Search

The introduction of rapid exome sequencing (rES) for critically ill neonates admitted to the neonatal intensive care unit has made it possible to impact clinical decision-making. Unbiased prospective studies to quantify the impact of rES over routine genetic testing are, however, scarce. We performed a clinical utility study to compare rES to conventional genetic diagnostic workup for critically ill neonates with suspected genetic disorders. In a multicenter prospective parallel cohort study involving five Dutch NICUs, we performed rES in parallel to routine genetic testing for 60 neonates with a suspected genetic disorder and monitored diagnostic yield and the time to diagnosis. To assess the economic impact of rES, healthcare resource use was collected for all neonates. rES detected more conclusive genetic diagnoses than routine genetic testing (20% vs. 10%, respectively), in a significantly shorter time to diagnosis (15 days (95% CI 10-20) vs. 59 days (95% CI 23-98, p < 0.001)). Moreover, rES reduced genetic diagnostic costs by 1.5% (€85 per neonate)., Conclusion:  Our findings demonstrate the clinical utility of rES for critically ill neonates based on increased diagnostic yield, shorter time to diagnosis, and net healthcare savings. Our observations warrant the widespread implementation of rES as first-tier genetic test in critically ill neonates with disorders of suspected genetic origin., What Is Known: • Rapid exome sequencing (rES) enables diagnosing rare genetic disorders in a fast and reliable manner, but retrospective studies with neonates admitted to the neonatal intensive care unit (NICU) indicated that genetic disorders are likely underdiagnosed as rES is not routinely used. • Scenario modeling for implementation of rES for neonates with presumed genetic disorders indicated an expected increase in costs associated with genetic testing., What Is New: • This unique prospective national clinical utility study of rES in a NICU setting shows that rES obtained more and faster diagnoses than conventional genetic tests. • Implementation of rES as replacement for all other genetic tests does not increase healthcare costs but in fact leads to a reduction in healthcare costs., (© 2023. The Author(s).)

Aim: To study the effect of in-line filtering on in-line pressure measurement in a simulated infusion system., Methods: The experimental setup consisted of a syringe pump, syringe, intravenous (IV) line, and extension line. For aqueous fluids, a 0.2-μm infusion filter was used, and for lipid emulsions, a 1.2-μm filter. Infusion speed varied from 0.5 to 10.0 mL/h. First, the effect of clamping the extension line was studied on reaching alarm threshold. Second, the effect of aqueous and lipid fluids was evaluated on in-line pressure measurements., Results: In-line placement of an infusion filter did not prolong the time to alarm threshold after occlusion. During 24 hours of monitoring, lipid emulsions and all-in-one admixture only caused a moderate increase in in-line pressure., Conclusion: Placement of an infusion filter does not have a significant effect on the in-line pressure monitoring and has no adverse effect on detecting pressure-related complications of IV administration.

Neocryptolepine, a minor alkaloid of Cryptolepis sanguinolenta, was investigated as a lead for new antiplasmodial agents, because of its lower cytotoxicity than cryptolepine, the major alkaloid. Synthetic 2- or 3-substituted neocryptolepine derivatives were evaluated for their biological activity. In addition to the antiplasmodial activity (Plasmodium falciparum chloroquine-sensitive and -resistant) also the cytotoxicity (MRC-5 cells) was determined. Several compounds such as 2-bromoneocryptolepine showing higher and more selective antiplasmodial activity than neocryptolepine were obtained. Several functional assays and in vitro tests were used to obtain additional information on the mechanism of action, i.e., the beta-haematin formation inhibitory assay (detoxification of haem) and the DNA-methylgreen displacement assay (interaction with DNA). It could be demonstrated that the 2- or 3-substituted neocryptolepine derivatives investigated here have about the same potency to inhibit the beta-haematin formation as chloroquine, indicating that inhibition of haemozoin formation makes at least an important contribution to their antiplasmodial activity, although their in vitro antiplasmodial activity is still less than chloroquine.

The synthesis of 2-(2,2-bis(4-chlorophenyl)ethyl]-2-(4-chlorophenyl)-thiazolidin-4-one (3) from p,p'-dichlorochalcone (1) via 1,3,3-tris(4-chlorophenyl)-propan-1-one (2) using thioglycollic acid in the presence of ammonium carbonate is described. Structural assignment, stereochemistry and biological assay are discussed.

The reaction between phenylglycidyl ether and 2'-deoxyguanosine or 2'-deoxyguanosine-5'-monophosphate yields a variety of different nucleoside and nucleotide adducts. The corresponding mixtures were analyzed by liquid chromatography/electrospray tandem mass spectrometry and the product ion spectra of the different isomers are discussed using the correct cone voltage and collision energy. The latter were selected by looking at the energy-resolved spectra. From these data the formation of N7 and N2 isomers was proposed. However, detailed NMR analysis of the latter proved this isomer to be the N(1)-alkylated adduct. The reaction between phenylglycidyl ether and 2'-deoxyguanosine or 2'-deoxyguanosine-5'-monophosphate yields a variety of different nucleoside and nucleotide adducts. The corresponding mixtures were analyzed by liquid chromatography/electrospray tandem mass spectrometry and the product ion spectra of the different isomers are discussed using the correct cone voltage and collision energy. The latter were selected by looking at the energy-resolved spectra. From these data the formation of N7 and N2 isomers was proposed. However, detailed NMR analysis of the latter proved this isomer to be the N(1)-alkylated adduct. 2'-Deoxyguanosine-5'-monophosphate was alkylated by phenylglycidyl ether at the 5'-phosphate position. If the nucleotide base moiety was alkylated, the corresponding tandem mass spectrometric data strongly suggested alkylation of N7. In the case of bis-PGE-dGMP adduct, evidence was found for simultaneous 5'-phosphate and N7-alkylation.2'-Deoxyguanosine-5'-monophosphate was alkylated by phenylglycidyl ether at the 5'-phosphate position. If the nucleotide base moiety was alkylated, the corresponding tandem mass spectrometric data strongly suggested alkylation of N7. In the case of bis-PGE-dGMP adduct, evidence was found for simultaneous 5'-phosphate and N7-alkylation., (Copyright 1999 John Wiley & Sons, Ltd.)