimental and the finite element GOA. Digital simulation revealed additional information such as the locations of stress concentrations. The FE results showed reasonable similarity with in vitro results. [ABSTRACT FROM AUTHOR]

In this study a controllable compression moulding process has been developed for the manufacturing of variable thickness polyurethane heart valves. An experimental facility was established for the compression moulding process. Additive manufactured polymer moulds (AM) were used to determine the suitable design configuration and test process parameters for the successful manufacturing of polyurethane heart valves. Experiments were carried out with a polyurethane solution (PC3595A-B20 and PC3595A) and solvents (N, N-Dimethylacetamide and Tetrahydrofuran) to investigate the effect of changing compression moulding parameters. Due to the capability of the compression mould to produce thin-walled parts with controlled thickness, experimental results demonstrated that a well-controlled compression moulding technique is a feasible alternative to the dip moulding process. The AM polymer moulds demonstrated that this process could be used in an automated experimental facility to create a working prototype polyurethane heart valve. The AM polymer moulds demonstrated that it is possible to obtain a suitable design configuration of a mould layout and to create a working prototype polyurethane heart valve.

Laser Powder Bed Fusion (LPBF) of cobalt-chrome (Co-Cr) alloys has been recognized for producing parts exhibiting the strength and being devoid of defects typically associated with cast Co-Cr alloys. Therefore, such parts are considered safe and comparable to cast Co-Cr alloys for intraoral use. Since additive manufacturing offers the advantage of creating complex geometries, the use of this thermo-physical process in a controlled manner allows for the homogenous production of the complex geometries typically required for dental products. This paper compares the mechanical properties claimed to be achievable through LPBF by the powder supplier against real world mechanical properties as used in dental applications. This comparison will serve as a baseline from which the mechanical properties achieved can be further enhanced to suit other possible applications of Co-Cr.

Background: Tuberculous meningitis (TBM) is the most lethal form of TB. To study the disease, drug concentrations in samples obtained from the spinal CSF are usually used to reflect brain concentrations. Emerging data suggest that transport of substances across capillaries in the brain (ventricular CSF) and spinal cord may differ., Methods: We examined paired, time-linked samples of ventricular CSF (VCSF) and lumbar CSF (LCSF) of 28 patients with TBM and analysed these for rifampicin and total protein concentrations. Clinically indicated samples from procedures to determine the level of CSF block were collected from children being treated for TBM and hydrocephalus. Total protein concentrations were determined using the bicinchoninic acid (BCA) or turbidimetry assay, and rifampicin concentrations were determined using a validated LC coupled with tandem MS method. A paired Wilcoxon signed-rank test was used to determine significance., Results: TBM was confirmed in 19 cases (68%) using TB culture or GeneXpert Mtb/Rifampicin assay. All other cases were classified as probable. The median total protein concentration in LCSF was 6.0 g/L and in VCSF was 1.3 g/L. The median rifampicin concentration in LCSF was 299 ng/mL and 133 ng/mL in VCSF. The median ratio of LCSF/VSCF for protein was 4.23 and 1.57 for rifampicin., Conclusions: Total protein and rifampicin concentrations differed significantly between the two compartments, both being higher in LCSF than in VCSF samples (P < 0.0001 for total protein and P = 0.0046 for rifampicin). Further studies are required to explore the causative reasons for the observed differences., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

The pauci-cellular nature of cerebrospinal (CSF), particularly ventricular CSF, and the rapid cell death following sampling, incumbers the use of flow cytometric analysis of these samples in the investigation of central nervous system (CNS) pathologies. Developing a method that allows long-term storage and batched analysis of CSF samples without compromising cell integrity is highly desirable in clinical research, given that CSF is often sampled after hours creating logistical difficulties for fresh processing. We examined percentages and relative proportion of peripheral and brain-derived immune cells in cryopreserved and transfix-treated CSF, compared to freshly processed CSF. Cell proportions were more comparable between Fresh and Cryopreserved CSF (mean of differences = 3.19), than between fresh and transfix-treated CSF (mean of differences = 14.82). No significant differences in cell percentages were observed in fresh versus cryopreserved CSF; however significantly lower cell percentages were observed in transfix-treated CSF compared to Fresh CSF [(CD11b ++ (p = 0.01), CD4 + (p = 0.001), CD8 + (p = 0.007), NK cells (p = 0.04), as well as CD69 + activation marker (p = 0.001)]. Furthermore, loss of marker expression of various lymphocyte sub-populations were observed in transfix-treated CSF. Cryopreservation is a feasible option for long-term storage of ventricular CSF and allows accurate immunophenotyping of peripheral and brain-derived cell populations by flow cytometry., (© 2024. The Author(s).)

The persistence of drug resistance poses a significant obstacle to the advancement of efficacious malaria treatments. The remarkable efficacy displayed by 1,2,3-triazole-based compounds against Plasmodium falciparum highlights the potential of triazole conjugates, with diverse pharmacologically active structures, as potential antimalarial agents. We aimed to synthesize 7-dichloroquinoline-triazole conjugates and their structure-activity relationship (SAR) derivatives to investigate their anti-plasmodial activity. Among them, QP11, featuring a m-NO 2 substitution, demonstrated efficacy against both chloroquine-sensitive and -resistant parasite strains. QP11 selectively inhibited FP2, a cysteine protease involved in hemoglobin degradation, and showed synergistic effects when combined with chloroquine. Additionally, QP11 hindered hemoglobin degradation and hemozoin formation within the parasite. Metabolic stability studies indicated high stability of QP11, making it a promising antimalarial candidate. In vivo evaluation using a murine malaria model demonstrated QP11's efficacy in eradicating parasite growth without neurotoxicity, presenting it as a promising compound for novel antimalarial development., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mohammad Abid, Babita Aneja, Bhumika Kumar, Sonal Gupta, Shailja Singh, Amaduddin has patent pending to 201811034848., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

A series of neutral and cationic Ir(III) and Rh(III) aminoquinoline-benzimidazole hybrid complexes were synthesised and their inhibitory activities evaluated against Plasmodium falciparum and Mycobacterium tuberculosis. In general, the hybrid complexes display good activity against the chloroquine-sensitive NF54 strain of P. falciparum. The neutral Ir(III)- and Rh(III)-Cp∗ complexes were the most active (IC 50  = 0.488 μM for Ir III ), maintaining activity against the multidrug-resistant K1 strain. Low to no cytotoxicity against the Chinese hamster ovarian cell line was observed for the tested complexes. Selected active hybrid complexes demonstrated significant inhibition of β-haematin formation in a cell-free NP-40 assay, suggesting an effect on the host haemoglobin degradation pathway as a potential contributing mechanism of action. When tested against M. tuberculosis H37Rv, most hybrid complexes displayed moderate to good activity. Again, the neutral complexes outperformed the cationic complexes, with the neutral Ir(III)-Cp∗ complexes proving most active (MIC 90  = 0.488-1.490 μM)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

The parasitic disease malaria places almost half of the world's population at risk of infection and is responsible for more than 400,000 deaths each year. The first-line treatment, artemisinin combination therapies (ACT) regimen, is under threat due to emerging resistance of Plasmodium falciparum strains in e.g. the Mekong delta. Therefore, the development of new antimalarial agents is crucial in order to circumvent the growing resistance. Chloroquine, the long-established antimalarial drug, still serves as model compound for the design of new quinoline analogues, resulting in numerous new active derivatives against chloroquine-resistant P. falciparum strains over the past twenty years. In this work, a set of functionalized quinoline analogues, decorated with a modified piperidine-containing side chain, was synthesized. Both amino- and (aminomethyl)quinolines were prepared, resulting in a total of 18 novel quinoline-piperidine conjugates representing four different chemical series. Evaluation of their in vitro antiplasmodium activity against a CQ-sensitive (NF54) and a CQ-resistant (K1) strain of P. falciparum unveiled highly potent activities in the nanomolar range against both strains for five 4-aminoquinoline derivatives. Moreover, no cytotoxicity was observed for all active compounds at the maximum concentration tested. These five new aminoquinoline hit structures are therefore of considerable value for antimalarial research and have the potency to be transformed into novel antimalarial agents upon further hit-to-lead optimization studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The tropical disease malaria is responsible for more than 400,000 deaths annually, especially in Southeast Asia and Africa. Although the number of malaria cases is declining, there still is an urgent need for novel antimalarial agents. The emergence of hybrid antimalarial agents and the precedence set by the antimalarial drug ferroquine (FQ) prompted us to design new ferrocene-containing quinoline structures. Herein, we report the efficient synthesis of three different series of ferrocene-quinoline conjugates and a class of ferrocene-containing heterotricycles in good to high yields. For all twenty novel ferrocenyl derivatives, electrochemical properties were investigated using cyclic voltammetry and antiplasmodium evaluation against a chloroquine-susceptible NF54 strain of the human malaria parasite Plasmodium falciparum was conducted, pointing to three compounds showing submicromolar potency. Subsequently, cytotoxicity assays against a Chinese Hamster Ovarian cell line and evaluation against a chloroquine-resistant strain of Plasmodium falciparum for these three compounds revealed selective and promising antiplasmodium activity., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Permeation models are often used to determine diffusion properties of a drug through a membrane as it is released from a delivery system. In order to circumvent problematic in vivo studies, diffusion studies can be performed in vitro, using (semi-)synthetic membranes. In this study salicylic acid permeation was studied, employing a nitrocellulose membrane. Both saturated and unsaturated salicylic acid solutions were studied. Additionally, the transport of salicylic acid through the nitrocellulose membrane was simulated by computational modelling. Experimental observations could be explained by the transport mechanism that was revealed by dissipative particle dynamics (DPD) simulations. The DPD model was developed with the aid of atomistic scale molecular dynamics (AA-MD). The choice of a suitable model membrane can therefore, be predicted by AA-MD and DPD simulations. Additionally, the difference in the magnitude of release from saturated and unsaturated salicylic acid and solutions could also be observed with DPD. Moreover, computational studies can reveal hidden variables such as membrane-permeant interaction that cannot be measured experimentally. A recommendation is made for the development of future model permeation membranes is to incorporate computational modelling to aid the choice of model.

In an attempt to improve the efficacy and stability of current, clinically used artemisinins, a series non-hemiacetal ester derivatives of artemisinin were synthesized and evaluated for their in vitro antiplasmodial and anticancer activities as well as cytotoxicities. These esters were synthesized through the reaction of acid anhydrides, or acid chlorides with artemisinin derived alcohol. In vitro antiplasmodial activity assessments were conducted against intraerythrocytic NF54 and Dd2 Plasmodium falciparum strains. Cytotoxicities were assessed, using normal human fetal lung fibroblast (WI-38) and Chinese hamster ovarian (CHO) mammalian cell lines, while anticancer activities were tested by using panels with three cell lines, consisting of renal (TK10), melanoma (UACC62) and breast (MCF7) cancer cells. Most compounds were found active against the breast cancer cell line. Since antiplasmodial activities for most compounds were found comparable only to that of artesunate, this study did not yield any esters with significantly improved antimalarial efficacies, nor did it deliver any promising antitumor hits. However, from the outcomes of this study, compounds with good safety profiles and increased thermal stabilities, compared to the clinically used artemisinins, were identified. The benzoate derivative 11 was found to have antimalarial activity, comparable to that of dihydroartemisinin and was it subsequently identified as a candidate for further investigation in the urgent search for new, safe and effective antimalarial drugs., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Emulsions are widely used as topical formulations in the pharmaceutical and cosmetic industries. They are thermodynamically unstable and require emulsifiers for stabilization. Studies have indicated that emulsifiers could affect topical delivery of actives, and this study was therefore designed to investigate the effects of different polymers, applied as emulsifiers, as well as the effects of pH on the release and topical delivery of the active. O/w emulsions were prepared by the layer-by-layer technique, with whey protein forming the first layer around the oil droplets, while either chitosan or carrageenan was subsequently adsorbed to the protein at the interface. Additionally, the emulsions were prepared at three different pH values to introduce different charges to the polymers. The active ingredient, salicylic acid, was incorporated into the oil phase of the emulsions. Physical characterization of the resulting formulations, i.e., droplet size, zeta potential, stability, and turbidity in the water phase, was performed. Release studies were conducted, after which skin absorption studies were performed on the five most stable emulsions, by using Franz type diffusion cells and utilizing human, abdominal skin membranes. It was found that an increase in emulsion droplet charge could negatively affect the release of salicylic acid from these formulations. Contrary, positively charged emulsion droplets were found to enhance dermal and transdermal delivery of salicylic acid from emulsions. It was hypothesized that electrostatic complex formation between the emulsifier and salicylic acid could affect its release, whereas electrostatic interaction between the emulsion droplets and skin could influence dermal/transdermal delivery of the active.