Preclustering Gelatin for Faster-Forming Injectable Hydrogels: A Strategy for Fabricating 3D Hydrogel Scaffolds with Improved Cell Dispersion.

Gelatin-based injectable hydrogels capable of encapsulating cells are pivotal in tissue engineering because they can conform to any geometry and exhibit physical properties similar to those of living tissues. However, the slow gelation process observed in these cell-encapsulating hydrogels often causes an uneven dispersion of cells. This study proposes an approach for achieving fast gelation of unmodified gelatin under physiological conditions through gelatin preclustering. By using tetrafunctional succinimidyl-terminated poly(ethylene glycol) as a clustering agent, the gelation process is successfully expedited fivefold without requiring chemical modifications, effectively addressing the associated challenges of uneven cell distribution.

Network of cyano-p-aramid nanofibres creates ultrastiff and water-rich hydrospongels.

The structure-property paradox of biological tissues, in which water-rich porous structures efficiently transfer mass while remaining highly mechanically stiff, remains unsolved. Although hydrogel/sponge hybridization is the key to understanding this phenomenon, material incompatibility makes this a challenging task. Here we describe hydrogel/sponge hybrids (hydrospongels) that behave as both ultrastiff water-rich gels and reversibly squeezable sponges. The self-organizing network of cyano-p-aramid nanofibres holds approximately 5,000 times more water than its solid content. Hydrospongels, even at a water concentration exceeding 90 wt%, are hard as cartilage with an elastic modulus of 50-80 MPa, and are 10-1,000 times stiffer than typical hydrogels. They endure a compressive strain above 85% through poroelastic relaxation and hydrothermal pressure at 120 °C. This performance is produced by amphiphilic surfaces, high rigidity and an interfibrillar, interaction-driven percolating network of nanofibres. These features can inspire the development of future biofunctional materials.

Injectable phase-separated tetra-armed poly(ethylene glycol) hydrogel scaffold allows sustained release of growth factors to enhance the repair of critical bone defects.

With the rising prevalence of bone-related injuries, it is crucial to improve treatments for fractures and defects. Tissue engineering offers a promising solution in the form of injectable hydrogel scaffolds that can sustain the release of growth factors like bone morphogenetic protein-2 (BMP-2) for bone repair. Recently, we discovered that tetra-PEG hydrogels (Tetra gels) undergo gel-gel phase separation (GGPS) at low polymer content, resulting in hydrophobicity and tissue affinity. In this work, we examined the potential of a newer class of gel, the oligo-tetra-PEG gel (Oligo gel), as a growth factor-releasing scaffold. We investigated the extent of GGPS occurring in the two gels and assessed their ability to sustain BMP-2 release and osteogenic potential in a mouse calvarial defect model. The Oligo gel underwent a greater degree of GGPS than the Tetra gel, exhibiting higher turbidity, hydrophobicity, and pore formation. The Oligo gel demonstrated sustained protein or growth factor release over a 21-day period from protein release kinetics and osteogenic cell differentiation studies. Finally, BMP-2-loaded Oligo gels achieved complete regeneration of critical-sized calvarial defects within 28 days, significantly outperforming Tetra gels. The easy formulation, injectability, and capacity for sustained release makes the Oligo gel a promising candidate therapeutic biomaterial.

Effect of rapid cefpodoxime disk screening for early detection of third-generation cephalosporin resistance in Escherichia coli and Klebsiella pneumoniae bacteremia.

BACKGROUND: Several methods have been reported for detecting resistance genes or phenotypic testing on the day of positive blood culture in Escherichia coli or Klebsiella pneumoniae bacteremia. However, some facilities have not introduced these methods because of costs or other reasons. Toyota Kosei Hospital introduced cefpodoxime (CPDX) rapid screening on May 7, 2018, to enable early detection of third-generation cephalosporin resistance. In this study, we aimed to evaluate the effects of intervention with an Antimicrobial Stewardship Team using CPDX rapid screening. METHODS: Cefotaxime (CTX)-resistant E. coli or K. pneumoniae bacteremia cases were selected retrospectively and divided into two groups: the pre-CPDX screening (June 1, 2015, to May 6, 2018) and CPDX screening groups (July 7, 2018, to August 31, 2021). The primary outcome was the proportion of cases in which modifications were made to the administration of susceptible antimicrobial agents within 24 h of blood culture-positive reports. RESULTS: Overall, 63 patients in the pre-CPDX screening group and 84 patients in the CPDX screening group were eligible for analysis. The proportion of patients who modified to susceptible antimicrobial agents within 24 h of blood culture-positive reports was significantly increased in the CPDX screening group compared to that in the pre-CPDX screening group (6.3% vs. 22.6%, p = 0.010). CONCLUSION: The results demonstrated that in CTX-resistant E. coli or K. pneumoniae bacteremia, CPDX rapid screening increased the proportion of early initiation of appropriate antimicrobial agents.

One-Pot Approach to Synthesize Tough and Cell Adhesive Double-Network Hydrogels Consisting of Fully Synthetic Materials of Self-Assembling Peptide and Poly(ethylene glycol).

Hydrogels with a double network (DN) structure are compelling biomaterials, holding potential for use as artificial extracellular matrices. Generally, the DN approach imparts hydrogels with high mechanical strength and cell-adhesive properties. However, achieving this often demands a complex multistep process involving potentially hazardous free-radical polymerization, which can result in toxicity. This limits their broad biological applications. In this work, we introduce a straightforward yet biocompatible method to fabricate tough and cell-adhesive DN hydrogels using entirely synthetic materials: the self-assembling peptide (RADA16) and poly(ethylene glycol) (PEG). An in situ mixing of these components leads to the sequential formation of DN hydrogels─first through the self-assembly of the RADA16 peptide and then via chemical cross-linking between PEG molecules. Hydrogels produced this way exhibited up to a 10-fold increase in fracture energy, and cells seeded on their surfaces showcased good attachment. Our design underscores the efficacy of the DN approach and the promising applications of peptides in tissue engineering.

Analysis of factors affecting pharmacists' ability to identify and solve problems.

BACKGROUND: Among Japanese pharmacists, there is a gap in their commitment to self-improvement and a possible gap in their ability to identify and solve problems. However, the factors causing this situation have not yet been clarified. This study was conducted to identify factors that influence the abilities of Japanese pharmacists to identify and solve problems, which are skills considered essential for this profession. A prior history of presenting at academic conferences was set as a surrogate outcome to clarify whether having this experience affects the factors. METHODS: A nationwide internet-based survey was conducted among 300 participating hospitals and 300 community pharmacists. The survey was discontinued when the sample size of each group reached 300. The respondents were categorized into two groups on the basis of their experience of presenting at academic conferences in the survey item "status of self-improvement after employment." Their association with other survey items was determined using univariate and multivariate logistic regression analyses. RESULTS: The multivariate analysis revealed that 152 (50.7%) hospital pharmacists and 41 (13.7%) community pharmacists had presented at academic conferences. Among the hospital pharmacists, the experience of presenting at academic conferences was significantly associated with the "age 30 s (*references 20 s)," "presence of pharmacists to consult," "experience supervising interns," and "number of types of self-improvement" factors. For the community pharmacists, prior conference presentation experience was significantly associated with "age over 70 s," "highest educational background (doctoral or master's degree)," and "number of types of self-improvement." CONCLUSION: This pioneering study suggests that having prior experience of presenting at academic conferences as a surrogate outcome of pharmacists' problem-finding and problem-solving skills may be related to the support provided by human environmental factors at the facility, the status of self-improvement, and the highest educational background.

Percolation-induced gel-gel phase separation in a dilute polymer network.

Cosmic large-scale structures, animal flocks and living tissues can be considered non-equilibrium organized systems created by dissipative processes. Replicating such properties in artificial systems is still difficult. Herein we report a dissipative network formation process in a dilute polymer-water mixture that leads to percolation-induced gel-gel phase separation. The dilute system, which forms a monophase structure at the percolation threshold, spontaneously separates into two co-continuous gel phases with a submillimetre scale (a dilute-percolated gel) during the deswelling process after the completion of the gelation reaction. The dilute-percolated gel, which contains 99% water, exhibits unexpected hydrophobicity and induces the development of adipose-like tissues in subcutaneous tissues. These findings support the development of dissipative structures with advanced functionalities for distinct applications, ranging from physical chemistry to tissue engineering.

Tissue-Adhesive Hydrogel Spray System for Live Cell Immobilization on Biological Surfaces.

Gelatin hydrogels are used as three-dimensional cell scaffolds and can be prepared using various methods. One widely accepted approach involves crosslinking gelatin amino groups with poly(ethylene glycol) (PEG) modified with N-hydroxysuccinimide ester (PEG-NHS). This method enables the encapsulation of live cells within the hydrogels and also facilitates the adhesion of the hydrogel to biological tissues by crosslinking their surface amino groups. Consequently, these hydrogels are valuable tools for immobilizing cells that secrete beneficial substances in vivo. However, the application of gelatin hydrogels is limited due to the requirement for several minutes to solidify under conditions of neutral pH and polymer concentrations suitable for live cells. This limitation makes it impractical for use with biological tissues, which have complex shapes or inclined surfaces, restricting its application to semi-closed spaces. In this study, we propose a tissue-adhesive hydrogel that can be sprayed and immobilized with live cells on biological tissue surfaces. This hydrogel system combines two components: (1) gelatin/PEG-NHS hydrogels and (2) instantaneously solidifying PEG hydrogels. The sprayed hydrogel solidified within 5 s after dispensing while maintaining the adhesive properties of the PEG-NHS component. The resulting hydrogels exhibited protein permeability, and the viability of encapsulated human mesenchymal stem/stromal cells (hMSCs) remained above 90% for at least 7 days. This developed hydrogel system represents a promising approach for immobilizing live cells on tissue surfaces with complex shapes.

Interstitial-fluid shear stresses induced by vertically oscillating head motion lower blood pressure in hypertensive rats and humans.

The mechanisms by which physical exercise benefits brain functions are not fully understood. Here, we show that vertically oscillating head motions mimicking mechanical accelerations experienced during fast walking, light jogging or treadmill running at a moderate velocity reduce the blood pressure of rats and human adults with hypertension. In hypertensive rats, shear stresses of less than 1 Pa resulting from interstitial-fluid flow induced by such passive head motions reduced the expression of the angiotensin II type-1 receptor in astrocytes in the rostral ventrolateral medulla, and the resulting antihypertensive effects were abrogated by hydrogel introduction that inhibited interstitial-fluid movement in the medulla. Our findings suggest that oscillatory mechanical interventions could be used to elicit antihypertensive effects.

[Literacy for Appropriate Use of Medical Big Data and Artificial Intelligence].

Recent developments have enabled daily accumulated medical information to be converted into medical big data, and new evidence is expected to be created using databases and various open data sources. Database research using medical big data was actively conducted in the coronavirus disease 2019 (COVID-19) pandemic and created evidence for a new disease. Conversely, the new term "infodemic" has emerged and has become a social problem. Multiple posts on social networking services (SNS) overly stirred up safety concerns about the COVID-19 vaccines based on the analysis results of the Vaccine Adverse Event Reporting System (VAERS). Medical experts on SNS have attempted to correct these misunderstandings. Incidents where research papers about the COVID-19 treatment using medical big data were retracted due to the lack of reliability of the database also occurred. These topics of appropriate interpretation of results using spontaneous reporting databases and ensuring the reliability of databases are not new issues that emerged during the COVID-19 pandemic but issues that were present before. Thus, literacy regarding medical big data has become increasingly important. Research related to artificial intelligence (AI) is also progressing rapidly. Using medical big data is expected to accelerate AI development. However, as medical AI does not resolve all clinical setting problems, we also need to improve our medical AI literacy.

Miscibility and ternary diagram of aqueous polyvinyl alcohols with different degrees of saponification.

Liquid-liquid phase separation (LLPS), an important phenomenon in the field of polymer science and material design, plays an essential role in cells and living bodies. Poly(vinyl alcohol) (PVA) is a popular semicrystalline polymer utilized in the synthesis of artificial biomaterials. The aqueous solutions of its derivatives with tuned degrees of saponification (DS) exhibit LLPS. However, the miscibility and LLPS behavior of PVA aqueous solution are still unclear. This study describes the miscibility diagram of the ternary mixture, where water and two types of poly(vinyl alcohol) (PVA) with different DSs [98 (PVA98), 88 (PVA88), 82 (PVA82), and 74 mol% (PVA74)] were blended. UV-Vis measurement was conducted to evaluate the miscibility. Immiscibility was more pronounced at elevated temperatures, exhibiting LLPS. The ternary immiscibility diagram, displaying miscible-immiscible behaviors in the aqueous mixtures of PVA74:PVA98, PVA82:PVA98, and PVA88:PVA98 (blended at a constant volume ratio), indicated that increasing the concentration, temperature, and blend ratio of PVAs at a lower DS increased immiscibility, suggesting that the free energy of mixing increases with increasing these parameters. The miscible-immiscible behaviors of PVAs/water systems provide fundamental knowledge about LLPS and the design of PVA-based materials.

In situ-formable, dynamic crosslinked poly(ethylene glycol) carrier for localized adeno-associated virus infection and reduced off-target effects.

The adeno-associated virus (AAV) is a potent vector for in vivo gene transduction and local therapeutic applications of AAVs, such as for skin ulcers, are expected. Localization of gene expression is important for the safety and efficiency of genetic therapies. We hypothesized that gene expression could be localized by designing biomaterials using poly(ethylene glycol) (PEG) as a carrier. Here we show one of the designed PEG carriers effectively localized gene expression on the ulcer surface and reduced off-target effects in the deep skin layer and the liver, as a representative organ to assess distant off-target effects, using a mouse skin ulcer model. The dissolution dynamics resulted in localization of the AAV gene transduction. The designed PEG carrier may be useful for in vivo gene therapies using AAVs, especially for localized expression.

Molecular Weight-Dependent Diffusion, Biodistribution, and Clearance Behavior of Tetra-Armed Poly(ethylene glycol) Subcutaneously Injected into the Back of Mice.

Four-armed poly(ethylene glycol) (PEG)s are essential hydrophilic polymers extensively utilized to prepare PEG hydrogels, which are valuable tissue scaffolds. When hydrogels are used in vivo, they eventually dissociate due to cleavage of the backbone structure. When the cleavage occurs at the cross-linking point, the hydrogel elutes as an original polymer unit, i.e., four-armed PEG. Although four-armed PEGs have been utilized as subcutaneously implanted biomaterials, the diffusion, biodistribution, and clearance behavior of four-armed PEG from the skin are not fully understood. This paper investigates time-wise diffusion from the skin, biodistribution to distant organs, and clearance of fluorescence-labeled four-armed PEGs with molecular weight (Mw) ranging from 5-40 kg/mol subcutaneously injected into the back of mice. Changes over time indicated that the fate of subcutaneously injected PEGs is Mw-dependent. Four-armed PEGs with Mw ≤ 10 kg/mol gradually diffused to deep adipose tissue beneath the injection site and distributed dominantly to distant organs, such as the kidney. PEGs with Mw ≥ 20 kg/mol stagnated in the skin and deep adipose tissue and were mainly delivered to the heart, lung, and liver. The fundamental understanding of the Mw-dependent behavior of four-armed PEGs is beneficial for preparing biomaterials using PEGs, providing a reference in the field of tissue engineering.

Effects of network junctions and defects on the crystallization of model poly(ethylene glycol) networks.

Polymer crystallization drastically changes the physical properties of polymeric materials. However, the crystallization in polymer networks has been little explored. This study investigated the crystallization behavior of a series of poly(ethylene glycol) (PEG) networks consisting of well-defined branched precursors. The PEG networks were prepared by drying gels synthesized at various conditions. The PEG networks showed slower crystallization with lower final crystallinity than uncrosslinked PEGs with amine end groups. Surprisingly, the effect of network formation was not as significant as that of the relatively bulky end-groups introduced in the uncrosslinked polymer. The molecular weight of the precursor PEG, or equivalently the chain length between neighboring junctions, was the primary parameter that affected the crystallization of the PEG networks. Shorter network chains led to lower crystallization rates and final crystallinity. This effect became less significant as the network chain length increased. On the other hand, the spatial and topological defects formed in the gel synthesis process did not affect the crystallization in the polymer networks at all. The crystallization in the polymer networks seems insensitive to these mesoscopic defects and can be solely controlled by the chain length between junctions.

Pharmacist's interventions in factors contributing to medication errors reduces medication errors in self-management of patients in the rehabilitation ward.

BACKGROUND: The number of medications, number of administrations per day, dosing frequency on indicated day, and medication from multiple prescriptions are the medication factors prone to medication errors in self-management that have been previously reported. However, whether pharmacists actually intervene in medication factors that affect medication error occurrences in self-management is unclear. Therefore, we conducted this study to clarify these issues. METHOD: This study included patients who underwent self-management in the rehabilitation ward of Higashinagoya National Hospital. From April 2019 to March 2020, a one-pharmacist period existed, and from April 2020 to March 2021, a two-pharmacist period existed. The number of patient instructions and interventions were expected to increase with an increase in the number of pharmacists. Considering this to be an environment of differential interventions by pharmacists, a pre-post-test design was conducted with all self-managed patients in both the time periods. The primary and secondary endpoints were the proportion of medication error occurrences and proportion of pharmacist's interventions in medication factors, respectively. RESULT: The proportions of medication error occurrences during the one-pharmacist and two-pharmacist periods were 41% (71/173) and 28% (51/180) (relative risk 0.690, 95% confidential interval 0.515-0.925), respectively. The proportion of pharmacist's interventions in medication factors in the one-pharmacist period was 13% (22/173) and 22% (40/180) in the two-pharmacist period; there was an increase in the proportion of pharmacist's interventions in medication factors in the two-pharmacist period. CONCLUSION: The proportion of medication error occurrences was significantly lower in the two-pharmacist period than that in the one-pharmacist period. This can be attributed to the increase in the proportion of pharmacist's interventions in medication factors. Therefore, an environment in which pharmacists could intervene in the medication factors to prevent medication errors in advance is necessary.

Quasi-elastic neutron scattering study on dynamics of polymer gels with controlled inhomogeneity under uniaxial deformation.

We study the segmental and monomer dynamics of polymer gels with controlled inhomogeneity under uniaxial deformation by means of quasi-elastic neutron scattering (QENS). In order to clarify the effect of the homogeneity of a network structure on the polymer dynamics in gels, we compare two types of polymer gels with controlled homogeneity: a homogeneous tetra-PEG gel (homo-gel) prepared from uniform tetra-arm pre-polymers and a heterogeneous tetra-PEG gel (hetero-gel) with a small amount of shorter tetra-PEG pre-polymer. The different inhomogeneity in the homo-gel and the hetero-gel has little effect on the average relaxation time of the chain dynamics in the undeformed state. The difference in the local dynamics in the gels is emphasized under uniaxial deformation: while the homo-gel shows a single relaxation mode, the hetero-gel exhibits a bimodal distribution of relaxation times with a slow dynamic mode ascribed to highly stretched short strands, which causes a more brittle macroscopic fracture compared with that in the case of the homo-gel.

Decoupling between Translational Diffusion and Viscoelasticity in Transient Networks with Controlled Network Connectivity.

The mobility of sustained molecules is influenced by viscoelasticity, which is strongly correlated with the diffusional property in polymeric liquid. However, the study of transient networks formed by a reversible crosslink, which is the viscoelastic liquid, was insufficient due to the absence of a model system. We compare the viscoelastic and diffusional properties of the transient networks, using the model system with controlled network connectivity (Tetra-PEG slime). According to independent measurements of viscoelasticity and diffusion, the root-mean-square distance the polymer diffuses during the viscoelastic relaxation time shows a large deviation from the self-size of the polymer, which is contrary to the conventional understanding. This decoupling between viscoelasticity and diffusion is unique for transient networks, suggesting that the viscoelastic relaxation is not induced by the diffusion of one prepolymer, particularly in the network with low connectivity. These findings will provide a definite basis for discussion to understand the viscoelasticity in transient networks.

Potential safety signal of pregnancy loss with vascular endothelial growth factor inhibitor intraocular injection: A disproportionality analysis using the Food and Drug Administration Adverse Event Reporting System.

Objectives: Intraocular administration of vascular endothelial growth factor (VEGF) inhibitors may be associated with pregnancy loss. However, little is known about intraocular anti-VEGF therapy during pregnancy. Here, we conducted a pharmacovigilance study using a spontaneous reporting database to evaluate the relationship between intraocular VEGF inhibitors and pregnancy loss. Methods: We used the JAPIC AERS database which is composed of the Food and Drug Administration Adverse Event Reporting System (FAERS) dataset preprocessed by the Japan Pharmaceutical Information Center (JAPIC) to investigate the VEGF inhibitors ranibizumab, aflibercept, and bevacizumab. Disproportionality analyses were conducted for VEGF inhibitors and pregnancy loss. The lower limit of the 95% confidence interval (CI) of the reporting odds ratio (ROR) > 1 and a minimum of three reported cases of pregnancy loss were the detection criteria used in the current study. Results: In the FAERS, 19 pregnancy loss cases were reported for ranibizumab with an ROR of 4.44 (95% CI: 2.42-8.16), 6 for intraocular bevacizumab with an ROR of 32.25 (95% CI: 3.88-267.9), and 4 for intraocular aflibercept with an ROR of 5.37 (95% CI: 1.34-21.49). All these drugs met the detection criteria. Conclusion: Potential safety signals of pregnancy loss were obtained from intraocular administration of VEGF inhibitors during pregnancy. These signals should be validated using a causal design study.

Analysis of medication and prescription background risk factors contributing to oral medication administration errors by nurses: A case-control study.

Medication errors, including overdose and underdose, have a significant impact on patients and the medical economy. We need to prevent or avoid recurring medication errors. Therefore, we conducted a survey to identify medication and prescription background risk factors contributing to the administration of medication by nurses. This study surveyed cases of medication administration errors. This study was conducted at Higashinagoya National Hospital from April 1, 2018, to October 31, 2019. Patients' backgrounds and medication and prescription background risk factors were investigated. Three control cases were randomly selected for each medication error case. We defined the group of medication error cases as the medication error group and the group of control cases as the no-medication-error group. A logistic regression analysis was performed for factors related to medication errors. A total of 202 patients were included in the medication error group. The median age and number of medications were 78 years and 7, respectively. A total of 606 cases were included in the no-medication-error group. The median age and number of medications were 77 years and 6, respectively. The factors that exhibited a relationship with the medication error group were the number of administrations per day, dosing frequency on indicated days, prescription and start dates were the same, medications from multiple prescriptions, and continuous use of a medication received prior to admission. This study identified existing medication and prescription background risk factors. Overlapping risk factors from these groups might contribute to medication administration errors. Therefore, reviewing these factors is necessary to avoid recurring medication administration errors.