Flowchart for predicting achieving the target area under the concentration-time curve of vancomycin in critically ill Japanese patients: A multicenter retrospective study.

INTRODUCTION: In therapeutic drug monitoring (TDM) of vancomycin (VCM), the area under the concentration-time curve (AUC) is related to the clinical efficacy and toxicity. Therefore, herein, we examined the factors associated with achieving the target AUC at follow-up and developed a decision flowchart for achieving the target AUC in critically ill patients. METHODS: This multicenter retrospective observational study was conducted at eight hospitals. We retrospectively analyzed data from patients who had received VCM in the intensive care unit from January 2020 to December 2022. Decision-tree (DT) analysis was performed using factors with p < 0.1 in univariate analysis as the independent variables. Case data were split up to two times, and four subgroups were included. The primary endpoint was achieving the target AUC at the follow-up TDM (AUCfollow-up) and target AUCfollow-up achievement was defined as an AUC of 400-600 µg‧h/mL. The initial AUC values were calculated with the 2-point concentrations (peak and trough) using the Bayesian estimation software Practical AUC-guided TDM (PAT). RESULTS: Among 70 patients (median age [interquartile range], 66 [56, 79] years; 50 % women), the AUCfollow-up was achieved in 70 % (49/70). Three factors were selected for the decision flow chart: predicted AUCfollow-up of 400-600 µg‧h/mL, dosing at 12-h intervals, and CCr of 130 mL/min/1.73 m2 or higher; the accuracy was adequate (92 %, R2 0.52). CONCLUSION: We successfully identified the factors associated with achieving the target AUC of VCM at follow-up TDM and developed a simple-to-use DT model. However, the validity of the findings needs to be evaluated.

Transmission electron microscopic study of the surface layer of surgical resected disc specimens in human temporomandibular joint.

In this study, we investigated specific and characteristic findings of the surface layer of surgical resected disc specimens in human temporomandibular joint osteoarthritis cases by transmission electron microscopy (TEM).Specimens were surgically removed from the TMJ of 5 cases (4 female patients: 5 cases) clinically osteoarthritis. Following findings were observed by TEM. Images were photographed on a JEM1400-Flash Electron microscope (JEOL, Japan) equipped with an EM-14661FLASH high-sensitivity digital complementary metal-oxide-semiconductor camera.Following findings were observed by TEM. 1) The surface is covered with plump fibroblastic and histiocytoid cells. 2) Collagen fiber bundles and collagenous matrix are exposed onto the eroded disc surface. 3) Fibrinous dense material is observed on the eroded disc surface. 4) Bundles of collagen fibers are densely observed. 5) Collagen bundles are rich around capillary vessels. 6) Synovial surface cells reveal features of activated macrophages with vacuole formation. Especially, plump fibroblastic and histiocytoid cells, and activated macrophages with vacuole, which were significant findings of the surface layer. These findings might have a significant effect on the regulation of synovial fluid.

Validation study for in vitro skin irritation test using reconstructed human skin equivalents constructed by layer-by-layer cell coating technology.

The aim of this study is to validate an in vitro skin irritation test (SIT) using three-dimensional reconstructed human epidermal (RhE) skin equivalents prepared by layer-by-layer (LbL) method (LbL-3D Skin) in a series of interlaboratory studies. The goal of these validation studies is to evaluate the ability of this in vitro test to reliably discriminate skin irritant from nonirritant chemicals, as defined by OECD and UN GHS. This me-too validation study is to assess the within- and between-laboratory reproducibility, as well as the predictive capacity, of the LbL-3D Skin SIT in accordance with performance standards for OECD TG 439. The developed skin model, LbL-3D Skin had a highly differentiated epidermis and dermis, similar to the validated reference methods (VRM) and native human skin. The quality parameters (cell survival in controls, tissue integrity, and barrier function) were similar to VRM and in accordance with OECD TG 439. The LbL-3D Skin SIT validation study was performed by three participating laboratories and consisted of three independent tests using 20 reference chemicals. The results obtained with the LbL-3D Skin demonstrated high within-laboratory and between-laboratory reproducibility, as well as high accuracy for use as a stand-alone assay to distinguish skin irritants from nonirritants. The predictive potency of LbL-3D Skin SIT using total 54 test chemicals were comparable to those in other RhE models in OECD TG 439. The validation study demonstrated that LbL-3D Skin has proven to be a robust and reliable method for predicting skin irritation.

IVM of human immature oocytes for infertility treatment and fertility preservation.

Background: Thousands of healthy babies are born from in vitro maturation (IVM) procedures, but the rate of efficiency differs with the source of immature oocytes obtained. Recently, there are different IVM protocols proposed for infertility treatment and fertility preservation. Methods: Based on the literature, the clinical application for IVM of immature oocytes was summarized. Main findings Results: Immature oocytes may be retrieved from women after priming with or without the use of follicular stimulation hormone (FSH), human chorionic gonadotrophin (hCG) or a combination of both FSH and hCG. Successful pregnancy rates with IVM technology seem to be correlated with the number of immature oocytes obtained. With the source and culture course of immature oocytes, there are various IVM protocols. IVM of immature oocytes is profoundly affected by the culture conditions, but no breakthrough has been made by improving the IVM medium itself. Thus, the clinical application of IVM technology continues to evolve. Conclusion: IVM technology is a useful technique for infertile women and fertility preservation. Mild stimulation IVF combined with IVM of immature oocytes is a viable alternative to the conventional stimulation IVF cycle treatment as it may prove to be an optimal first-line treatment approach.

Clinical outcomes of personalized blastocyst embryo transfer after endometrial receptivity analysis: A multicenter, retrospective cohort study.

Purpose: To evaluate clinical outcomes after endometrial receptivity analysis (ERA). Methods: This was a multicenter, retrospective cohort study involving 861 women who underwent ERA testing at certified fertility clinics in Japan, and who received subsequent personalized blastocyst embryo transfers (ET) between 2018 and 2020. Clinical outcomes, including pregnancies, miscarriages, and live births, were evaluated according to receptivity status for ERA. Results: Mean patient age was 37.7 years (SD = 4.0), and the median number of previous ETs was 2 (interquartile range, 2-3). 41.0% (353/861) of patients were non-receptive for ERA testing. Clinical pregnancy, miscarriage, and live birth rates for personalized blastocyst ET were 44.5% (226/508), 26.1% (59/226), and 26.8% (136/508) for receptive patients, and 43.1% (152/353), 28.3% (43/152), and 28.9% (102/353) for non-receptive patients, all statistically nonsignificant. Multiple logistic regression demonstrated similar nonsignificant associations between receptivity and clinical outcomes. Greater patient age, smoking, and longer duration of infertility were significantly and negatively associated with receptivity, whereas a history of delivery was positively associated and statistically significant. Conclusions: Clinical outcomes after ERA testing were similar between receptive and non-receptive patients. Further prospective study including an appropriate comparison group are warranted to evaluate the efficacy of ERA testing.

An Oxysulfide Photocatalyst Evolving Hydrogen with an Apparent Quantum Efficiency of 30 % under Visible Light.

Photocatalytic water splitting is a simple means of converting solar energy into storable hydrogen energy. Narrow-band gap oxysulfide photocatalysts have attracted much attention in this regard owing to the significant visible-light absorption and relatively high stability of these compounds. However, existing materials suffer from low efficiencies due to difficulties in synthesizing these oxysulfides with suitable degrees of crystallinity and particle sizes, and in constructing effective reaction sites. The present work demonstrates the production of a Gd2 Ti2 O5 S2 (λ<650 nm) photocatalyst capable of efficiently driving photocatalytic reactions. Single-crystalline, plate-like Gd2 Ti2 O5 S2 particles with atomically ordered surfaces were synthesized by flux and chemical etching methods. Ultrafine Pt-IrO2 cocatalyst particles that promoted hydrogen (H2 ) and oxygen (O2 ) evolution reactions were subsequently loaded on the Gd2 Ti2 O5 S2 while ensuring an intimate contact by employing a microwave-heating technique. The optimized Gd2 Ti2 O5 S2 was found to evolve H2 from an aqueous methanol solution with a remarkable apparent quantum efficiency of 30 % at 420 nm. This material was also stable during O2 evolution in the presence of a sacrificial reagent. The results presented herein demonstrates a highly efficient narrow-band gap oxysulfide photocatalyst with potential applications in practical solar hydrogen production.

Preparation and Characterization of Thermoresponsive Poly(N-vinylisobutyramide) Microgels.

Microgels are soft, adaptive materials exhibiting various properties not only like hydrogels and microparticles but also like macromolecules, colloids, and surfactants. To widen the range of their biomedical and environmental applications, the exploration of an alternative for poly(N-alkylacrylamide)s without potential safety risks is of great importance. In this article, thermoresponsive poly(N-vinylisobutyramide) (PNVIBA) microgels of uniform size were synthesized with NVIBA as a monomer and N,N'-5-oxanonamethyene-bis-N-vinylacetamide as a cross-linker in the presence of sodium dodecyl sulfate by aqueous free radical precipitation polymerization. The introduction of cationic groups into PNVIBA microgels was also accomplished using N-vinylformamide (NVF) as a comonomer and the subsequent conversion of NVF into vinylamine by hydrolysis.

High concentration of dopamine treatment may induce acceleration of human sperm motility.

Purpose: In humans, catecholamines (including dopamine) have been identified in semen and fallopian tubes, while dopamine D2 receptors (D2DR) are found in the sperm midpiece region. How dopamine dose affects human sperm function and whether dopamine treatment is useful in assisted reproductive technology is unclear. Methods: Sperm samples were obtained from patients with normal semen parameters undergoing fertility treatment. We investigated the effects of dopamine treatment on tyrosine phosphorylation and sperm motility. Sperm motility was analyzed using the computer-assisted sperm analysis (CASA) system. Results: This study revealed that various dopamine concentrations (0.1-100 µM) did not increase sperm tyrosine phosphorylation. Progressive motility increased substantially when treated with high concentrations of dopamine (10 and 100 µM) and was blocked by raclopride (a D2DR antagonist). After 24-h sperm culture, the addition of 10 µM dopamine significantly increased curvilinear velocity and amplitude of lateral head displacement, which are indicators of hyperactivation. Conclusion: Dopamine did not affect tyrosine phosphorylation, but increased sperm motility. High concentrations of dopamine were more effective to accelerate sperm motility in cases where sperm motile capacity was low.

Creation, effects on embryo quality, and clinical outcomes of a new embryo culture medium with 31 optimized components derived from human oviduct fluid: A prospective multicenter randomized trial.

Purpose: Our aim is to make an ideal embryo culture medium close to human oviduct fluid (HOF) components, and to evaluate the quality of this medium with embryo quality and clinical outcomes in assisted reproductive technology (ART) by a prospective randomized controlled trial (RCT). Methods: Study I: HOF was collected laparoscopically from patients (n = 28) with normal pelvic findings. According to HOF analysis results, the new medium "HiGROW OVIT®" (OVIT) was designed. Study II: Embryos (2 pronuclei (2PN) = 9633) were assigned from 1435 patients. The blastulation rate (BR), good BR (gBR), utilized (transferred/cryo-preserved) BR (uBR), pregnancy rate (PR), and miscarriage rate (MR) were compared between the OVIT and control groups by RCT. Results: The novel medium 'OVIT' was produced according to 31 HOF components. The concentrations of essential amino acids (e-AAs) were lower in OVIT than in current media, yet the opposite was true for ne-AA concentrations. gBR and uBR were higher in the OVIT group than in the control group. In the older female group, gBT and uBR were significantly higher in the OVIT group. Conclusions: The novel medium 'OVIT' was produced according to HOF data. The OVIT had significantly better embryo quality and clinical outcomes than the current media.

Successful monozygotic triplet pregnancy after a single blastocyst transfer following in vitro maturation of oocytes from a woman with polycystic ovary syndrome: a case report.

BACKGROUND: Although women with polycystic ovarian syndrome (PCOS)-related sub-fertility are high responders to controlled ovarian stimulation, it is difficult to obtain mature oocytes in these women. Therefore, in vitro maturation (IVM), which is the technique of letting the contents of the ovarian follicles and the oocytes inside mature in vitro, has often been proposed in such women. We describe the first successful delivery of monozygotic triplets resulting from transfer of a single blastocyst following IVM of oocytes. CASE PRESENTATION: A 32-year-old nulligravida female with PCOS underwent IVM. She underwent vitrified-warmed single blastocyst transfer following IVM, and a dichorionic triamniotic triplet pregnancy was confirmed at 8 weeks. Healthy triplets were delivered by cesarean section at 33 weeks' gestation. This is the first case of monozygotic triplets derived from IVM oocytes that were successfully delivered. The determination of chorionicity and amnionicity is generally supposed until 3 days after fertilization, and no division or splitting of her embryo was observed on transfer. Interestingly, her embryo might have split after the transfer, resulting in a dichorionic triamniotic triplet pregnancy. CONCLUSIONS: Patients should be informed of a possible increased risk of monozygotic multiple pregnancies after single embryo transfer following IVM.

Scanning electoronmicroscopical analysis of the loose bodies of synovial chondoromatosis in temporomandibular joint.

The aim of this study is to reveal the morphological property about the loose bodies (LBs) of temporomandibular joint (TMJ) by scanning electron microscope (SEM). We obtained specimens from two female cases of released loose body by surgical operation. These specimens were fixed by soaking in a mixture of 5% glutaraldehyde or 4% formaldehyde for one week. They were cut into half pieces. These specimens were observed at an accelerating voltage of 3 kV under a SEM (JSM-5500, JEOL, Tokyo). In the electron microscopic findings, it seems to be separated into two different parts as inside part and outside part. On the inside part, collagen fibers were running very densely in the same direction in an orderly neatly manner. Whereas, we observed waved collagen fibers running irregularly with many spaces on the outside part. Outside part seems to be porous pattern compared with inside part. It might be that the surface and outside part included many active fibroblasts. As results, it seems that the LBs might develop in a multi-layer style, in which fibrous tissues were piled up loosely around the inside part. The proliferating activity of LBs grows from the inside to outside of SC in TMJ.

Clinical outcomes of microdissection testicular sperm extraction and intracytoplasmic sperm injection in Japanese men with Y chromosome microdeletions.

PURPOSE: We investigated the clinical results of Japanese men with Y chromosome microdeletions. METHODS: This study retrospectively examined 2163 azoospermic or severe oligozoospermic patients. We investigated the frequency of azoospermia factor (AZF) deletions and sperm retrieval rate (SRR) by microTESE in patients with these deletions, then analyzed the ICSI outcomes. RESULTS: Azoospermia factor deletions were found in 201 patients. SRR was significantly higher than that of the control group (74.0% vs 20.4%, P < .001). Thirty-three couples underwent ICSI using testicular spermatozoa retrieved by microTESE, and eight couples underwent ICSI using ejaculatory spermatozoa. The fertilization rate and clinical pregnancy rate per embryo transfer cycle were significantly higher in the ejaculatory group than that of the testicular group (66.4% vs 43.7%, P < .001, 53.3% vs 24.7%, P = .03, respectively). When compared with the control group, the fertilization rate was significantly lower in the testicular group with AZFc microdeletions (43.7% vs 53.6%, P < .001). CONCLUSIONS: Our study highlights that although microTESE in azoospermic men with AZFc microdeletions led to a higher SRR, ICSI outcomes of these men were worse than that of men without AZF deletions, even if testicular spermatozoa were retrieved.

Comparison of range of motion during movement from supine to sitting position in healthy young and elderly participants.

[Purpose] The purpose of this study was to compare the range of motion (ROM) during supine-to-sitting position (StSP) movement between healthy young and elderly participants to understand age-related tendencies, which is beneficial for the assessment and treatment of frail elderly. [Participants and Methods] The participants were 14 healthy young males (age, 19-24 years) and 16 healthy elderly individuals (8 males and 8 females; age, 65-74 years). Rising movement was performed 5 times freely at a comfortable speed. [Results] The joint angles during StSP movements in right shoulder abduction, extension of both shoulder joints, right elbow flexion, trunk extension, and adduction of both hip joints were significantly larger, whereas neck flexion, trunk flexion, and left hip joint abduction were significantly smaller in the healthy elderly participants than in the healthy young participants. All joint movements were earlier in the elderly participants than in the healthy young participants. [Conclusion] The results of this study suggest that focusing on how to use both upper limbs is important, in addition to the neck and trunk, when evaluating StSP movement. Similarly, to encourage independence during StSP movement, the elbow extensors must be strengthened.

Fabrication of supramolecular cyclodextrin-fullerene nonwovens by electrospinning.

Direct electrospinning of small molecules has great potential to fabricate a new class of fiber materials because this approach realizes the creation of various functional materials through the numerous molecular combinations. In this paper, we demonstrate a proof-of-concept to fabricate supramolecular fiber materials composed of cyclodextrin (CD)-fullerene inclusion complexes by electrospinning. Similar to the molecular state of fullerenes in solution, the resulting fibers include molecularly-dispersed fullerenes. We believe such a concept could be expanded to diverse host-guest complexes, opening up supramolecular solid materials science and engineering.

Grhl2 regulation of SPINT1 expression controls salivary gland development.

Development of the salivary gland is characterized by extensive branching morphogenesis and lumen formation, the latter of which is closely associated with differentiation into acinar and ductal cells. Although various molecules, including signaling and cell adhesion molecules, have been implicated in salivary gland development, transcription factors (TFs) regulating the expression of those molecules and morphological development of the gland are largely unknown. Here we show that knockdown of the epithelial TF, Grainyhead-like 2 (Grhl2), with siRNA in developing mouse submandibular salivary gland (SMG) cultured ex vivo resulted in retardation of epithelial development. This retardation was concomitant with suppression of gene expression for the cell adhesion molecules, such as E-cadherin and the extracellular protease inhibitor SPINT1, and with the disorganized deposition of the basal lamina protein laminin. ChIP-PCR demonstrated the binding of Grhl2 protein to the Spint1 gene in the SMG. Notably, addition of recombinant SPINT1 protein in cultured SMG overcame the suppressive effects of Grhl2 siRNA on epithelial development and laminin deposition. These findings show that Grhl2 regulation of SPINT1 expression controls salivary gland development.

Potassium bromate disrupts mitochondrial distribution within murine oocytes during in vitro maturation.

PURPOSE: As disturbed mitochondrial distribution is thought to be a cause of the aging of oocytes, it was investigated whether oxidizing agents exert harmful effects on nuclear maturation and mitochondrial cluster formation in murine oocytes and whether antioxidants could rescue such harmful effects in vitro. METHODS: Oocytes were obtained from female Institute of Cancer Research mice 48 h after an intraperitoneal injection of 7.5 IU pregnant mare serum gonadotropin. The oocytes were cultured with potassium bromate, an oxidizing agent, in the presence or absence of the antioxidant, resveratrol. After 12 h, the nuclear phases and mitochondrial distribution were observed. RESULTS: Significantly decreased rates of metaphase II (MII) oocytes were observed with 750 µM and 1000 µM of potassium bromate, while a significant increase in abnormal mitochondrial clusters was induced at 500 µM, 750 µM, and 1,000 µM. The addition of 10 µM or 20 µM resveratrol improved both MII maturity and the cluster formation rates in the presence of potassium bromate. CONCLUSIONS: The addition of potassium bromate reduced MII maturity rates and induced abnormal mitochondrial cluster formation. This effect was alleviated by the antioxidant, resveratrol. The in vitro model used herein is useful for investigating the functions of antioxidants in the aging of oocytes.

Osmotic and diffusio-osmotic flow generation at high solute concentration. II. Molecular dynamics simulations.

In this paper, we explore osmotic transport by means of molecular dynamics (MD) simulations. We first consider osmosis through a membrane and investigate the reflection coefficient of an imperfectly semi-permeable membrane, in the dilute and high concentration regimes. We then explore the diffusio-osmotic flow of a solute-solvent fluid adjacent to a solid surface, driven by a chemical potential gradient parallel to the surface. We propose a novel non-equilibrium MD (NEMD) methodology to simulate diffusio-osmosis, by imposing an external force on every particle, which properly mimics the chemical potential gradient on the solute in spite of the periodic boundary conditions. This NEMD method is validated theoretically on the basis of linear-response theory by matching the mobility with their Green-Kubo expressions. Finally, we apply the framework to more realistic systems, namely, a water-ethanol mixture in contact with a silica or a graphene surface.

Osmotic and diffusio-osmotic flow generation at high solute concentration. I. Mechanical approaches.

In this paper, we explore various forms of osmotic transport in the regime of high solute concentration. We consider both the osmosis across membranes and diffusio-osmosis at solid interfaces, driven by solute concentration gradients. We follow a mechanical point of view of osmotic transport, which allows us to gain much insight into the local mechanical balance underlying osmosis. We demonstrate in particular how the general expression of the osmotic pressure for mixtures, as obtained classically from the thermodynamic framework, emerges from the mechanical balance controlling non-equilibrium transport under solute gradients. Expressions for the rejection coefficient of osmosis and the diffusio-osmotic mobilities are accordingly obtained. These results generalize existing ones in the dilute solute regime to mixtures with arbitrary concentrations.

Genome-wide analysis of DNA methylation dynamics during early human development.

DNA methylation is globally reprogrammed during mammalian preimplantation development, which is critical for normal development. Recent reduced representation bisulfite sequencing (RRBS) studies suggest that the methylome dynamics are essentially conserved between human and mouse early embryos. RRBS is known to cover 5-10% of all genomic CpGs, favoring those contained within CpG-rich regions. To obtain an unbiased and more complete representation of the methylome during early human development, we performed whole genome bisulfite sequencing of human gametes and blastocysts that covered>70% of all genomic CpGs. We found that the maternal genome was demethylated to a much lesser extent in human blastocysts than in mouse blastocysts, which could contribute to an increased number of imprinted differentially methylated regions in the human genome. Global demethylation of the paternal genome was confirmed, but SINE-VNTR-Alu elements and some other tandem repeat-containing regions were found to be specifically protected from this global demethylation. Furthermore, centromeric satellite repeats were hypermethylated in human oocytes but not in mouse oocytes, which might be explained by differential expression of de novo DNA methyltransferases. These data highlight both conserved and species-specific regulation of DNA methylation during early mammalian development. Our work provides further information critical for understanding the epigenetic processes underlying differentiation and pluripotency during early human development.

Catalytic Enantioselective Synthesis of N-C Axially Chiral Phenanthridin-6-one Derivatives.

N-C axially chiral phenanthridin-6-one derivatives bearing various ortho-substituted phenyl groups on the nitrogen atom were enantioselectively prepared through (R)-DTBM-SEGPHOS-Pd(OAc)2-catalyzed intramolecular Buchwald-Hartwig amination. The enantioselectivity strongly depended on solvents, bases, and reaction temperature as well as on the bulkiness of ortho-substituents.