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ABSTRACT Aims/Introduction To conduct a multicenter survey of visually impaired patients with diabetes mellitus (DM) and to identify the physical and ocular characteristics that lead to blindness in Japan. Materials and Methods Visually impaired patients with diabetes mellitus in Japan were divided into blind and low‐vision groups according to the World Health Organization classification. Data on parameters related to diabetes mellitus and ocular complications in the right and left eyes were collected from 19 highly advanced medical facilities and compared between the two groups. Results Among 408 visually impaired persons (blind group: 257, low‐vision group: 151), 72.1% were under 70 years of age. The rates of neovascular glaucoma (NVG) (right eye, P = 0.041; left eye, P = 0.0031) or proliferative diabetic retinopathy (PDR) (right eye: P = 0.014, left eye: P = 0.0047) and the rate of proliferative membrane beyond half of the retinal area (right eye: P = 0.0263, left eye: P = 0.037) were significantly higher in the blind group. The direct cause of visual impairment was retinal atrophy, common in both groups. Neovascular glaucoma and diabetic macular edema were equally prevalent in the blind and low‐vision groups, respectively. Conclusions In Japan, blind patients with diabetes mellitus are characterized by severe conditions such as neovascular glaucoma and progressive proliferative diabetic retinopathy upon their initial visit to an advanced care facility. These results highlight the importance of monitoring retinopathy through regular ophthalmological examinations, internal medicine, and appropriate therapeutic intervention.

Abstract Background Although immune checkpoint blockade (ICB) therapy has proven to be extremely effective at managing certain cancers, its efficacy in treating pancreatic ductal adenocarcinoma (PDAC) has been limited. Therefore, enhancing the effect of ICB could improve the prognosis of PDAC. In this study, we focused on the histamine receptor H1 (HRH1) and investigated its impact on ICB therapy for PDAC. Methods We assessed HRH1 expression in pancreatic cancer cell (PCC) specimens from PDAC patients through public data analysis and immunohistochemical (IHC) staining. The impact of HRH1 in PCCs was evaluated using HRH1 antagonists and small hairpin RNA (shRNA). Techniques including Western blot, flow cytometry, quantitative reverse transcription polymerase chain reaction (RT-PCR), and microarray analyses were performed to identify the relationships between HRH1 and major histocompatibility complex class I (MHC-I) expression in cancer cells. We combined HRH1 antagonism or knockdown with anti-programmed death receptor 1 (αPD-1) therapy in orthotopic models, employing IHC, immunofluorescence, and hematoxylin and eosin staining for assessment. Results HRH1 expression in cancer cells was negatively correlated with HLA-ABC expression, CD8+ T cells, and cytotoxic CD8+ T cells. Our findings indicate that HRH1 blockade upregulates MHC-I expression in PCCs via cholesterol biosynthesis signaling. In the orthotopic model, the combined inhibition of HRH1 and αPD-1 blockade enhanced cytotoxic CD8+ T cell penetration and efficacy, overcoming resistance to ICB therapy. Conclusions HRH1 plays an immunosuppressive role in cancer cells. Consequently, HRH1 intervention may be a promising method to amplify the responsiveness of PDAC to immunotherapy.

Introduction: Post-vitrectomy cystoid macular edema (CME) can lead to failure of macular hole (MH) closure. We report 2 cases of failure of MH closure due to post-vitrectomy CME, which were successfully treated using sub-Tenon triamcinolone acetonide (STTA) injection. Case Presentations: Case 1 involved a 72-year-old male patient with a Gass Stage 3 MH in the right eye. He underwent pars plana vitrectomy (PPV), internal limiting membrane translocation, and sulfur hexafluoride (SF6) gas injection with cataract surgery in his right eye. The MH did not close postoperatively; further, CME developed at the edge of the MH. Accordingly, the patient underwent an STTA injection. Approximately 2 weeks after the STTA injection, the CME disappeared and the MH closed, which has remained closed 1 year after PPV. Case 2 involved a 78-year-old female patient with Gass Stage 3 MH in the left eye. The patient underwent the same surgical procedure as that performed in case 1. Further, she presented with failure of MH closure caused by CME; therefore, an STTA injection was performed. Approximately 6 weeks after STTA injection, the CME disappeared and the MH closed; further, there was maintained improvement of best-corrected visual acuity for 6 months. Conclusions: STTA injection could be considered before reoperation in cases involving failure of MH closure due to postoperative CME.

Introduction: Hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, used in the treatment of renal anemia, hold the potential to increase the production of vascular endothelial growth factors. Therefore, HIF-PH inhibitors may exacerbate retinal hemorrhage in diseases such as diabetic retinopathy. Here, we present a case involving the administration of an HIF-PH inhibitor, resulting in the exacerbation of retinal hemorrhage in a patient with diabetic retinopathy. Case Presentation: A 32-year-old man with diabetes mellitus and renal anemia caused by diabetic nephropathy was referred to our department for ophthalmic examination, revealing diabetic retinopathy with scattered retinal hemorrhages, exudates, and diabetic maculopathy in both eyes. Darbepoetin alfa was initially administered and switched to the HIF-PH inhibitor roxadustat on day 74. By day 88, fresh retinal hemorrhage was observed in the right eye. On day 132, the retinal hemorrhage had further worsened, with new preretinal hemorrhage in both eyes. Roxadustat was discontinued, replaced with darbepoetin alfa, resulting in retinal hemorrhage improvement by day 181 (49 days post-roxadustat cessation). On day 201, fundus hemorrhage further improved, optical coherence tomography showed no macular edema or subretinal fluid, and the retina was thinning. Fluorescein angiography showed neovascular vessels, active fluorescein leakage, and extensive avascular areas in both eyes, prompting pan-retinal photocoagulation. Visual acuity remained stable throughout treatment. Conclusion: Patients with advanced diabetic retinopathy taking HIF-PH inhibitors should be aware of retinal hemorrhage exacerbations. If observed, the treatment plan, including discontinuation of the HIF-PH inhibitor or switching to another agent, should be discussed with a diabetologist, nephrologist, and ophthalmologist.

Abstract The potential risks associated with organs from COVID-19-infected donors were unclear. To determine the SARS-CoV-2 infection status of corneas transplanted during the COVID-19 pandemic, we performed a polymerase chain reaction (PCR) using the corneal preservation solution that was used for corneal transplantation. We also examined the postoperative health status of the recipients. This study included 144 transplants in 143 eyes. Ninety-nine eyes of imported corneas and 10 of the 14 corneas donated in the prefecture were PCR tested at our hospital, and all were SARS-CoV-2 negative. All corneal transplants were performed after confirming their SARS-CoV-2 negativity by a PCR using a corneal preservation solution at our hospital or a nasopharyngeal swab at a previous facility. Despite postoperative steroid administration, no patient developed COVID-19 infection until discharge. Hence, if the donor's nasopharyngeal swab test is SARS-CoV-2 negative, COVID-19 infection in the recipient due to corneal transplantation may be prevented. Since corneal transplant recipients are susceptible to infection due to prolonged steroid administration and are at high risk for severe diseases if infection occurs, SARS-CoV-2 detection testing using nasopharyngeal swabs in donors should be performed.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate owing to its late diagnosis and aggression. In addition, there are relatively few minimally invasive screening methods for the early detection of PDAC, making the identification of biomarkers for this disease a critical priority. Recent studies have reported that microRNAs in extracellular vesicles (EV‐miRs) from bodily fluids can be useful for the diagnosis of PDACs. Given this, we designed this study to evaluate the utility of cancer EVs extracted from duodenal fluid (DF) and their resident EV‐miRs as potential biomarkers for the detection of PDAC. Methods EV‐miRs were evaluated and identified in the supernatants of various pancreatic cancer cell lines (Panc‐1, SUIT2, and MIAPaca2), human pancreatic duct epithelial cells, and the DF from patients with PDAC and healthy controls. EVs were extracted using ultracentrifugation and the relative expression of EV‐miR‐20a was quantified. Results We collected a total of 34 DF samples (27 PDAC patients and seven controls) for evaluation and our data suggest that the relative expression levels of EV‐miR‐20a were significantly higher in patients with PDAC than in controls (p = 0.0025). In addition, EV‐miR‐20a expression could discriminate PDAC from control patients regardless of the location of the tumor with an area under the curve values of 0.88 and 0.88, respectively. Conclusions We confirmed the presence of EVs in the DF and suggest that the expression of EV‐miR‐20a in these samples may act as a potential diagnostic biomarker for PDAC.

Introdução: Avaliar o clima da equipe é fundamental para identificar os desafios que as equipes de saúde enfrentam na implementação dos processos de trabalho interprofissional. Objetivo: O objetivo deste estudo foi determinar qual é o clima da equipe na APS e se há associação entre clima da equipe e a qualidade da assistência oferecida ao usuário. Métodos: Este estudo teve como objetivo realizar uma revisão sistemática da literatura para definir o clima da equipe de atenção primária à saúde e determinar se existe uma associação entre o clima da equipe e a qualidade do cuidado. O protocolo foi registrado sob o número de protocolo CRD 42019133389 no International Prospective Register of Systematic Reviews (PROSPERO). Uma busca de artigos sobre clima de equipe na atenção primária à saúde foi realizada usando qualquer versão do instrumento de inventário de clima de equipe em seis bases de dados. Não houve restrições quanto à data de publicação ou idioma (espanhol, inglês e português). Resultados: Dos 1.106 estudos obtidos após a remoção de duplicatas, 23 foram selecionados para uma leitura completa com base nas avaliações dos resumos. Observou-se que equipes com melhores climas de trabalho alcançaram melhores resultados de saúde. No entanto, por causa da heterogeneidade metodológica entre os estudos, não foi possível determinar um valor médio para o clima da equipe de atenção primária à saúde como proposto inicialmente. Conclusões: O estudo concluiu que, embora existam indícios de uma possível associação positiva entre o clima da equipe e a qualidade da atenção à saúde em ambientes de atenção primária à saúde, ainda não existem estudos suficientes que nos permitam afirmar categoricamente que essa associação existe.

Introduction: Clinical roles of plasma IL-6 levels have been reported in patients with various cancers, including non-small cell lung cancer (NSCLC), treated with immune checkpoint inhibitors (ICIs). However, the roles of other IL-6 signaling components, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130), in the plasma have not been elucidated.Methods: Blood was collected from 106 patients with NSCLC before initiation of ICI treatment (anti-PD-1 or anti-PD-L1 antibody). Plasma levels of IL-6, sIL-6R, sgp130, and their complexes were assessed by Cox regression hazard model to evaluate their clinical significance. The clinical role of IL-6 or IL-6R genetic polymorphisms was also analyzed.Results: Cox regression analysis showed that higher plasma IL-6 levels significantly predicted unfavorable overall survival (OS; hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.05–1.68, p = 0.012) in NSCLC patients treated with ICIs. However, plasma sIL-6R and sgp130 levels showed no prognostic significance (p = 0.882 and p = 0.934, respectively). In addition, the estimated concentrations of binary IL-6:sIL-6R and ternary IL-6:sIL-6R:sgp130 complexes and their ratios (binary/ternary complex) were not significantly associated with OS (p = 0.647, p = 0.727, and p = 0.273, respectively). Furthermore, the genetic polymorphisms of IL-6 (−634G>C) and IL-6R (48892A>C) showed no clinical role by Kaplan-Meier survival analysis (p = 0.908 and p = 0.639, respectively).Discussion: These findings demonstrated the clinical significance of plasma levels of IL-6, but not of other IL-6 signaling components, sIL-6R and sgp130, suggesting that classical IL-6 signaling, but not trans-signaling, may be related to anti-tumor immune responses in cancer patients treated with ICIs.

Background/Aim: In recent years, switch maintenance after platinum-based chemotherapy has been a standard of care. However, the appropriate number of systemic chemotherapy cycles against advanced-stage urothelial carcinoma (UC) remains unclear. This study assessed the survival outcomes of first-line platinum-based chemotherapy according to treatment cycles in patients with metastatic disease. Patients and Methods: We retrospectively evaluated patients with metastatic bladder and upper urinary tract cancer who received platinum-based combination therapy. Overall survival (OS) was evaluated using the Kaplan-Meier method and the log-rank test. Results: Of 179 patients, 47 (26.3%) were women, and 73 (40.8%) had upper urinary tract cancer. Furthermore, 47 (26.3%) who were not eligible for cisplatin received carboplatin. The median number of treatment cycles was 3 (range=1-14 cycles). The rates of progressive disease within two cycles, from two to four cycles, and from four to six cycles were 18.4%, 19.2%, and 30.6%, respectively. The median OS of patients with 2, 3, 4, 5-6, and ≥7 treatment cycles were 8.6, 14.3, 21.3, 24.4, and 26.1 months, respectively. The OS did not significantly differ between patients receiving four treatment cycles and those receiving ≥5 treatment cycles. In patients with disease control (complete or partial response or stable disease) receiving ≥4 treatment cycles, there was no significant difference in terms of OS between patients receiving four cycles and those receiving six cycles. Conclusion: Four cycles of first-line platinum-based chemotherapy can be effective in patients with metastatic UC. [ABSTRACT FROM AUTHOR]

This paper explores the dynamic relationship between electoral manipulation and popular trust in political institutions. Governments often manipulate election results by resorting to electoral fraud. They also tilt the electoral field by opportunistically deciding when to hold elections, in other words, election timing maneuvering. How do these two different types of electoral manipulation affect citizens' trust in the government, legislature, and election management bodies (EMBs)? We suggest that although the short-term effects of election timing manipulation are unclear due to its ambiguous nature as an electioneering strategy, substantial electoral margins created by timing maneuvering facilitate smooth decision-making, leading to boosting trust in the government and legislature over the long run. In contrast, as electoral fraud is an unambiguous form of manipulation, it may undermine trust in the government and parliament, although such effects may not last. By combining an original dataset of election timing with existing survey data comprising 335,000 citizens from fifty-eight democratic countries, we find evidence in support of our theoretical expectations. [ABSTRACT FROM AUTHOR]

What drives refugee movements? Focusing on host countries' domestic political institutions, we argue that refugee entry is determined by the political regimes that shape the incentives of both host governments and displaced persons. Specifically, we theorize that there is an inverted U-shaped relationship between political regimes and the volume of refugee entries. When the host country is autocratic, refugee volume becomes smaller due to displaced persons' unwillingness to risk the high uncertainty of life under such regimes, and when the host country is democratic, refugee volume is similarly curbed due to democratic constraints on the host government. Consequently, a majority of refugees are clustered into anocratic regimes. Using a global dataset, a series of statistical analyses found strong evidence in support of our theoretical expectations regarding not only the hypothesized correlation between regime type and refugee movements but also the preferences of host governments and displaced persons that we theorize underlie this relationship. [ABSTRACT FROM AUTHOR]

The selection of highly specific target antigens is critical for the development of clinically efficient and safe chimeric antigen receptors (CARs). In search of diagnostic marker for malignant mesothelioma (MM), we have established SKM9‐2 monoclonal antibody (mAb) which recognizes a MM‐specific molecule, sialylated Protein HEG homolog 1 (HEG1), with high specificity and sensitivity. In this study, to develop a novel therapeutic approach against MM, we generated SKM9‐2 mAb‐derived CARs that included the CD28 (SKM‐28z) or 4‐1BB (SKM‐BBz) costimulatory domain. SKM‐28z CAR‐T cells showed continuous growth and enhanced Tim‐3, LAG‐3, and PD‐1 expression in vitro, which might be induced by tonic signaling caused by self‐activation; however, these phenotypes were not observed in SKM‐BBz CAR‐T cells. In addition, SKM‐BBz CAR‐T cells exhibited slightly stronger in vitro killing activity against MM cell lines than SKM‐28z CAR‐T cells. More importantly, only SKM‐BBz CAR‐T cells, but not SKM‐28z CAR‐T cells, significantly inhibited tumor growth in vivo in a MM cell line xenograft mouse model. Gene expression profiling and reporter assays revealed differential signaling pathway activation; in particular, SKM‐BBz CAR‐T cells exhibited enhanced NF‐kB signaling and reduced NFAT activation. In addition, SKM‐BBz CAR‐T cells showed upregulation of early memory markers, such as TCF7 and CCR7, as well as downregulation of pro‐apoptotic proteins, such as BAK1 and BID, which may be associated with phenotypical and functional differences between SKM‐BBz and SKM‐28z CAR‐T cells. In conclusion, we developed novel SKM9‐2‐derived CAR‐T cells with the 4‐1BB costimulatory domain, which could provide a promising therapeutic approach against refractory MM. [ABSTRACT FROM AUTHOR]

Background/Aim: Variant urothelial carcinoma (VUC, defined herein as urothelial carcinoma with any histological variant) is frequently observed at an advanced stage. However, the efficacy of systemic chemotherapy against VUC in metastatic disease has rarely been reported. This study assessed the therapeutic response and survival outcomes of platinum-based chemotherapy as first-line treatment in patients with metastatic VUC. Patients and Methods: We retrospectively analyzed consecutive patients with metastatic bladder and upper urinary tract cancer who received gemcitabine plus cisplatin (or carboplatin) at the University of Occupational and Environmental Health Hospital between November 2008 and November 2022. Progression-free survival and overall survival were evaluated using the Kaplan-Meier method and Cox proportional hazard models. Results: Out of 131 patients recorded, 86 (65.6%) had pure urothelial carcinoma (PUC) and 45 (34.4%) had VUC. The most common variant element was squamous differentiation (44.4%). Compared to those with PUC, patients with VUC showed a comparable objective response rate (33.3% vs. 41.9%, p=0.451) and disease control rate (64.5% vs. 75.6%, p=0.221). They also had poorer progression-free survival (median=4.9 months vs. 7.9 months, p=0.014) and overall survival (median=10.9 months vs. 18.2 months, p=0.037) than those with PUC. On multivariate analysis, VUC was an independent predictor of progression (hazard ratio=1.79; 95% confidence interval=1.19-2.69; p=0.005) and mortality (hazard ratio=1.64; 95% confidence interval=1.08-2.48; p=0.020). Conclusion: Although the response of metastatic VUC to platinum-based chemotherapy was not inferior to that of PUC, VUC had progressed faster than PUC. VUC was significantly associated with a poor prognosis after platinum-based chemotherapy as first-line treatment. [ABSTRACT FROM AUTHOR]

Introduction: Hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, used in the treatment of renal anemia, hold the potential to increase the production of vascular endothelial growth factors. Therefore, HIF-PH inhibitors may exacerbate retinal hemorrhage in diseases such as diabetic retinopathy. Here, we present a case involving the administration of an HIF-PH inhibitor, resulting in the exacerbation of retinal hemorrhage in a patient with diabetic retinopathy. Case Presentation: A 32-year-old man with diabetes mellitus and renal anemia caused by diabetic nephropathy was referred to our department for ophthalmic examination, revealing diabetic retinopathy with scattered retinal hemorrhages, exudates, and diabetic maculopathy in both eyes. Darbepoetin alfa was initially administered and switched to the HIF-PH inhibitor roxadustat on day 74. By day 88, fresh retinal hemorrhage was observed in the right eye. On day 132, the retinal hemorrhage had further worsened, with new preretinal hemorrhage in both eyes. Roxadustat was discontinued, replaced with darbepoetin alfa, resulting in retinal hemorrhage improvement by day 181 (49 days post-roxadustat cessation). On day 201, fundus hemorrhage further improved, optical coherence tomography showed no macular edema or subretinal fluid, and the retina was thinning. Fluorescein angiography showed neovascular vessels, active fluorescein leakage, and extensive avascular areas in both eyes, prompting pan-retinal photocoagulation. Visual acuity remained stable throughout treatment. Conclusion: Patients with advanced diabetic retinopathy taking HIF-PH inhibitors should be aware of retinal hemorrhage exacerbations. If observed, the treatment plan, including discontinuation of the HIF-PH inhibitor or switching to another agent, should be discussed with a diabetologist, nephrologist, and ophthalmologist. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion Adenosinergic system has been implicated in the pathophysiology of bipolar disorder and drugs that affect adenosine neurotransmission have shown some efficacy as add‐on therapy in manic patients.Thus, the aim of the present study was to screen adenosinergic drugs for antimanic‐like effect in methylphenidate (MPH)‐induced hyperlocomotion in mice.Male and female Swiss mice received a single allopurinol (50 and 200 mg/kg, ip), dipyridamole (20 mg/kg, ip), or inosine (50 mg/kg, ip) administration before an acute MPH challenge (5 mg/kg, sc). In experiments with repeated treatment, male mice received a daily administration of allopurinol (25 and 50 mg/kg, ip), dipyridamole (20 mg/kg, ip), or inosine (50 mg/kg, ip) for 14 days. Finally, pretreatment with aminophylline (2 mg/kg, sc), an unspecific adenosine receptor antagonist, was used to evaluate a putative adenosinergic mediation. Locomotor activity was measured in the automated activity chamber for 20 min.Acute and repeated dipyridamole reduced the increase in locomotor activity induced by MPH, while allopurinol and inosine had no effect. Aminophylline blocked the effect of dipyridamole in MPH‐induced hyperlocomotion.The present results suggest that dipyridamole may have an antimanic‐like effect through adenosine receptors and reinforce the proposal that the adenosine system may be an interesting target for new antimanic drugs. [ABSTRACT FROM AUTHOR]