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Background: Pharmacogenomic testing can optimize drug efficacy and minimize adverse effects. CYP3A5 polymorphisms affect the metabolism of tacrolimus. We sought to estimate the budget impact of preemptive pharmacogenomic testing for CYP3A5 in pediatric heart transplantation patients from an institutional perspective., Methods: A decision tree was constructed to estimate the budget impact of pediatric heart transplant patients (age ≤18 years) initiated on tacrolimus with and without CYP3A5 pharmacogenomic testing. The budget impact of preemptive pharmacogenomic testing versus no pharmacogenomic testing was calculated. One-way sensitivity analysis and alternative analyses were conducted to assess the robustness of results to changes in model parameters., Results: CYP3A5 genotype-guided dosing provided savings of up to $17 225 per patient compared to standard dosing. These savings decreased to $11 759 when using another institution's data for the standard-dosing group. The time to achieve therapeutic concentration in the poor metabolizer genotype-guided dosing group had the largest impact on cost savings while the cost of the pharmacogenetic test had the smallest impact on cost savings., Conclusion: Implementing CYP3A5 testing could save $17 225 per pediatric heart transplant patient receiving tacrolimus. As pharmacogenomic testing becomes more widespread, institutions should track resource requirements and outcomes to determine the best implementation policies going forward., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Oral commissure stenosis and lower eyelid ectropion from burns are functionally impairing and challenging to treat. Evaluation of various treatment modalities is limited by a lack of preclinical models. Described is a method for inducing controlled, titratable oral commissure and lower eyelid burns in swine for future treatment research., Methods: Burn wounds 3 cm in diameter were applied to the lower eyelid and oral commissure of seven anesthetized Yorkshire swine for 10, 15, 20, or 30 s at 100 °C with a custom designed thermocouple-controlled burn device and observed for 3, 30, or 90 days. Tissue underwent laser speckle imaging (LSI) to assess vascular perfusion and histologic analysis after harvest. Statistical comparisons were calculated using Wilcoxon rank-sum tests., Results: Subdermal extension was noted in oral commissure and lower eyelid burns with contact time of 20 s or greater. Wound area progressively contracted from post-operative day (POD) 0 to 90 in both sites, but this was not statistically significant based on contact time or burn site (p > 0.20). Burns of 20-30 s demonstrated increased neutrophil influx for oral commissure injuries (p < 0.01) and leukocyte and macrophage influx for lower eyelid injuries (p = 0.02). Degree of vascular congestion increased with 20-30 second burns in both the oral commissure (p = 0.015) and lower eyelid (p = 0.04). Normalized LSI readings showed increased speckle size in both oral commissure (4.0-fold increase, p < 0.01) and lower eyelid (3.2-fold increase, p < 0.01) burns on POD 90 compared to pre-injury. No change in oral or ocular function was noted in any of the groups (p = 0.96)., Conclusion: Oral commissure and lower eyelid burns create scars which may be modified by burn duration. This model may evaluate a therapeutic's ability to limit functional impairment from burns., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gregory Dion reports financial support was provided by US Army Institute of Surgical Research., (Published by Elsevier Ltd.)

Background: Pharmacogenomic testing identifies gene polymorphisms impacting drug metabolism, aiding in optimizing treatment efficacy and minimizing toxicity, thus potentially reducing healthcare utilization. 6-Mercaptopurine metabolism is affected by thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) polymorphisms. We sought to estimate the budget impact of preemptive pharmacogenomic testing for these genes in pediatric acute lymphoblastic leukemia (ALL) patients from an institutional perspective., Methods: A Markov model was constructed to model the first cycle of the maintenance phase of chemotherapy for pediatric ALL patients transitioning between one of three health states: stable, moderately myelosuppressed, and severely myelosuppressed over 16 weeks, with each health state's associated costs derived from the literature. The patient's likelihood to experience moderate or severe myelosuppression based on metabolism phenotype was calculated from the literature and applied on a weekly basis, and the marginal budget impact of preemptive pharmacogenomic testing vs. no pharmacogenomic testing was calculated. One-way sensitivity analysis was conducted to assess parameter influence on results., Results: Preemptive pharmacogenomic testing of TPMT and NUDT15 provided savings of up to $26 028 per patient during the maintenance phase. In the sensitivity analysis, the cost of outpatient management of moderate myelosuppression had the greatest impact on the budget, resulting in cost savings ranging from $8592 to $30 129 when the minimum and maximum costs of management were used in the model., Conclusion: Preemptive pharmacogenomic testing for TPMT and NUDT15 polymorphisms before initiation of maintenance therapy for pediatric ALL patients yielded considerable cost savings., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Rare-earth triiodides free of donor solvents, LnI 3 (Ln = Sc, Y, La-Lu), have been prepared in quantities as high as 76 g and in yields between 72% (Sc) and 98% (La) by the reaction between the corresponding metal and excess ammonium iodide in a two-step, one-pot procedure that is conducted in borosilicate glassware at temperatures of 350-430 °C in commercial tube furnaces. Procedures for both large-scale and small-scale syntheses are described, with specific examples for Ln = Sc, Y, La, Pr, Nd, Gd, Dy, Ho, and Lu. While the large-scale synthesis described here utilizes specialized glassware, the small-scale preparation may be performed in commercially available glassware.

The complex non-centrosymmetric and chiral nature of helical structures endow materials that possess such motifs with unusual properties. However, despite their ubiquity in biological and organic systems, there is a severe lack of inorganic crystals that display helicity in extended lattices, where these unusual properties are expected to be most pronounced. Here, we report a new inorganic helical structure, gallium sulfur iodide (GaSI), within the exfoliable class of III-VI-VII (1:1:1) one-dimensional (1D) van der Waals (vdW) crystals. Through detailed structural analyses, including single-crystal X-ray diffraction, electron microscopy, and density functional theory (DFT), we elucidate the apparent noncrystallographic screw axis and the first example of an atomic scale helical structure bearing a " squircular " cross-section in GaSI. Crystallizing in the non-centrosymmetric P 4̅ space group, we found that GaSI crystals exhibit pronounced second-harmonic generation. From diffuse reflectance spectroscopy, GaSI displays a sizeable bandgap of 3.69 eV, owing tostrong covalent interactions arising from the smaller sulfur atoms within the helix core. These results position GaSI as a promising exfoliable nonlinear optical material across a broad optical window.

The current toolkit for genetic manipulation in the model animal Drosophila melanogaster is extensive and versatile but not without its limitations. Here, we report a powerful and heritable method to knockdown gene expression in D. melanogaster using the self-cleaving N79 hammerhead ribozyme, a modification of a naturally occurring ribozyme found in the parasite Schistosoma mansoni. A 111-bp ribozyme cassette, consisting of the N79 ribozyme surrounded by insulating spacer sequences, was inserted into 4 independent long noncoding RNA genes as well as the male-specific splice variant of doublesex using scarless CRISPR/Cas9-mediated genome editing. Ribozyme-induced RNA cleavage resulted in robust destruction of 3' fragments typically exceeding 90%. Single molecule RNA fluorescence in situ hybridization results suggest that cleavage and destruction can even occur for nascent transcribing RNAs. Knockdown was highly specific to the targeted RNA, with no adverse effects observed in neighboring genes or the other splice variants. To control for potential effects produced by the simple insertion of 111 nucleotides into genes, we tested multiple catalytically inactive ribozyme variants and found that a variant with scrambled N79 sequence best recapitulated natural RNA levels. Thus, self-cleaving ribozymes offer a novel approach for powerful gene knockdown in Drosophila, with potential applications for the study of noncoding RNAs, nuclear-localized RNAs, and specific splice variants of protein-coding genes., Competing Interests: Conflicts of interest The author(s) declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The monitoring of body temperature is a recent addition to the plethora of parameters provided by wellness and fitness wearable devices. Current wearable temperature measurements are made at the skin surface, a measurement that is impacted by the ambient environment of the individual. The use of near-infrared spectroscopy provides the potential for a measurement below the epidermal layer of skin, thereby having the potential advantage of being more reflective of physiological conditions. The feasibility of noninvasive temperature measurements is demonstrated by using an in vitro model designed to mimic the near-infrared spectra of skin. A miniaturizable solid-state laser-diode-based near-infrared spectrometer was used to collect diffuse reflectance spectra for a set of seven tissue phantoms composed of different amounts of water, gelatin, and Intralipid. Temperatures were varied between 20-24 °C while collecting these spectra. Two types of partial least squares (PLS) calibration models were developed to evaluate the analytical utility of this approach. In both cases, the collected spectra were used without pre-processing and the number of latent variables was the only optimized parameter. The first approach involved splitting the whole dataset into separate calibration and prediction subsets for which a single optimized PLS model was developed. For this first case, the coefficient of determination (R 2 ) is 0.95 and the standard error of prediction (SEP) is 0.22 °C for temperature predictions. The second strategy used a leave-one-phantom-out methodology that resulted in seven PLS models, each predicting the temperatures for all spectra in the held-out phantom. For this set of phantom-specific predicted temperatures, R 2 and SEP values range from 0.67-0.99 and 0.19-0.65 °C, respectively. The stability and reproducibility of the sample-to-spectrometer interface are identified as major sources of spectral variance within and between phantoms. Overall, results from this in vitro study justify the development of future in vivo measurement technologies for applications as wearables for continuous, real-time monitoring of body temperature for both healthy and ill individuals.

Background: Thiopurines such as mercaptopurine (MP) are widely used to treat acute lymphoblastic leukemia (ALL). Thiopurine-S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) inactivate thiopurines, and no-function variants are associated with drug-induced myelosuppression. Dose adjustment of MP is strongly recommended in patients with intermediate or complete loss of activity of TPMT and NUDT15. However, the extent of dosage reduction recommended for patients with intermediate activity in both enzymes is currently not clear., Methods: MP dosages during maintenance were collected from 1768 patients with ALL in Singapore, Guatemala, India, and North America. Patients were genotyped for TPMT and NUDT15, and actionable variants defined by the Clinical Pharmacogenetics Implementation Consortium were used to classify patients as TPMT and NUDT15 normal metabolizers (TPMT/NUDT15 NM), TPMT or NUDT15 intermediate metabolizers (TPMT IM or NUDT15 IM), or TPMT and NUDT15 compound intermediate metabolizers (TPMT/NUDT15 IM/IM). In parallel, we evaluated MP toxicity, metabolism, and dose adjustment using a Tpmt/Nudt15 combined heterozygous mouse model (Tpmt+/-/Nudt15+/-)., Results: Twenty-two patients (1.2%) were TPMT/NUDT15 IM/IM in the cohort, with the majority self-reported as Hispanics (68.2%, 15/22). TPMT/NUDT15 IM/IM patients tolerated a median daily MP dose of 25.7 mg/m2 (interquartile range = 19.0-31.1 mg/m2), significantly lower than TPMT IM and NUDT15 IM dosage (P < .001). Similarly, Tpmt+/-/Nudt15+/- mice displayed excessive hematopoietic toxicity and accumulated more metabolite (DNA-TG) than wild-type or single heterozygous mice, which was effectively mitigated by a genotype-guided dose titration of MP., Conclusion: We recommend more substantial dose reductions to individualize MP therapy and mitigate toxicity in TPMT/NUDT15 IM/IM patients., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The factors affecting the formation and crystal structures of unusual 6d 1 Th(III) square planar aryloxide complexes, as exemplified by [Th(OAr Me ) 4 ] 1- (OAr Me = OC 6 H 2 t Bu 2 -2,6-Me-4), were explored by synthetic and reduction studies of a series of related Th(IV) tetrakis(aryloxide) complexes, Th(OAr R ) 4 (OAr R = OC 6 H 2 t Bu 2 -2,6-R-4). Specifically, electronic, steric, and countercation effects were explored by varying the aryloxide ligand, the alkali metal reducing agent, and the alkali metal chelating agent. Salt metathesis reactions between ThBr 4 (DME) 2 (DME = 1,2-dimethoxyethane) and 4 equiv of the appropriate potassium aryloxide salt were used to prepare a series of Th(IV) aryloxide complexes in high yields: Th(OAr H ) 4 (OAr H = OC 6 H 3 t Bu 2 -2,6), Th(OAr tBu ) 4 (OAr tBu = OC 6 H 2 t Bu 3 -2,4,6), Th(OAr OMe ) 4 (OAr OMe = OC 6 H 2 t Bu 2 -2,6-OMe-4), and Th(OAr Ph ) 4 (OAr Ph = OC 6 H 2 t Bu 2 -2,6-Ph-4). Th(OAr H ) 4 can be reduced by KC 8 , Na, or Li in the absence or presence of 2.2.2-cryptand (crypt) or 18-crown-6 (crown) to form dark purple solutions that have EPR and UV-visible spectra similar to those of the square planar Th(III) complex, [Th(OAr Me ) 4 ] 1- . Hence, the para position of the aryloxide ligand does not have to be alkylated to obtain the Th(III) complexes. Furthermore, reduction of Th(OAr OMe ) 4 , Th(OAr tBu ) 4 , and Th(OAr Ph ) 4 with KC 8 in THF generated purple solutions with EPR and UV-visible spectra that are similar to those of the previously reported Th(III) anion, [Th(OAr Me ) 4 ] 1- . Although many of these reduction reactions did not produce single crystals suitable for study by X-ray diffraction, reduction of Th(OAr H ) 4 , Th(OAr tBu ) 4 , and Th(OAr OMe ) 4 with Li provided X-ray quality crystals whose structures had square planar coordination geometries. Reduction of Th(OAr Ph ) 4 with Li also gave a product with EPR and UV-visible spectra that matched those of [Th(OAr Me ) 4 ] 1- , but X-ray quality crystals of the reduction product were too unstable to provide data. Neither Th(Odipp) 4 (THF) 2 (Odipp = OC 6 H 3 i Pr 2 -2,6) nor Th(Odmp) 4 (THF) 2 (Odmp = OC 6 H 3 Me 2 -2,6) could be reduced to Th(III) products under similar conditions. Reduction of U(OAr H ) 3 (THF) with KC 8 in the presence of 2.2.2-cryptand (crypt) was examined for comparison and formed [K(crypt)][U(OAr H ) 4 ], which has a tetrahedral arrangement of the aryloxide ligands. Moreover, no further reduction was observed when either [K(crypt)][U(OAr H ) 4 ] or [K(crown)(THF) 2 ][U(OAr H ) 4 ] were treated with KC 8 or Li.