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Background: No municipal-level study has elucidated the social determinants associated with multimorbidity prevalence (MP). Objective: This article aimed to determine the differences in MP among municipalities and investigate factors associated with such differences through an ecological study of data obtained from a nationwide survey. This article focused on social participation and household income, which are associated with single chronic diseases, such as hypertension. Methods: Study design was a cross sectional study, which used the data from the Japan Gerontological Evaluation Study, a population-based gerontological study among functionally independent older adults aged ≥65 years in Japan. Overall, 152 212 participants from 2016 to 2017 across 91 municipalities were included in the final analysis. Multiple regression analysis was performed with MP as objective variable; social participation or household income were explanatory variables, and education, population density, and health check-ups were adjustment variables. Results: Intermunicipal differences in MP were 28.4% to 43.1% and 23.2% to 38.8% among men and women, respectively. Significant negative correlation was observed between MP and proportion of social participation (non-standardized coefficient [ B ] = −.18 for men and women). A significant positive correlation was noted between MP and equivalent household income of ≤2 million yen in women ( B = .21). Conclusion: Considerable differences in MP existed among municipalities. Areas with high proportion of social participation showed significantly lower MP. Considering the difficulty in managing multimorbidity within the primary care field and limited evidence on effective interventions, community-level interventions encouraging social participation among older individuals might reduce MP. Primary care physicians should consider a community health approach for multimorbidity.

Abstract This single-center retrospective cohort study analyzed the 1-year real-world treatment outcomes of 63 consecutive eyes (of 60 patients) with neovascular age-related macular degeneration (nAMD) that were switched from intravitreal brolucizumab (IVBr) to intravitreal faricimab (IVF) and managed on a treat-and-extend regimen with discontinuation criteria. After the switch, patients opted to continue IVF, to switch back to IVBr, or receive photodynamic therapy (PDT). Thirty-eight patients continued IVF, 16 patients were switched back to IVBr, 2 patients received PDT, and 4 patients paused treatment. Best-corrected visual acuity (BCVA), central subfield thickness (CST), subfoveal choroidal thickness (sf-CT), and injection intervals were compared immediately before and 1 year after the initial IVF. Whereas there was no change in BCVA and CST; 0 [− 0.0969 to 0.125, P = 0.58], − 1.5 [− 27.8 to 13.5, P = 0.11] µm, respectively, sf-CT decreased significantly; − 19.5 [− 45.5 to 7.75, P = 0.015] µm. The patients switched back showed no significant change in sf-CT. The injection interval extended significantly in the IVF continuation and the switch-back group (2.0 and 3.0 weeks, respectively; [P = 0.0007 and 0.0078]) in eyes with a pre-switching interval of less than 12 weeks. Faricimab shows promise as a safe and effective alternative to brolucizumab for treating nAMD.

Abstract Background This study reports the first cases of scleritis following intravitreal brolucizumab (IVBr) injection for nAMD, emphasizing the need to be aware of the possibility of scleritis following IVBr injections. Case presentation Case 1. A 74-year-old Japanese man with nAMD complained of conjunctivitis and decreased vision in the right eye 8 days after his eighth IVBr injection. Examination revealed scleritis without anterior inflammation. Topical 0.1% betamethasone and 0.3% gatifloxacin eye drops were started. The scleritis worsened in the following 2 weeks and became painful. He underwent sub-Tenon’s capsule triamcinolone acetonide (STTA) injection. Two days later, he returned with a complaint of severe vision loss. Fundus examination revealed retinal artery occlusion, vasculitis, and vitreous opacity in the right eye. Vitreous surgery was performed. Case 2. An 85-year-old Japanese woman with nAMD in the right eye complained of reddening of the eye 27 days after her fifth IVBr injection. Examination showed conjunctivitis and scleritis without anterior inflammation in the right eye. She was started on 0.1% fluorometholone and 0.5% levofloxacin hydrate eye drops. The scleritis worsened in the following 3 weeks. Her treatment was switched to 0.1% betamethasone eye drops. One month later, the scleritis had improved and a sixth IVBr injection was administered. There was no worsening of the scleritis at that time. However, 1 month after a seventh IVBr injection, she complained of severe hyperemia and decreased vision. Fundus examination revealed vitreous opacification. She underwent STTA, and the vitreous opacity improved in 24 days. Case 3. A 57-year-old Japanese man with nAMD complained of pain and decreased vision in the right eye 21 days after a fourth IVBr injection. Examination revealed scleritis with high intraocular pressure but no anterior chamber or fundus inflammation. STTA and topical eye drops were performed. One month later, scleritis improved but visual acuity didn’t due to progression of nAMD. Conclusions Intraocular inflammation following IVBr injection may progress to the posterior segment. Scleritis can occur after IVBr injection, and topical eye drops alone may not be sufficient for initial treatment. Clinicians should consider the possibility of scleritis in patients with worsening inflammation after IVBr injection.

Abstract A new anti-vascular endothelial growth factor agent, brolucizumab, was approved by the United States Food and Drug Administration in 2019. We evaluated whether brolucizumab reduces the treatment burden of neovascular age-related macular degeneration (nAMD) after switching by examining 1-year treatment outcomes in a real-world setting. This retrospective single-institution study included 107 consecutive eyes with nAMD treated with brolucizumab. Among these eyes, 30 with treatment-naïve nAMD and 77 treated with other anti-VEGF agents for more than a year were included. All eyes were managed using a treat and extend (TAE) or modified TAE regimen. The last injection intervals at 52 weeks were 12.9 and 12.1 weeks in the treatment-naïve and switch therapy groups, respectively. Among switch therapy group patients whose pre-switch injection intervals were shorter than 120 days (n = 62 eyes), the injection interval was significantly longer after the switch than before, with a mean difference of 2.7 weeks (P

Abstract Introduction The aim of this study was to investigate the safety and efficacy of a single injection of intravitreal faricimab (IVF) in patients with neovascular age-related macular degeneration (nAMD) who had a prior treatment history. Methods A retrospective analysis was conducted on a consecutive cohort of 80 eyes of 75 patients with nAMD who had a prior history of treatment with an injection of anti-vascular endothelial growth factor. Best-corrected visual acuity (BCVA), central subfield thickness (CST), and central choroidal thickness (CCT) were compared before the initial IVF injection and after a treatment interval matching the previous duration. Results Central choroidal thickness decreased significantly following the IVF injection, but there was no significant change in BCVA or CST. Mean (± standard deviation) BCVA changed from 0.34 ± 0.37 to 0.36 ± 0.40 (P = 0.29), CST changed from 242 ± 72 to 242 ± 82 µm (P = 0.99), and CCT changed from 189 ± 98 to 179 ± 97 µm (P

Abstract The increased incidence of obesity in the global population has increased the risk of several chronic inflammation-related diseases, including non-alcoholic steatohepatitis (NASH)-hepatocellular carcinoma (HCC). The progression from NASH to HCC involves a virus-independent liver carcinogenic mechanism; however, we currently lack effective treatment and prevention strategies. Several reports have suggested that fecal volatile organic compounds (VOCs) are strongly associated with NASH-HCC; therefore, we explored the biomarkers involved in its pathogenesis and progression. Fecal samples collected from control and NASH-HCC model STAM mice were subjected to headspace autosampler gas chromatography-electron ionization-mass spectrometry. Non-target profiling analysis identified diacetyl (2,3-butandione) as a fecal VOC that characterizes STAM mice. Although fecal diacetyl levels were correlated with the HCC in STAM mice, diacetyl is known as a cytotoxic/tissue-damaging compound rather than genotoxic or mutagenic; therefore, we examined the effect of bioactivity associated with NASH progression. We observed that diacetyl induced several pro-inflammatory molecules, including tumor necrosis factor-α, cyclooxygenase-2, monocyte chemoattractant protein-1, and transforming growth factor-β, in mouse macrophage RAW264.7 and Kupffer KPU5 cells. Additionally, we observed that diacetyl induced α-smooth muscle actin, one of the hallmarks of fibrosis, in an ex vivo cultured hepatic section, but not in in vitro hepatic stellate TWNT-1 cells. These results suggest that diacetyl would be a potential biomarker of fecal VOC in STAM mice, and its ability to trigger the macrophage-derived inflammation and fibrosis may partly contribute to NASH-HCC carcinogenesis.

Abstract Recent researches have proposed the use of enhanced geothermal system reservoirs consisting of dense networks of microfractures, created by hydraulic and/or thermal fracturing in superhot/supercritical geothermal environments, because of their suitability for thermal energy harvesting. During fracturing and energy extraction, the fracture networks are exposed to cooling due to the injection of cold fluid into the reservoirs. Previous studies showed such cooling enhanced reservoir permeability in conventional geothermal environments. However, the cooling may result in a higher risk of seismicity, owing to decreased normal stress on the fractures. Nevertheless, it is unclear whether cooling-induced permeability enhancement and a higher risk of seismicity occurs within networks of microfractures which consist of numerous interconnected microfractures at various orientations to the in situ triaxial stress. Thus, no dominant fractures have the possibility to cause permeability enhancement/induced seismicity. In this study, results are presented for borehole cooling experiments on a dense network of microfractures in granite, at 400 °C, under true triaxial stress. Permeability and acoustic emissions were measured with decreases in borehole temperature (up to ~ 90 °C). Results showed that permeability increased with increasing temperature drop at relatively low stress levels (15 and 20 MPa). The permeability enhancement occurred without intensive failure, and was reversible. However, permeability was almost constant at a higher stress level (65 MPa). Results showed that permeability enhancement required a thermal stress equivalent to the mean stress, so that the normal stress was reduced to near-zero, for a considerable amount of the microfractures. Additionally, the permeability of dense microfracture networks can be increased by cooling primarily through thermo-elastic deformation (without intensive failure), which may be useful to compensate for the reduction in injectivity due to cooling-induced fluid property changes.

Abstract Porcine edema disease (ED) is an enterotoxaemia that frequently occurs in 4–12 week-old piglets and results in high mortality. ED is caused by Shiga toxin 2e (Stx2e), produced by host-adapted Shiga toxin-producing Escherichia coli (STEC) strains. We constructed a recombinant protein in which the B subunit of Stx2e (Stx2eB) was linked to Cartilage Oligomeric Matrix Protein (COMP)’s pentameric domain to enhance antigenicity to induce neutralizing antibodies against Stx2e. We evaluated the efficacy of this antigen as a vaccine on the farm where ED had occurred. The suckling piglets were divided into two groups. The pigs in the vaccinated group were intramuscularly immunized with the vaccine containing 30 µg/head of Stx2eB-COMP at 1 and 4 weeks of age. The control pigs were injected with saline instead of the vaccine. The neutralizing antibody titer to Stx2e, mortality, clinical score, and body weight was evaluated up to 11 weeks after the first vaccination. In the vaccinated group, the Stx2e neutralizing antibody was detected 3 weeks after the first vaccination, its titer increased during the following weeks. The antibody was not detected in the control group during the test period. The STEC gene was detected in both groups during the test period, but a typical ED was observed only in control pigs; the mortality and clinical score were significantly lower in the vaccinated group than in the control group. These data indicate that the pentameric B subunit vaccine is effective for preventing ED and offers a promising tool for pig health control.

Abstract Improving geothermal systems through hydraulic stimulation to create highly permeable fractured rocks can induce seismicity. Therefore, the technique must be applied at a moderate intensity; this has led to concerns of insufficient permeability enhancement. Adding chemical stimulation can mitigate these issues, but traditional methods using strong mineral acids have challenges in terms of achieving mineral dissolution over long distances and highly variable fluid chemistry. Here, we demonstrate a novel chemical stimulation method for improving the permeability of rock fractures using a chelating agent that substantially enhances the dissolution rate of specific minerals to create voids that are sustained under crustal stress without the challenges associated with the traditional methods. Applying this agent to fractured granite samples under confining stress at 200 °C in conjunction with 20 wt% aqueous solutions of sodium salts of environmentally friendly chelating agents (N-(2-hydroxyethyl)ethylenediamine-N, N′, N′-triacetic acid and N, N-bis(carboxymethyl)-l-glutamic acid) at pH 4 was assessed. A significant permeability enhancement of up to approximately sixfold was observed within 2 h, primarily due to the formation of voids based on the selective dissolution of biotite. These results demonstrate a new approach for chemical stimulation.

Oxaliplatin is a key drug used in the management of solid tumors, such as colorectal cancer; however, it causes peripheral neuropathy. In this study, we investigated the effect of ibudilast, a phosphodiesterase inhibitor, on oxaliplatin-induced mechanical allodynia and histological changes in rats. Ibudilast (7.5 mg/kg, i.p., 5 times per week) reduced mechanical allodynia and histological changes induced by oxaliplatin (4 mg/kg, i.p., twice a week). In contrast, ibudilast (0.01–10 μM) had no effect on oxaliplatin-induced tumor cytotoxicity in murine colon adenocarcinoma 26 cells. These findings suggest that ibudilast could be useful for preventing oxaliplatin-induced peripheral neuropathy in clinical settings.

In selective laser melting (SLM) metal powder is completely melted using a high-power laser beam of 200-400 W to form metallic parts which are almost completely dense and do not require post processing. To reduce the effective Young's modulus of fabricated parts by SLM to that of human bone, strut structures with interconnected pores of mm size are usually adopted for bone implants. In contrast, parts fabricated by SLM or selective laser sintering (SLS) under laser power below about 50 W are not fully dense and contain micropores, resulting in the reduction of the part’s Young's modulus. However, low-power laser SLM/SLS techniques have yet to be extensively studied. In this study, we examine the densities, effective Young's modulus, and metal structure of parts fabricated by low laser power SLM from pure Ti powder under various experimental conditions. The effective Young’s moduli of as-sintered cubic specimens were a few GPa independent of energy density. After applying normal loads, the effective Young’s moduli increased in various rates, according to energy density. At a normal load of 10kN, the effective Young’s moduli were divided into three groups, 10, 40 and 100 GPa. The relative density ranged from 50 to 75% and cluster size from 70 to 330 μm depending on the energy density.

Acetylcholine regulates intestinal epithelial secretion via muscarinic Gq-coupled receptors but its role in cell differentiation is unclear. Here, the authors show that Prox1-positive endocrine cells are sensors for the cholinergic intestinal niche and can trigger increased differentiation of enteroendocrine DCLK1-positive tuft cells.

As an extension of combinatorial molecular layer epitaxy via ablation of perovskite oxides by a pulsed excimer laser, we have developed a laser molecular beam epitaxy (MBE) system for parallel integration of nano-scaled thin films of organic–inorganic hybrid materials. A pulsed infrared (IR) semiconductor laser was adopted for thermal evaporation of organic halide (A-site: CH3NH3I) and inorganic halide (B-site: PbI2) powder targets to deposit repeated A/B bilayer films where the thickness of each layer was controlled on molecular layer scale by programming the evaporation IR laser pulse number, length, or power. The layer thickness was monitored with an in situ quartz crystal microbalance and calibrated against ex situ stylus profilometer measurements. A computer-controlled movable mask system enabled the deposition of combinatorial thin film libraries, where each library contains a vertically homogeneous film with spatially programmable A- and B-layer thicknesses. On the composition gradient film, a hole transport Spiro-OMeTAD layer was spin-coated and dried followed by the vacuum evaporation of Ag electrodes to form the solar cell. The preliminary cell performance was evaluated by measuring I-V characteristics at seven different positions on the 12.5 mm × 12.5 mm combinatorial library sample with seven 2 mm × 4 mm slits under a solar simulator irradiation. The combinatorial solar cell library clearly demonstrated that the energy conversion efficiency sharply changes from nearly zero to 10.2% as a function of the illumination area in the library. The exploration of deposition parameters for obtaining optimum performance could thus be greatly accelerated. Since the thickness ratio of PbI2 and CH3NH3I can be freely chosen along the shadow mask movement, these experiments show the potential of this system for high-throughput screening of optimum chemical composition in the binary film library and application to halide perovskite solar cell.

Abstract Electrochemiluminescence (ECL) refers to light emission induced by an electrochemical redox reaction. The stability, emission response, and light intensity of the ECL device are known to be improved by using an alternating current (AC) voltage. In this paper, an AC-driven ECL device is fabricated with DNA/Ru(bpy)3 2+ hybrid film-modified electrode. The Ru(bpy)3 2+ complex exhibits significant electrochemical reactivity in the DNA/Ru(bpy)3 2+ hybrid film prepared by electrochemical adsorption. The hybrid film contains unique micrometre-scale aggregates of Ru(bpy)3 2+ in DNA matrix. The physicochemical properties of the hybrid film and its AC-driven ECL characteristics in the electrochemical device are studied. Orange-coloured ECL is observed to be emitted from only the aggregated structures in the hybrid film at the high AC frequency of 10 kHz, which corresponds to a response time shorter than 100 μs.

Nanoscale designs are known to increase the energy conversion efficiency of photoelectrochemical water splitting. Here, the authors report a self-organized nanocomposite formed by embedding self-assembled metal nanopillars in a semiconductor thin film, for enhanced photocarrier separation efficiency.

Cripto-1 is a glycophosphatidylinositol (GPI) anchored signaling protein of epidermal growth factor (EGF)-Cripto-1-FRL1-Cryptic (CFC) family and plays a significant role in the early developmental stages and in the different types of cancer cells, epithelial to mesenchymal transition and tumor angiogenesis. Previously, we have developed cancer stem cells (miPS-LLCcm) from mouse iPSCs by culturing them in the presence of conditioned medium of Lewis Lung Carcinoma (LLC) cells for four weeks. Nodal and Cripto-1 were confirmed to be expressed in miPS-LLCcm cells by quantitative reverse transcription PCR (rt-qPCR) implying that Cr-1 was required in maintaining stemness. To investigate the biological effect of adding exogenous soluble CR-1 to the cancer stem cells, we have prepared a C-terminally truncated soluble form of recombinant human CR-1 protein (rhsfCR-1), in which the GPI anchored moiety was removed by substitution of a stop codon through site-directed mutagenesis. rhsfCR-1 effectively suppressed the proliferation and sphere forming ability of miPS-LLCcm cells in a dose-dependent manner in the range of 0 to 5 µg/mL, due to the suppression of Nodal-Cripto-1/ALK4/Smad2 signaling pathway. Frequency of sphere-forming cells was dropped from 1/40 to 1/69 by rhsfCR-1 at 1 µg/mL. Moreover, rhsfCR-1 in the range of 0 to 1 µg/mL also limited the differentiation of miPS-LLCcm cells into vascular endothelial cells probably due to the suppression of self-renewal, which should reduce the number of cells with stemness property. As demonstrated by a soluble form of exogenous Cripto-1 in this study, the efficient blockade would be an attractive way to study Cripto-1 dependent cancer stem cell properties for therapeutic application.

Between September 2009 and January 2010, 6 members of the Japanese Eastern Army, who had completed the same training program, were diagnosed with active tuberculosis (TB) on different occasions. The Ministry of Defense conducted a contact investigation of all members who had come into contact with the infected members. The purpose of this study was to verify the efficacy of the TB screening protocol used in this investigation. A total of 884 subjects underwent interferon-gamma release assay (IGRA) and chest X-ray. The 132 subjects who were IGRA positive or with X-ray findings suggestive of TB subsequently underwent chest computer tomography (CT). Chest CT was performed for 132 subjects. Based on CT findings, 24 (2.7%) subjects were classified into the active TB group, 107 (12.1%) into the latent tuberculosis infection (LTBI) group, and 753 (85.2%) into the non-TB group. The first 2 groups underwent anti-TB therapy, and all 3 groups were followed for 2 years after treatment. Although one subject in the active TB group experienced relapse during the follow-up period, no patient in the LTBI or non-TB groups developed TB. IGRA and chest X-ray, followed by chest CT for those IGRA positive or with suspicious X-ray findings, appears to be an effective means of TB contact screening and infection prevention.

Interleukin-6 (IL-6) is a pleiotropic cytokine that affects various functions, including tumor development. Although the importance of IL-6 in gastric cancer has been documented in experimental and clinical studies, the mechanism by which IL-6 promotes gastric cancer remains unclear. In this study, we investigated the role of IL-6 in the epithelial-stromal interaction in gastric tumorigenesis. Immunohistochemical analysis of human gastritis, gastric adenoma, and gastric cancer tissues revealed that IL-6 was frequently detected in the stroma. IL-6-positive cells in the stroma showed positive staining for the fibroblast marker α-smooth muscle actin, suggesting that stromal fibroblasts produce IL-6. We compared IL-6 knockout (IL-6(-/-)) mice with wild-type (WT) mice in a model of gastric tumorigenesis induced by the chemical carcinogen N-methyl-N-nitrosourea. The stromal fibroblasts expressed IL-6 in tumors from WT mice. Gastric tumorigenesis was attenuated in IL-6(-/-) mice, compared with WT mice. Impaired tumor development in IL-6(-/-) mice was correlated with the decreased activation of STAT3, a factor associated with gastric cancer cell proliferation. In vitro, when gastric cancer cell line was co-cultured with primary human gastric fibroblast, STAT3-related genes including COX-2 and iNOS were induced in gastric cancer cells and this response was attenuated with neutralizing anti-IL-6 receptor antibody. IL-6 production from fibroblasts was increased when fibroblasts were cultured in the presence of gastric cancer cell-conditioned media. IL-6 production from fibroblasts was suppressed by an interleukin-1 (IL-1) receptor antagonist and siRNA inhibition of IL-1α in the fibroblasts. IL-1α mRNA and protein were increased in fibroblast lysate, suggesting that cell-associated IL-1α in fibroblasts may be involved. Our results suggest the importance of IL-6 mediated stromal-epithelial cell interaction in gastric tumorigenesis.

We investigated the effect of Mg doping on the electron affinity of ZnO thin films. MgxZn1-xO (x=0-0.29) composition-gradient films were deposited on an a-Al2O3(001) substrate using combinatorial pulsed laser deposition. The combinatorial high-throughput analysis of the optical transmittance systematically revealed that the bandgap of ZnO films was tunable between 3.3 and 4.0 eV by doping the ZnO thin films with Mg2+ ions. To investigate the electronic structure, photoelectron yield spectroscopy measurements were performed on the MgxZn1-xO composition-gradient films. The ionization potential, which denotes the distance between the valence band maximum and vacuum level, was independent of the Mg content in the ZnO films. By comparing with the optical bandgap results, the electron affinity was tunable from 4.1 to 3.5 eV by the Mg content in the MgxZn1-xO films. [ABSTRACT FROM AUTHOR]