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Background: Salivary lactate dehydrogenase (LD) levels are a feasible and useful parameter for screening periodontal diseases. The periodontal inflamed surface area (PISA) is useful to clinically assess periodontal diseases. However, PISA is difficult to calculate and PISA-compatible screening kits are required. We aimed to investigate the association between salivary LD levels, using a test kit, and PISA and PISA-Japanese and determine the feasibility and reliability of the salivary LD test kit for evaluation of periodontal status. Methods: This study included 110 patients (66.4% female, median and 25-75 percentiles of age were 66.5 and 53.0-75.0 years, respectively) who visited the Dental University Clinic in Japan. Resting saliva samples were collected from each participant and LD levels were evaluated in real time using a kit featuring an integer scale ranging from 1 to 10. PISA and PISA-Japanese were calculated using periodontal parameters. Results: The median salivary LD level was 4.0. The medians of PISA and PISA-Japanese were 46.9 and 61.0, respectively. Salivary LD levels were positively correlated with the bleeding on probing rate ( r = 0.626, p < 0.001), PISA (r = 0.560, p < 0.001), and PISA-Japanese ( r = 0.581, p < 0.001). Conclusions: Our results suggest that salivary LD levels assessed using the salivary LD kit showed a significantly positive correlation with PISA and PISA-Japanese. In addition, we developed the PISA estimation formula using salivary LD levels measured with a test kit, sex, and age.

Background: Pancreatic ductal adenocarcinoma tumors exhibit resistance to chemotherapy, targeted therapies, and even immunotherapy. Dendritic cells use glucose to support their effector functions and play a key role in anti-tumor immunity by promoting cytotoxic CD8 + T cell activity. However, the effects of glucose and lactate levels on dendritic cells in pancreatic ductal adenocarcinoma are unclear. In this study, we aimed to clarify how glucose and lactate can impact the dendritic cell antigen-presenting function and elucidate the relevant mechanisms., Methods: Glycolytic activity and immune cell infiltration in pancreatic ductal adenocarcinoma were evaluated using patient-derived organoids and resected specimens. Cell lines with increased or decreased glycolysis were established from KPC mice. Flow cytometry and single-cell RNA sequencing were used to evaluate the impacts on the tumor microenvironment. The effects of glucose and lactate on the bone marrow-derived dendritic cell antigen-presenting function were detected by flow cytometry., Results: The pancreatic ductal adenocarcinoma tumor microenvironment exhibited low glucose and high lactate concentrations from varying levels of glycolytic activity in cancer cells. In mouse transplantation models, tumors with increased glycolysis showed enhanced myeloid-derived suppressor cell infiltration and reduced dendritic cell and CD8 + T cell infiltration, whereas tumors with decreased glycolysis displayed the opposite trends. In three-dimensional co-culture, increased glycolysis in cancer cells suppressed the antigen-presenting function of bone marrow-derived dendritic cells. In addition, low-glucose and high-lactate media inhibited the antigen-presenting and mitochondrial functions of bone marrow-derived dendritic cells., Conclusions: Our study demonstrates the impact of dynamic glycolytic reprogramming on the composition of immune cells in the tumor microenvironment of pancreatic ductal adenocarcinoma, especially on the antigen-presenting function of dendritic cells., (© 2024. The Author(s).)

The effect of immune checkpoint inhibitors is extremely limited in patients with pancreatic ductal adenocarcinoma (PDAC) due to the suppressive tumor immune microenvironment (TIME). Autophagy, which has been shown to play a role in anti-tumor immunity, has been proposed as a therapeutic target for PDAC. Here, single-cell RNA-sequencing of autophagy-deficient murine PDAC tumors revealed that autophagy inhibition in cancer cells induced dendritic cell (DC) activation. Analysis of human PDAC tumors substantiated a negative correlation between autophagy and DC activation signatures. Mechanistically, autophagy inhibition increased intracellular accumulation of tumor antigens, which could activate DCs. Administration of chloroquine (CQ), an autophagy inhibitor, in combination with Flt3 ligand (Flt3L)-induced DC infiltration inhibited tumor growth and increased tumor-infiltrating T lymphocytes. However, autophagy inhibition in cancer cells also induced CD8+ T cell exhaustion with high expression of immune checkpoint LAG3. A triple therapy comprising CQ, Flt3L, and an anti-LAG3 antibody markedly reduced tumor growth in orthotopic syngeneic PDAC mouse models. Thus, targeting autophagy in cancer cells and activating DCs sensitizes PDAC tumors to immune checkpoint inhibitor therapy, warranting further development of this treatment approach to overcome immunosuppression in pancreatic cancer.

Currently, there is no effective treatment for glioblastoma multiforme (GBM), the most frequent and malignant type of brain tumor. The blood-brain (tumor) barrier (BB(T)B), which is composed of tightly connected endothelial cells and pericytes (with partial vasculature collapse), hampers nanomedicine accumulation in tumor tissues. We aimed to explore the effect of nanomedicine size on passive targeting of GBM. A series of size-tunable poly(ethylene glycol) (PEG)-grafted copolymers (gPEGs) were constructed with hydrodynamic diameters of 8-30 nm. Biodistribution studies using orthotopic brain tumor-bearing mice revealed that gPEG brain tumor accumulation was maximized at 10 nm with ∼14 dose %/g of tumor, which was 19 times higher than that in the normal brain region and 4.2 times higher than that of 30-nm gPEG. Notably, 10-nm gPEG exhibited substantially higher brain tumor accumulation than 11-nm linear PEG owing to the prolonged blood circulation property of gPEGs, which is derived from a densely PEG-packed structure. 10 nm gPEG exhibited deeper penetration into the brain tumor tissue than the larger gPEGs did (>10 nm). This study demonstrates, for the first time, the great potential of a nanomedicine downsizing strategy for passive GBM targeting.

Carrier-free naked mRNA vaccines may reduce the reactogenicity associated with delivery carriers; however, their effectiveness against infectious diseases has been suboptimal. To boost efficacy, we targeted the skin layer rich in antigen-presenting cells (APCs) and utilized a jet injector. The jet injection efficiently introduced naked mRNA into skin cells, including APCs in mice. Further analyses indicated that APCs, after taking up antigen mRNA in the skin, migrated to the lymph nodes (LNs) for antigen presentation. Additionally, the jet injection provoked localized lymphocyte infiltration in the skin, serving as a physical adjuvant for vaccination. Without a delivery carrier, our approach confined mRNA distribution to the injection site, preventing systemic mRNA leakage and associated systemic proinflammatory reactions. In mouse vaccination, the naked mRNA jet injection elicited robust antigen-specific antibody production over 6 months, along with germinal center formation in LNs and the induction of both CD4- and CD8-positive T cells. By targeting the SARS-CoV-2 spike protein, this approach provided protection against viral challenge. Furthermore, our approach generated neutralizing antibodies against SARS-CoV-2 in non-human primates at levels comparable to those observed in mice. In conclusion, our approach offers a safe and effective option for mRNA vaccines targeting infectious diseases., Competing Interests: Declaration of interests S.Abbasi, M.M.M., H.A., K.K., and S.U. have filed a patent application related to this study, and NANO MRNA Co., Ltd. (M.M.M., S.Akinaga) holds a right to the patent. K.K. is a founder and a member of the Board of NANO MRNA Co., Ltd. M.M. is an employee of NANO MRNA Co., Ltd. S.Akinaga is a CEO and CSO of NANO MRNA Co., Ltd., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The differential enzymatic activity in the endo/lysosomes of particular cells could trigger targeted endosomal escape functions, enabling selective intracellular protein delivery. However, this strategy may be jeopardized due to protein degradation during endosomal trafficking. Herein, using custom made fluorescent probes to assess the endosomal activity of cathepsin B (CTSB) and protein degradation, we found that certain cancer cells with hyperacidified endosomes grant a spatiotemporal window where CTSB activity surpass protein digestion. This inspired the engineering of antibody-loaded polymeric nanocarriers having CTSB-activatable endosomal escape ability. The nanocarriers selectively escaped from the endo/lysosomes in the cells with high endosomal CTSB activity and delivered active antibodies to intracellular targets. This study provides a viable strategy for cell-specific protein delivery using stimuli-responsive nanocarriers with controlled endosomal escape., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Introduction: Drugs often show differing pharmacokinetic (PK) profiles, such as higher plasma concentrations, in older people than in younger people owing to age-related decreases in physiological functions. However, it is difficult to evaluate the PK in older populations. Therefore, we simulated the plasma age-related changes in the PK of teneligliptin, a dipeptidyl peptidase-4 inhibitor, using physiologically based PK (PBPK) models., Methods: The previously developed PBPK model was revalidated by comparison between simulated data and clinical study data that included older subjects (up to 75 years old). We then simulated the plasma concentration-time profiles for teneligliptin at a dose of 20 mg (single and multiple doses) in virtual Japanese (20-70 years old) and European descent (20-98 years old) subjects. PK parameters were calculated by race and age group., Results: We confirmed the validity of the previous PBPK model by comparison between simulated data and clinical study data. In the evaluation of age-related changes in PK after single and multiple doses using the PBPK model, the area under the plasma concentration-time curve (AUC) of teneligliptin tended to increase slightly with age in both populations up to 70 years old. However, no clear age-related change in the maximum plasma concentration (C max ) of teneligliptin was observed. In the European descent subjects aged ≥ 70 years, the AUC tended to increase but the ratio of the change in C max was smaller than that in AUC. In both populations, there were positive correlations between AUC and age, but not between C max and age., Conclusion: The simulation using a PBPK model showed a tendency for the AUC of teneligliptin to increase with age, whereas C max was less affected by age than AUC., (© 2023. The Author(s).)

We aimed to investigate the relationship between the risk of oral frailty and awareness of oral frailty among Japanese adults in an adult dental health field study conducted in Kanagawa Prefecture. Questionnaire data from a total of 5051 individuals (1907 males, 3144 females; mean age; 59.9 years) were used. The risk of oral frailty was assessed using the Oral Frailty Index-8. Of the participants, 1418 (28.1%) had a high risk of oral frailty and 1495 (29.6%) had knowledge of oral frailty. Logistic regression analysis indicated that the risk of oral frailty was significantly associated with awareness of oral frailty. We further found that awareness of oral frailty was significantly related to gender (female), age (20-39 compared to 70-79, ≥ 80), residential areas (Yokohama compared to Kawasaki, Sagamihara), exercise habits (yes), eating a balanced diet (yes), consciousness of oral health (yes), risk of oral frailty (low) and outpatient category (hospital visit). For groups with low levels of awareness obtained from the results of this study, it is necessary to consider the means of accessibility and increase awareness further., (© 2024. The Author(s).)

Adjuvanticity and delivery are crucial facets of mRNA vaccine design. In modern mRNA vaccines, adjuvant functions are integrated into mRNA vaccine nanoparticles, allowing the co-delivery of antigen mRNA and adjuvants in a unified, all-in-one formulation. In this formulation, many mRNA vaccines utilize the immunostimulating properties of mRNA and vaccine carrier components, including lipids and polymers, as adjuvants. However, careful design is necessary, as excessive adjuvanticity and activation of improper innate immune signalling can conversely hinder vaccination efficacy and trigger adverse effects. mRNA vaccines also require delivery systems to achieve antigen expression in antigen-presenting cells (APCs) within lymphoid organs. Some vaccines directly target APCs in the lymphoid organs, while others rely on APCs migration to the draining lymph nodes after taking up mRNA vaccines. This review explores the current mechanistic understanding of these processes and the ongoing efforts to improve vaccine safety and efficacy based on this understanding.

A 74-year-old woman with a 34-year history of hemodialysis presented with an intermittent fever, which later coincided with recurrent bilateral shoulder and hip joint pain. Imaging studies suggested amyloid arthropathy, which was histologically confirmed by a synovial biopsy. Increasing β 2 -microglobulin clearance during dialysis alone attenuated the intermittent fever and joint pain, but the symptoms did not disappear until the administration of prednisolone 10 mg/day. Reported cases of dialysis-related amyloidosis with a fever imply that changing to blood purification methods with high β 2 -microglobulin clearance is crucial for controlling the condition long-term, whereas concurrent use of anti-inflammatory agents promptly alleviates the symptoms.

Background: We examined the association between body mass index (BMI) and outcomes in patients with out-of-hospital cardiac arrest (OHCA) undergoing extracorporeal cardiopulmonary resuscitation (ECPR)., Methods: We retrospectively analyzed the database of an observational multicenter cohort in Japan. Adult patients with OHCA of cardiac etiology who received ECPR between 2013 and 2018 were categorized as follows: underweight, BMI < 18.5; normal weight, BMI = 18.5-24.9; overweight, BMI = 25-29.9; and obese, BMI ≥ 30 kg/m 2 . The primary outcome was in-hospital mortality; secondary outcomes were unfavorable neurological outcomes at discharge (cerebral performance category ≥ 3) and ECPR-related complications. BMI's association with outcomes was assessed using a logistic regression model adjusted for age, sex, comorbidities, witness/bystander CPR, initial rhythm, prehospital return of spontaneous circulation, and low-flow time., Results: In total, 1,044 patients were analyzed. Their median age was 61 (IQR, 49-69) years; the median BMI was 24.2 (21.5-26.9) kg/m 2 . The overall rates of in-hospital mortality, unfavorable neurological outcome, and ECPR-related complications were 62.2%, 79.9%, and 31.7%, respectively. In multivariate analysis, the overweight and obese groups had higher in-hospital mortality odds than the normal BMI group (odds ratio [95%CI], 1.37 [1.02-1.85], p  = 0.035; and 2.09 [1.31-3.39], p  < 0.001, respectively). The odds ratio for unfavorable neurological outcomes increased more in the obese than in the normal BMI group (3.17 [1.69-6.49], p  < 0.001). ECPR-related complications were not significantly different among groups., Conclusions: In OHCA patients undergoing ECPR, a BMI ≥ 25 kg/m 2 was associated with increased in-hospital mortality, and a BMI ≥ 30 kg/m 2 was also associated with a worse neurological outcome., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

X-ray-triggered scintillators (Sc) and photosensitizers (Ps) have been developed for X-ray-induced photodynamic therapy (X-PDT) to selectively destruct deep tissue tumors with a low X-ray dose. This study designed terbium (Tb)-rose bengal (RB) coordination nanocrystals (T-RBNs) by a solvothermal treatment, aiming to reduce photon energy dissipation between Tb 3+ and RB and thus increase the reactive oxygen species (ROS) production efficiency. T-RBNs synthesized at a molar ratio of [RB]/[Tb] = 3 exhibited a size of 6.8 ± 1.2 nm with a crystalline property. Fourier transform infrared analyses of T-RBNs indicated successful coordination between RB and Tb 3+ . T-RBNs generated singlet oxygen ( 1 O 2 ) and hydroxyl radicals ( • OH) under low-dose X-ray irradiation (0.5 Gy) via scintillating and radiosensitizing pathways. T-RBNs produced ∼8-fold higher ROS amounts than bare RB and ∼3.6-fold higher ROS amounts than inorganic nanoparticle-based controls. T-RBNs did not exhibit severe cytotoxicity up to 2 mg/mL concentration in cultured luciferase-expressing murine epithelial breast cancer (4T1-luc) cells. Furthermore, T-RBNs were efficiently internalized into cultured 4T1-luc cells and induced DNA double strand damage, as evidenced by an immunofluorescence staining assay with phosphorylated γ-H 2 AX. Ultimately, under 0.5 Gy X-ray irradiation, T-RBNs induced >70% 4T1-luc cell death via simultaneous apoptosis/necrosis pathways. Overall, T-RBNs provided a promising Sc/Ps platform under low-dose X-PDT for advanced cancer therapy.

Aim: To identify risk factors for relapse after methotrexate (MTX) dose reduction in rheumatoid arthritis (RA) patients receiving golimumab (GLM)/MTX combination therapy., Method: Data on RA patients ≥20 years old receiving GLM (50 mg) + MTX for ≥6 months were retrospectively collected. MTX dose reduction was defined as a reduction of ≥12 mg from the total dose within 12 weeks of the maximum dose (≥1 mg/wk average). Relapse was defined as Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP) score ≥3.2 or sustained (≥ twice) increase of ≥0.6 from baseline., Results: A total of 304 eligible patients were included. Among the MTX-reduction group (n = 125), 16.8% of patients relapsed. Age, duration from diagnosis to the initiation of GLM, baseline MTX dose, and DAS28-CRP were comparable between relapse and no-relapse groups. The adjusted odds ratio (aOR) of relapse after MTX reduction was 4.37 (95% CI 1.16-16.38, P = 0.03) for prior use of non-steroidal anti-inflammatory drugs (NSAIDs), and the aORs for cardiovascular disease (CVD), gastrointestinal disease and liver disease were 2.36, 2.28, and 3.03, respectively. Compared to the non-reduction group, the MTX-reduction group had a higher proportion of patients with CVD (17.6% vs 7.3%, P = 0.02) and a lower proportion of prior use of biologic disease-modifying antirheumatic drugs (11.2% vs. 24.0%, P = 0.0076)., Conclusion: Attention should be given to RA patients with history of CVD, gastrointestinal disease, liver disease, or prior NSAIDs-use when considering MTX dose reduction to ensure benefits outweigh the risks of relapse., (© 2023 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

The abrupt morphological changes of the intestine during metamorphosis have been detailed in frogs. The features of intestinal metamorphosis are shortening of the intestine and remodeling of the intestinal epithelium. It is believed that the purpose of the morphological changes of the intestine is adaptation from aquatic herbivorous to carnivorous life. However, little is known about the physiological importance of these morphological changes. To elucidate the functional changes during metamorphosis, we measured luminal Na + concentrations and Na + -dependent glucose uptake in tadpoles and adult African clawed frogs Xenopus laevis . The small intestine was isolated and divided into four segments in length, the luminal contents collected for analysis of ion concentration by ion chromatography. Phlorizin-sensitive glucose-induced short-circuit current (Δ I sc ) was measured in intestinal preparations mounted in Ussing chambers. Although dietary sodium intake was extremely low in tadpoles, luminal Na + concentration gradually increased along the proximal to the middle part of the intestine (>70 mM), and this Na + concentration was comparable with that of carnivorous adult frogs. The increment of glucose-induced Δ I sc was observed in tadpole intestine. We also measured the Δ I sc induced by acetic acid, which is the major short-chain fatty acid produced by fermentation. The expression levels of mRNA for Na + -dependent glucose transporter 1 and tight junction protein claudin-15 in each intestinal segment was measured. These results suggest that luminal Na + homeostasis is important and luminal Na + is kept at a high concentration for Na + -dependent nutrient absorption mechanisms.

The recent discovery of mechanosensitive ion channels has promoted mechanobiological research in the field of hypertension and nephrology. We previously reported Piezo2 expression in mouse mesangial and juxtaglomerular renin-producing cells, and its modulation by dehydration. This study aimed to investigate how Piezo2 expression is altered in hypertensive nephropathy. The effects of the nonsteroidal mineralocorticoid receptor blocker, esaxerenone, were also analyzed. Four-week-old Dahl salt-sensitive rats were randomly assigned to three groups: rats fed a 0.3% NaCl diet (DSN), rats fed a high 8% NaCl diet (DSH), and rats fed a high salt diet supplemented with esaxerenone (DSH + E). After six weeks, DSH rats developed hypertension, albuminuria, glomerular and vascular injuries, and perivascular fibrosis. Esaxerenone effectively decreased blood pressure and ameliorated renal damage. In DSN rats, Piezo2 was expressed in Pdgfrb-positive mesangial and Ren1-positive cells. Piezo2 expression in these cells was enhanced in DSH rats. Moreover, Piezo2-positive cells accumulated in the adventitial layer of intrarenal small arteries and arterioles in DSH rats. These cells were positive for Pdgfrb, Col1a1, and Col3a1, but negative for Acta2 (αSMA), indicating that they were perivascular mesenchymal cells different from myofibroblasts. Piezo2 upregulation was reversed by esaxerenone treatment. Furthermore, Piezo2 inhibition by siRNA in the cultured mesangial cells resulted in upregulation of Tgfb1 expression. Cyclic stretch also upregulated Tgfb1 in both transfections of control siRNA and Piezo2 siRNA. Our findings suggest that Piezo2 may have a contributory role in modulating the pathogenesis of hypertensive nephrosclerosis and have also highlighted the therapeutic effects of esaxerenone on salt-induced hypertensive nephropathy. Mechanochannel Piezo2 is known to be expressed in the mouse mesangial cells and juxtaglomerular renin-producing cells, and this was confirmed in normotensive Dahl-S rats. In salt-induced hypertensive Dahl-S rats, Piezo2 upregulation was observed in the mesangial cells, renin cells, and notably, perivascular mesenchymal cells, suggesting its involvement in kidney fibrosis., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Although chemotherapy has been an essential treatment for cancer, the development of immune checkpoint blockade therapy was revolutionary, and a comprehensive understanding of the immunological tumor microenvironment (TME) has become crucial. Here, we investigated the impact of neoadjuvant chemotherapy (NAC) on immune cells in the TME of human esophageal squamous cell carcinoma using single cell RNA-sequencing. Analysis of 30 fresh samples revealed that CD8+/CD4+ T cells, dendritic cells (DCs), and macrophages in the TME of human esophageal squamous cell carcinoma showed higher levels of an anti-tumor immune response in the NAC(+) group than in the NAC(-) group. Furthermore, the immune cells of the NAC(+) group interacted with each other resulting in enhanced anti-tumor immune response via various cytokines, including IFNG in CD8+/CD4+ T cells, EBI3 in DCs, and NAMPT in macrophages. Our results suggest that NAC potentially enhances the anti-tumor immune response of immune cells in the TME., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Background: Although hemodialysis (HD) patients have an elevated risk of strokes, there are few reports about transcranial doppler (TCD) echography measurements. It is well-known that angiotensin II receptor blockades (ARBs) protect against cardiovascular complications. In this study, we measured intracranial artery (ICA) velocity using TCD echography and studied the associated factors with its velocity in HD patients by a comparison with or without ARBs., Methods: We conducted a cross-sectional study in a single hospital. We included 61 patients who had measurable ICA velocity by TCD echography. Among them, the ARB usage group consisted of 22 subjects, whilst the non-ARB usage group consisted of 39 subjects., Results: Patients in the ARB (+) and ARB (-) groups did not show any difference in basic characteristics. ICA blood flow velocity in all intracranial arteries tended to show greater values in the ARB group than those in the non-ARB group. Particularly, blood velocity in the middle cerebral artery (MCA) (maximal flow velocity) statistically increased in the ARB group, respectively. In a univariate analysis, MCA maximum velocity was significantly associated with ARB usage ( p = 0.011) and low hematocrit levels ( p = 0.045). The multivariate analysis chose only ARB usage as an independent factor associated with left MCA maximum velocity ( p = 0.022)., Conclusions: We showed that dialysis patients with ARBs have significantly higher ICA blood velocity. ARBs might have a potential benefit for maintaining ICA blood flow in HD patients.

Background: We sought to determine the prevalence of metabolic syndrome (Mets) and whether 100 cm 2 of visceral fatty area (VFA) measured by computed tomography (CT) validates the criteria of waist circumference (WC) in hemodialysis (HD) patients., Methods: The study comprised 141 HD patients. Mets was defined according to the criteria of Adult Treatment Panel III (ATP III) and the modified criteria of National Cholesterol Education Program (NCEP) that defines abdominal obesity as a WC of >=85 cm in men and >=90 cm in women., Results: The prevalence of Mets was 31.9% in men and 13.6% in women. However, the prevalence of patients with a body mass index over 25 in all HD patients was only 11.2%. The visceral fatty area (VFA) measured by CT showed a strong positive correlation with WC. The patients with Mets, comparing with those without Mets, have significantly shorter duration of HD, higher high-sensitive C-reactive protein, and higher Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). In the patients with Mets, there was a significant negative correlation between HOMA-IR and serum albumin levels. Multivariate logistic regression analysis showed that HOMA-IR and short duration of HD were chosen as independent risk factors for Mets., Conclusions: Mets is more prevalent in HD patients. In Japanese HD patients, 100 cm 2 of VFA corresponded to a WC of 85 cm in men and 90 cm in women, thus confirming the validity of the modified criteria. HOMA-IR and serum albumin were significantly correlated in HD patients with Mets.

Background: The link between arterial stiffness and mild cognitive impairment (MCI) in patients on hemodialysis (HD) has been receiving increased attention. The purpose of this study was to investigate the relationship between cognitive function and ankle brachial index (ABI) and toe brachial index (TBI) values in patients on hemodialysis. Of the 100 participants (mean age: 67.9 years; average history of hemodialysis: 7.3 years). Of these, 46.0% had MCI. The MoCA-J scores were significantly higher in the ABI ≥ 1.06 group. However, the MoCA-J scores divided into the two groups according to the TBI cutoff value were not significantly different. In a multiple regression model with the MoCA-J scores as the objective variable, the ABI was a significantly associated factor. This study indicates that a low ABI might be associated with MCI.

The field of epithelial stem cell development has been irrevocably shaped by the work of American scientist Howard Green, whose breakthroughs in stem cell culture methods translated to therapeutic practice. In this review, we chronicle the milestones that propelled the field of regenerative medicine of the skin forward over the last fifty years. We detail the early discoveries made by Green and his collaborators, highlight clinical cases that made life-saving use of his findings, and discuss the accomplishments of other scientists who later innovated upon his discoveries.

Lower limbs' arterial calcification is significantly associated with the clinical severity of lower extremity artery disease (LEAD) in patients undergoing hemodialysis (HD). However, the association between arterial calcification of the lower limbs and long-term clinical outcomes in patients on HD has not been elucidated. Calcification scores of the superficial femoral artery (SFACS) and below-knee arteries (BKACS) were quantitatively evaluated in 97 HD patients who were followed for 10 years. Clinical outcomes, including all-cause and cardiovascular mortality, cardiovascular events, and limb amputation were evaluated. Risk factors for clinical outcomes were evaluated using univariate and multivariate Cox proportional hazard analyses. Furthermore, SFACS and BKACS were divided into three groups (low, middle, and high), and their associations with clinical outcomes were evaluated using Kaplan-Meier analysis. SFACS, BKACS, C-reactive protein, serum albumin, age, diabetes, presence of ischemic heart disease, and critical limb-threatening ischemia were significantly associated with 3-year and 10-year clinical outcomes in the univariate analysis. Multivariate analysis showed that SFACS was an independent factor associated with 10-year cardiovascular events and limb amputations. Kaplan-Meier life table analysis showed that higher SFACS and BKACS levels were significantly associated with cardiovascular events and mortality. In conclusion, long-term clinical outcomes and the risk factors in patients undergoing HD were evaluated. Arterial calcification of the lower limbs was strongly associated with 10-year cardiovascular events and mortality in patients undergoing HD.

It is unclear whether the severity of sleep-disordered breathing (SDB) affects the risk of cardiovascular events and mortality in patients undergoing hemodialysis (HD). We determined the severity of SDB with the 3% oxygen desaturation index (ODI) via overnight pulse oximetry. This study was a retrospective cohort, observational study of 134 patients on maintenance HD at a single center. They were divided into four groups according to SDB severity (normal, mild, moderate, and severe), and were followed. The baseline characteristics of all patients were as follows: the median age was 67 (interquartile range, 59-75) years, 64.2% were men, 37.3% were diabetic, and the median duration of HD was 69 (29-132) months. During follow-up, major adverse cardiovascular events (MACEs) occurred in 71 patients and deaths in 60 (including 32 cardiovascular deaths). Severe SDB was an independent risk factor for MACEs (hazard ratio [HR] = 4.66, 95% confidence interval [CI] = 1.87-11.61, p = 0.001) and all-cause death (HR = 5.74, 95% CI = 1.92-16.70, p = 0.001). Severe SDB had a statistically significant impact on the risk of MACEs and mortality in patients undergoing HD. The severity of the 3% ODI via overnight pulse oximetry may be a useful marker as a risk factor for cardiovascular outcomes and mortality in these patients.

Objectives: Zinc deficiency (Zn < 60 μg/dL) is known to play an important role for vascular calcification. However, little data is available regarding the association between zinc deficiency and aorta stiffness in dialysis patients. Thus, we studied the relationship between zinc deficiency and aorta stiffness in non-diabetic hemodialysis (HD) patients., Methods: Of 150 patients receiving maintenance HD at our hospital, we included 79 non-diabetic HD patients (age: 70±11 years, 49 men) after excluding 71 diabetic HD patients. Zinc deficiency was defined as Zn <60 μg/dL during pre-HD blood sampling. The association between zinc deficiency and aorta stiffness was analyzed. Aorta stiffness was evaluated as brachial-ankle pulse wave velocity (baPWV). Other surrogate markers for cardiovascular complications were also measured., Results: The zinc deficiency group (ZD group) included 45 patients (57.0%). Compared to the zinc non-deficiency group (ZND group), patients with ZD group were significantly older, higher levels of CRP and hypoalbuminemia. Moreover, they had significantly higher levels of baPWV, and lower levels of ankle-brachial pressure index (ABI) (p<0.05). After adjusting for hypoalbuminemia, and CRP, multivariate analysis showed that age and zinc level were independent predictors of baPWV., Conclusion: The study suggested that zinc deficiency may be an independent risk factor for aorta stiffness, even after adjusting for malnutrition and inflammation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Ishioka et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Tumour immune microenvironment is related with carcinogenesis and efficacy of immunotherapy. B cells play major roles in humoral immunity, but detailed functions of tumour-infiltrating B lymphocytes (TIL-Bs) are unknown. Therefore, our aim was to investigate the functional heterogeneity of TIL-Bs in oesophageal squamous cell carcinoma (ESCC) and lymph nodes (LNs) during chemotherapy., Methods: Single-cell transcriptome analysis was performed on 23 specimens. We also performed immunohistochemical analysis of immunoglobulin κ C (IGKC), an antibody-secreting cell (ASC) marker, in 166 ESCC samples and evaluated the implication of IGKC in 2-year recurrence free survival (RFS) and 3-year overall survival (OS)., Results: A total of 81,246 cells were grouped into 24 clusters. We extracted B cell clusters based on canonical markers and identified 12 TIL-B subtypes in ESCC. We found that several functions, such as co-stimulation and CD40 signalling, were enhanced in TIL-Bs after chemotherapy. The proportion of naive B cells (NBCs) decreased and B cell activation genes were up-regulated in NBCs after chemotherapy. The proportion of ASCs in tumours increased with the loss of migratory abilities and antibody production in ASCs was promoted after chemotherapy. Differentially expressed genes up-regulated with chemotherapy in ASCs correlated with prolonged survival with oesophageal cancer (p = .028). In a metastatic LN, the ASC proportion increased and B cell differentiation was enhanced. In immunohistochemical analysis, RFS and OS of high IGKC expression cases were significantly better than those of low IGKC expression cases (RFS: p < .0001, OS: p < .0001). And in multivariable analysis, the expression of IGKC was an independent favourable prognostic factor for RFS (hazard ratio (HR): 0.23, 95% confidence interval (CI): 0.12-0.45, p < .0001) and OS (HR: 0.20, 95% CI: 0.086-0.47, p = .0002) in ESCC., Conclusions: Our findings provide novel insights for the heterogeneity of TIL-Bs during chemotherapy and will be useful to understand the clinical importance of TIL-Bs., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

A statistical model to predict oral frailty based on information obtained from questionnaires might help to estimate its prevalence and clarify its determinants. In this study, we aimed to develop and validate a predictive model to assess oral frailty thorough a secondary data analysis of a previous cross-sectional study on oral frailty conducted on 843 patients aged ≥ 65 years. The data were split into training and testing sets (a 70/30 split) using random sampling. The training set was used to develop a multivariate stepwise logistic regression model. The model was evaluated on the testing set and its performance was assessed using a receiver operating characteristic (ROC) curve. The final model in the training set consisted of age, number of teeth present, difficulty eating tough foods compared with six months ago, and recent history of choking on tea or soup. The model showed good accuracy in the testing set, with an area of 0.860 (95% confidence interval: 0.806-0.915) under the ROC curve. These results suggested that the prediction model was useful in estimating the prevalence of oral frailty and identifying the associated factors.

Cardiac dysfunction is an important prognostic predictor of cardiovascular mortality in patients on hemodialysis (HD). Erythropoietin (EPO) has been reported to improve cardiac function by binding to the EPO receptor (EPOR) on cardiomyocytes. This study investigated whether anti-EPOR antibodies were associated with left ventricular cardiac function in patients undergoing HD. This multicenter, cross-sectional observational study included 377 patients (median age, 70 years; 267 (70.8%) males) with chronic kidney disease (CKD) undergoing stable maintenance HD. Serum levels of anti-EPOR antibodies were measured, and echocardiography was used to assess the left ventricular mass index (LVMI) and left ventricular ejection fraction (LVEF). Anti-EPOR antibodies were found in 17 patients (4.5%). LVMI was greater (median of 135 g/m2 vs. 115 g/m2, p = 0.042), and the prevalence of LVEF < 50% was higher (35.3% vs. 15.6%, p = 0.032) in patients with anti-EPOR antibodies than in those without. Multivariable linear regression and logistic regression analysis (after adjusting for known risk factors of heart failure) revealed that anti-EPOR antibodies were independently associated with LVMI (coefficient 16.2%; 95% confidence interval (CI) 1.0−35.0%, p = 0.043) and LVEF <50% (odds ratio 3.20; 95% CI 1.05−9.73, p = 0.041). Thus, anti-EPOR antibody positivity was associated with left ventricular dysfunction in patients undergoing HD.

The periodontal inflamed surface area (PISA) is a useful indicator of periodontal status. However, its formula was based on a meta-analysis involving five countries, and racial differences in tooth root morphology could have affected the calculations. This study aimed to develop a Japanese version of the PISA and compare it with the original version. The formulas reported by a previous Japanese study calculating the amount of remaining periodontal ligament from clinical attachment measurements were used to calculate the PISA. A simulation was performed to compare the Japanese version with the original version by inputting probing pocket depth (PPD) from 1 to10 mm and by using clinical data. The PISA values in the Japanese version were larger and smaller than those in the original version for PPDs of 1-5 mm and 6-10 mm, respectively. The PISA values for the clinical data from the Japanese version were significantly higher than those from the original version. Both versions of the PISA values correlated equally well with body mass index. The Japanese version of the PISA can be used to assess the amount of inflamed periodontal tissue resulting from periodontitis in Japanese populations, taking into account racial heterogeneity in root morphologies.

For efficient delivery of messenger (m)RNA, delivery carriers need two major functions: protecting mRNA from nucleases and translocating mRNA from endolysosomes to the cytoplasm. Herein, these two complementary functionalities are integrated into a single polyplex by fine-tuning the catiomer chemical structure and incorporating the endosomal escape modality. The effect of the methylene spacer length on the catiomer side chain is evaluated by comparing poly(l-lysine) (PLL) with a tetramethylene spacer and poly(L-ornithine) (PLO) with a trimethylene spacer. Noteworthily, the nuclease stability of the mRNA/catiomer polyplexes is largely affected by the difference in one methylene group, with PLO/mRNA polyplex showing enhanced stability compared to PLL/mRNA polyplex. To introduce the endosomal escape function, the PLO/mRNA polyplex is wrapped with a charge-conversion polymer (CCP), which is negatively charged at extracellular pH but turns positive at endosomal acidic pH to disrupt the endosomal membrane. Compared to the parent PLO/mRNA polyplex, CCP facilitated the endosomal escape of the polyplex in cultured cells to improve the protein expression efficiency from mRNA by approximately 80-fold. Collectively, this system synergizes the protective effect of PLO against nucleases and the endosomal escape capability of CCP in mRNA delivery., (© 2022 Wiley-VCH GmbH.)

The Enhanced Permeability and Retention (EPR) effect is a golden strategy for the nanoparticle (NP)-based targeting of solid tumors, and the surface property of NPs might be a determinant on their targeting efficiency. Poly(ethylene glycol) (PEG) is commonly used as a shell material; however, it has been pointed out that PEG-coated NPs may exhibit accumulation near tumor vasculature rather than having homogenous intratumor distribution. The PEG shell plays a pivotal role on prolonged blood circulation of NPs but potentially impairs the intratumor retention of NPs. In this study, we report on a shell material to enhance tumor-targeted delivery of NPs by maximizing the EPR effect: polyzwitterion based on ethylenediamine-based carboxybetaine [PGlu(DET-Car)], which shows the changeable net charge responding to surrounding pH. The net charge of PGlu(DET-Car), is neutral at physiological pH 7.4, allowing it to exhibit a stealth property during the blood circulation; however, it becomes cationic for tissue-interactive performance under tumorous acidic conditions owing to the stepwise protonation behavior of ethylenediamine. Indeed, the PGlu(DET-Car)-coated NPs (i.e., gold NPs in the present study) exhibited prolonged blood circulation and remarkably enhanced tumor accumulation and retention than PEG-coated NPs, achieving 32.1% of injected dose/g of tissue, which was 4.2 times larger relative to PEG-coated NPs. Interestingly, a considerable portion of PGlu(DET-Car)-coated NPs clearly penetrated into deeper tumor sites and realized the effective accumulation in hypoxic regions, probably because the cationic net charge of PGlu(DET-Car) is augmented in more acidic hypoxic regions. This study suggests that the changeable net charge on the NP surface in response to tumorous acidic conditions is a promising strategy for tumor-targeted delivery based on the EPR effect., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Traumatic tension gastrothorax is a rare and potentially fatal condition occurring in patients with congenital or acquired diaphragmatic defects. Traumatic tension gastrothorax leads to acute and severe respiratory distress. Delayed tension gastrothorax that develops late during injury can be more severe., Case Presentation: An 84-year-old woman was brought to our facility with cardiac arrest and returned to spontaneous circulation after 2 min of cardiopulmonary resuscitation. Computed tomography showed diaphragmatic injury and tension gastrothorax due to trauma because of a fall episode few days earlier. Emergency thoracotomy and laparotomy was performed, because nasogastric tube insertion failed. There was a partially necrotic stomach in the chest cavity. The stomach was retracted from the thoracic cavity into the abdominal cavity and placed in its proper position. There was a 5 cm tear of the diaphragm. The tear was sutured and closed and then the necrotic area of the stomach was resected. Although the surgery relieved the intrathoracic compression, it resulted in re-expansion pulmonary edema immediately after surgery and hypoxemia. The patient was unable to overcome the hypoxemic state and eventually died., Conclusions: Delayed tension gastrothorax can lead not only to obstructive shock due to intrathoracic compression but also to more severe organ ischemia and re-expansion pulmonary edema due to insufflation., (© 2022. The Author(s).)

Background: Aplastic anemia (AA) is a rare but fatal disorder characterized by pancytopenia due to bone marrow hypoplasia. Anti-glomerular basement membrane disease (anti-GBM disease) is an immune complex small-vessel vasculitis that presents as rapidly progressive glomerulonephritis and/or pulmonary hemorrhage. Although both involve autoreactive T cells that are partially triggered by human leukocyte antigen (HLA)-DR15, there have been no reports of their co-existence and the treatment strategy is not well understood., Case Presentation: A 67-year-old woman presented with fever, malaise, and acute kidney injury with proteinuria and hematuria requiring hemodialysis. She was diagnosed with anti-GBM antibody disease based on high serum anti-GBM antibody titer and crescentic glomerulonephritis on a renal biopsy. Pulse administration of methylprednisolone (MP), oral prednisolone (PSL), and plasmapheresis were performed. Only 2 weeks after the diagnosis of anti-GBM disease, the patient developed pancytopenia requiring frequent blood transfusions. The blood cell count did not recover even 1 month after discontinuing the drugs that could cause pancytopenia. Bone marrow examination showed hypocellularity without abnormal infiltrates or fibrosis, which led to the diagnosis of severe acquired AA. Further HLA phenotyping revealed that she had HLA-DR15. Increased dose of PSL with the secondary MP pulse and the addition of cyclosporine improved pancytopenia. Although she remained dialysis-dependent, anti-GBM disease and pancytopenia did not recur for more than 2 years., Conclusions: We report the first case of acquired AA complicated with anti-GBM disease in an elderly woman with HLA-DR15, which was successfully treated with immunosuppressive therapy (IST). This report is valuable not only because it shows they may co-occur, but also because it provides a therapeutic option for this complex condition. It was also suggested that pancytopenia in patients with anti-GBM disease recalls serious hematologic diseases including AA that require immediate treatment based on bone marrow examination., (© 2022. The Author(s).)

Objectives: To evaluate the cost-effectiveness of biologics and methotrexate (MTX) for rheumatoid arthritis (RA) using the number needed to treat (NNT) concept and total actual health care cost., Methods: This study included 121 RA patients with newly prescribed biologics and/or MTX between 2012 and 2017. The NNT was calculated based on the 24 week remission rate of Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR) and Clinical Disease Activity Index (CDAI)., Results: Remission rates were 76.4% for DAS28-ESR and 45.4% for CDAI in the biologics group and 63.6% and 24.2%, respectively, in the MTX group. The NNT was calculated as 6.4 and 4.2 in the biologics group and 34.2 and 35.2 in the MTX group, respectively. Mean total actual health care costs were 1,044,066 JPY (9835 US$)/24 weeks per treated patient in the biologics group and 75,860 JPY (715 US$)/24 weeks in the MTX group. Although the effectiveness of biologics was superior to MTX from the standpoint of NNT, the mean total health care cost and mean cost per NNT were much higher in the biologics group., Conclusions: Cost-effectiveness is clearly higher for MTX than biologics from the standpoint of mean total health care cost per adjusted NNT under the Japanese health insurance system., (© 2022. The Author(s).)

Amelogenesis Imperfecta (AI) represents a group of hereditary conditions that manifest tooth enamel defects. Several causative mutations in the WDR72 gene have been identified and patients with WDR72 mutations have brown (or orange-brown) discolored enamel, rough enamel surface, early loss of enamel after tooth eruption, and severe attrition. Although the molecular function of WDR72 is not yet fully understood, a recent study suggested that WDR72 could be a facilitator of endocytic vesicle trafficking, which appears inconsistent with the previously reported cytoplasmic localization of WDR72. Therefore, the aims of our study were to investigate the tissues and cell lines in which WDR72 was expressed and to further determine the sub-cellular localization of WDR72. The expression of Wdr72 gene was investigated in mouse tissues and cell lines. Endogenous WDR72 protein was detected in the membranous fraction of ameloblast cell lines in addition to the cytosolic fraction. Sub-cellular localization studies supported our fractionation data, showing WDR72 at the Golgi apparatus, and to a lesser extent, in the cytoplasmic area. In contrast, a WDR72 AI mutant form that lacks its C-terminal region was exclusively detected in the cytoplasm. In addition, our studies identified a putative prenylation/CAAX motif within the last four amino acids of human WDR72 and generated a WDR72 variant, called CS mutant, in which the putative motif was ablated by a point mutation. Interestingly, mutation of the putative CAAX motif impaired WDR72 recruitment to the Golgi. Cell fractionation assays confirmed subcellular distribution of wild-type WDR72 in both cytosolic and membranous fractions, while the WDR72 AI mutant and CS mutant forms were predominantly detected in the cytosolic fraction. Our studies provide new insights into the subcellular localization of WDR72 and demonstrate a critical role for the C-terminal CAAX motif in regulating WDR72 recruitment to the Golgi. In accordance with structural modelling studies that classified WDR72 as a potential vesicle transport protein, our findings suggest a role for WDR72 in vesicular Golgi transport that may be key to understanding the underlying cause of AI., (© 2022. The Author(s).)

Study Design: A retrospective cohort study., Objective: To examine factors related to severe aggravation of preexisting cervical lesions in patients with rheumatoid arthritis (RA) under current pharmacologic treatments with biologics., Summary of Background Data: Advanced RA cervical lesions carry a risk of irreversible damage to the spinal cord; however, risk factors for aggravation are unclear after the use of biologics became more popular., Methods: Of 166 patients with preexisting cervical lesions at baseline, 87 who had cervical X-ray images taken at baseline and at the final visit (with an interval of more than 1 yr) were evaluated retrospectively. Aggravated instabilities determined at the final visit, were defined as follows: atlantoaxial subluxation (AAS) = atlantodental interval ≧ 10 mm; vertebral subluxation (VS) = a Ranawat value < 10 mm; and subaxial subluxation (SAS) = an anterior vertebral slip ≧ 4 mm or a multilevel slip ≧ 2 mm. Patients were divided into two groups based on the radiographic results: severe aggravation and non-severe aggravation. Explanatory variables were gender, age of RA onset, duration of disease, average observation period, Disease Activity Score 28 based on C-reactive protein (DAS28-CRP) at baseline, drug treatment history, presence of mutilating deformities in the hands, presence of RA-related joint surgery, and the prevalence of each cervical lesion at baseline., Results: The severe group comprised 14 patients (16.1%). There was no significant difference between the two groups with respect to demographic data. Multivariate logistic regression analysis revealed that preexisting SAS lesions (odds ratio: 7.59, 95% confidence interval: 1.16-49.6) and no history of biologic treatment (odds ratio, 0.10; 95% confidence interval, 0.17-0.58) were associated with aggravation., Conclusion: Preexisting SAS lesions were associated with aggravation. Meanwhile, biologics may be effective at preventing aggravation.Level of Evidence: 3., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The kidney plays a central role in body fluid homeostasis. Cells in the glomeruli and juxtaglomerular apparatus sense mechanical forces and modulate glomerular filtration and renin release. However, details of mechanosensory systems in these cells are unclear. Piezo2 is a recently identified mechanically activated ion channel found in various tissues, especially sensory neurons. Herein, we examined Piezo2 expression and regulation in mouse kidneys. RNAscope in situ hybridization revealed that Piezo2 expression was highly localized in mesangial cells and juxtaglomerular renin-producing cells. Immunofluorescence assays detected GFP signals in mesangial cells and juxtaglomerular renin-producing cells of Piezo2 GFP reporter mice. Piezo2 transcripts were observed in the Foxd1-positive stromal progenitor cells of the metanephric mesenchyme in the developing mouse kidney, which are precursors of mesangial cells and renin-producing cells. In a mouse model of dehydration, Piezo2 expression was downregulated in mesangial cells and upregulated in juxtaglomerular renin-producing cells, along with the overproduction of renin and enlargement of the area of renin-producing cells. Furthermore, the expression of the renin coding gene Ren1 was reduced by Piezo2 knockdown in cultured juxtaglomerular As4.1 cells under static and stretched conditions. These data suggest pivotal roles for Piezo2 in the regulation of glomerular filtration and body fluid balance., (© 2022. The Author(s).)

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma in which microenvironmental (niche) factors promote PDAC progression. In mouse models, reduction of the stroma increased the proportion of poorly differentiated PDAC with a worse prognosis. Here, we aimed to clarify the effects of stroma on PDAC that may define the PDAC phenotype and induce distinct therapeutic responses., Methods: The molecular features of PDAC based on differentiation grade were clarified by genome and transcriptome analysis using PDAC organoids (PDOs). We identified the dependency on niche factors that might regulate the differentiation grade. A three-dimensional co-culture model with cancer-associated fibroblasts (CAFs) was generated to determine whether CAFs provide niche factors essential for differentiated PDAC. PDOs were subtyped based on niche factor dependency, and the therapeutic responses for each subtype were compared., Results: The expression profiles of PDOs differed depending on the differentiation grade. Consistent with the distinct profiles, well differentiated types showed high niche dependency, while poorly differentiated types showed low niche dependency. The three-dimensional co-culture model revealed that well differentiated PDOs were strongly dependent on CAFs for growth, and moderately differentiated PDOs showed plasticity to change morphology depending on CAFs. Differentiated PDOs upregulated the expression of mevalonate pathway-related genes correlated with the niche dependency and were more sensitive to simvastatin than poorly differentiated PDOs., Conclusions: Our findings suggest that CAFs maintain the differentiated PDAC phenotype through secreting niche factors and induce distinct drug responses. These results may lead to the development of novel subtype-based therapeutic strategies., (© 2022. The Author(s).)

Studies suggest that intensive oral health promotion programs in the workplace reduce dental and medical care expenditures. The purpose of this longitudinal study was to evaluate the short version of an oral health promotion program in the workplace from the viewpoint of dental and medical care expenditures. Data for annual expenditures and number of days of dental, periodontal, and medical treatment in fiscal year 2018 and participation in the short version of a workplace oral health promotion program of 2545 workers (20-68 years old) in a company in fiscal year 2017 and prior were obtained. Zero-inflated negative binomial regression models or negative binomial regression models were used to evaluate the association between participation in the program and expenditures or number of days of treatment after adjusting for sex and age. Program participants were more likely than non-participants to visit dentists for dental and periodontal treatment. Those who participated twice or more spent less on dental, periodontal, and medical treatment and had fewer visits to dentists than non-participants. These results suggest that the short version of an oral health promotion program in the workplace decreases expenditures for dental, periodontal, and medical treatment.

Background: It remains unclear whether contrast-induced nephropathy (CIN) has a prognostic impact on subsequent renal dysfunction and whether deteriorating renal function is a risk factor for CIN. This study aimed to evaluate the occurrence of CIN in patients with pre-existing renal dysfunction and investigate the long-term effects of worsening renal function after coronary angiography or contrast-enhanced computed tomography (CT). The prognostic factors of worsening renal dysfunction were also analyzed., Methods: This was a prospective cohort study of patients at risk for CIN, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 on coronary angiography or eGFR <45 mL/min/1.73 m 2 on contrast-enhanced CT. Serum creatinine levels and the 2-year prognosis were evaluated. CIN was defined as an increase in serum creatinine level by more than 0.5 mg/dL or a 25% increase from the previous value within 72 hours after contrast administration. The primary endpoint was the proportion of patients who had serum Cr doubling or induction of dialysis within 2 years according to CIN occurrence., Results: Of the 410 patients, 19 patients developed CIN (8/142 patients on coronary angiography and 11/268 patients on contrast-enhanced CT), and 38 patients had worsened renal function (21/142 patients on coronary angiography and 17/268 patients on contrast-enhanced CT). CIN was not associated with worsening renal function at 2 years. Analysis by renal function at the time of coronary angiography or contrast-enhanced CT (i.e., eGFR ≥30 ml/min/1.73 m 2 and eGFR ≤1.73 m 2 ) found no between-group difference in the occurrence of CIN., Conclusions: CIN is not a prognostic risk factor for the long-term of chronic kidney disease after coronary angiography or contrast-enhanced CT. Pre-existing renal dysfunction is also not a risk factor for CIN, even if the eGFR is <30 ml/min/1.73 m 2 ., Competing Interests: Competing Interests The authors report no conflicts of interest.