Exosomal miR-493 suppresses MAD2L1 and induces chemoresistance to intraperitoneal paclitaxel therapy in gastric cancer patients with peritoneal metastasis.

Intraperitoneal (IP) chemotherapy with paclitaxel (PTX) for gastric cancer (GC) with peritoneal metastasis (PM) is considered a promising treatment approach, however, there are no useful biomarkers to predict the efficacy of IP therapy. We examined the association between intra-peritoneal exosomes, particularly exosomal micro-RNAs (exo-miRNAs), and IP-chemo sensitivity. MKN45 cells that were cultured with intra-peritoneal exosomes from patients who did not respond to IP therapy with PTX (IPnon-respond group) exhibited resistance to PTX compared with exosomes from responding patients (IPrespond group) (p = 0.002). A comprehensive search for exo-miRNAs indicated that miR-493 was significantly up-regulated in exosomes from the IPnon-respond group compared with those collected from the IPrespond group. The expression of miR-493 in PTX-resistant MKN45 cells (MKN45PTX-res) was higher compared with that in MKN45. In addition, MKN45PTX-res cells exhibited lower MAD2L1 gene and protein expression compared with MKN45. Finally, miR-493 enhancement by transfection of miR-493 mimics significantly down-regulated MAD2L1 expression in MKN45 cells and reduced PTX sensitivity. Our results suggest that intra-peritoneal exo-miR-493 is involved in chemoresistance to PTX by downregulating MAD2L1 in GC with PM. Exo-miR-493 may be a biomarker for chemoresistance and prognosis of GC patients with PM and may also be a promising therapeutic target.

Understanding Reasons for Vaccination Hesitancy and Implementing Effective Countermeasures: An Online Survey of Individuals Unvaccinated against COVID-19.

This online survey of unvaccinated people living in Japan aimed to identify the reasons for declining vaccination and to develop effective countermeasures. We conducted a hierarchical class analysis to classify participants, examine factors influencing their classification, and provide the information they needed about coronavirus disease 2019 (COVID-19) and trusted sources of COVID-19 information for each group. A total of 262 participants were classified into three groups: Group 1 with no specific reason (28 participants, 10.69%); Group 2 with clear concerns about trust in the vaccine (85 participants, 32.44%), and Group 3 with attitudinal barriers, such as distrust of the vaccine and complacency towards COVID-19, and structural barriers, such as vaccination appointments (149 participants, 56.87%). For each group, females tended to be classified in Group 2 more than Group 1 (Odds ratio (OR) [95% confidential intervals (95%CI)] = 1.64 (0.63 to 2.66), p = 0.001) and in Group 3 more than Group 1 (OR [95%CI] = 1.16 (0.19 to 2.12), p = 0.019). The information that the participants wanted to know about COVID-19 was different among each group (Safety: p < 0.001, Efficacy: p < 0.001, Genetic effects: p < 0.001). Those who did not receive the COVID-19 vaccine also had lower influenza vaccination coverage (8.02%). Additionally, 38 participants (14.50%) were subject to social disadvantages because they had not received the COVID-19 vaccine. Countermeasures should be carefully tailored according to the target population, reasons for hesitancy, and specific context. The findings of this study may help develop individualized countermeasures to address vaccine hesitancy.

Association Between Gender and Payments Received From Pharmaceutical Companies Among Medical Professors and Associate Professors in Japan.

Introduction While prior research showed gender gaps in industry payments for medical professionals in the United States, there are limited data in Japan. So, this study seeks to investigate the potential gender gap in the receipt of pharmaceutical companies (PFCs) across all medical fields in Japan. Based on the results of previous studies, we developed a hypothesis that male doctors get more PFC than female doctors. Materials and methods Data from 92 pharmaceutical companies in Japan, covering 2016 to 2019, were analyzed. The analysis was conducted on professors and associate professors at all national and public medical universities in Japan, with gender as a factor variable and payments as an outcome variable, and variables that may have influenced the factor or outcome variables in previous studies, such as specialization, university type, region, rank and years since graduation, as control variables. Payments were converted to US dollars using the December 31, 2021, rate of 115 yen to the dollar for comparison purposes. Results Out of 1,825 subjects, 1,755 were males and 70 females. Males consistently received higher median payments from pharmaceutical companies (PFCs) than females across categories. In particular, among physicians specializing in internal medicine, the median PFC for men was $25 compared to $8 for women. For physicians affiliated with former imperial universities (the seven former imperial universities founded before World War II), the median PFC for men was $32 compared to $5 for women. Multivariate analysis confirmed significantly higher total benefits for males from 2016 to 2019, with the gender gap widening during this period (incidence rate ratio (IRR) for 2016: 0.51, IRR for 2019: 0.44). Conclusions Japanese male professors and associate professors received significantly higher PFCs than their female counterparts, and this gender gap expanded from 2016 to 2019, highlighting persistent gender inequality in the medical field in Japan, similar to trends observed in the United States.

Two-Year-Span Breast Cancer Screening Uptake in Japan after the COVID-19 Pandemic and Its Association with the COVID-19 Vaccination.

There is limited information on whether the COVID-19 pandemic was associated with decreased breast cancer screening uptake and if COVID-19 vaccination was associated with an increase in screening uptake. Our study explored the uptake of breast cancer screening in Japan after the COVID-19 pandemic and assessed its association with the COVID-19 vaccination. We analyzed data from the Japan COVID-19 and Society Internet Survey (JACSIS), a web-based prospective cohort survey, and we included 6110 women without cancer history who were aged 40 to 74 years that participated in the 2012 and 2022 surveys. We examined the regular breast cancer screening uptake before and after the pandemic and employed a multivariable Poisson regression model to seek any association between COVID-19 vaccination and screening uptake. Of 6110, 38.2% regularly participated in screening before the pandemic and 46.9% did so after the pandemic. Individuals unvaccinated due to health reasons (incidence rate ratio (IRR) = 0.47, 95% CI: 0.29-0.77, p = 0.003) and for other reasons (IRR = 0.73, 95% CI: 0.62-0.86, p < 0.001) were less likely to undergo screening compared to fully vaccinated individuals. There was no long-term decrease in breast cancer screening uptake after the pandemic in Japan. Vaccination was linked to increased uptake, but there was no dose relationship.

Tgif1-deficiency impairs cytoskeletal architecture in osteoblasts by activating PAK3 signaling.

Osteoblast adherence to bone surfaces is important for remodeling bone tissue. This study demonstrates that deficiency of TG-interacting factor 1 (Tgif1) in osteoblasts results in altered cell morphology, reduced adherence to collagen type I-coated surfaces, and impaired migration capacity. Tgif1 is essential for osteoblasts to adapt a regular cell morphology and to efficiently adhere and migrate on collagen type I-rich matrices in vitro. Furthermore, Tgif1 acts as a transcriptional repressor of p21-activated kinase 3 (Pak3), an important regulator of focal adhesion formation and osteoblast spreading. Absence of Tgif1 leads to increased Pak3 expression, which impairs osteoblast spreading. Additionally, Tgif1 is implicated in osteoblast recruitment and activation of bone surfaces in the context of bone regeneration and in response to parathyroid hormone 1-34 (PTH 1-34) treatment in vivo in mice. These findings provide important novel insights in the regulation of the cytoskeletal architecture of osteoblasts.

Using the geriatric nutritional risk index to predict outcomes in older patients with remnant gastric cancer after gastrectomy: a retrospective multicenter study in Japan.

PURPOSE: This study investigated the prognostic value of the geriatric nutritional risk index (GNRI) in patients undergoing curative gastrectomy for remnant gastric cancer (RGC). METHODS: This multicenter retrospective study included 105 patients with RGC of ≥ 65 years of age who underwent curative gastrectomy at 10 institutions in Japan between January 2000 and December 2016. Postoperative complications, overall survival (OS), and disease-specific survival (DSS) were analyzed. RESULTS: Receiver operating curve analyses indicated that the optimal cutoff value of the GNRI for OS was 95.4. Patients were categorized into high and low GNRI groups based on the optimal GNRI cutoff value. The GNRI was significantly correlated with body mass index (p < 0.001), amount of bleeding (p = 0.021), Clavien-Dindo grade 5 postoperative complications (p = 0.040), death caused by primary disease (p = 0.010), and death caused by other diseases (p = 0.002). The OS and DSS were significantly worse in the low GNRI group. A low GNRI and T3 or deeper tumor invasion were independent prognostic factors for OS and DSS. CONCLUSIONS: The GNRI is a promising predictor of both short- and long-term outcomes in older patients with RGC.

Nature and Trend of Pharmaceutical Payments to Japanese Board-Certified Neurologists Between 2016 and 2019: A Pre-emergence Analysis Amidst the Development of Next-Generation Alzheimer's Disease Drugs.

OBJECTIVE: There is insufficient data on the financial relationships between Japanese neurologists and pharmaceutical companies prior to the advent of new-generation Alzheimer's disease drugs. The purpose of this study is to evaluate the magnitude, prevalence, and trend of the financial relationship between Japanese neurologists and pharmaceutical companies between 2016 and 2019. METHODS: A cross-sectional study was undertaken to evaluate the financial relationships between all board-certified neurology specialists and pharmaceutical companies in Japan from 2016 and 2019. Descriptive statistics were applied to measure the magnitude and prevalence of payments among specialists, as well as their trends during the study periods. RESULTS: In a four-year analysis, 77 pharmaceutical companies disbursed a total of USD 36,869,204 across 50,050 payments to 2,696 neurologists in Japan, revealing a mean payment of USD 10,809 per specialist. Notably, the Gini index of 0.997 indicated a high inequality in payment distribution, with a minority of specialists receiving a substantial proportion of payments. Trends displayed irregularities, but an overall increase in total payments from 2016 to 2019, with a significant contribution from the top 10 pharmaceutical companies accounting for 74.2% of total payments, with Takeda Pharmaceutical and Eisai Company notably increasing payments in 2019. There were notable geographical variations in neurologist and payment distribution across 47 prefectures. CONCLUSION: Our analysis of neurologist payments from pharmaceutical companies in Japan showed a substantial financial relationship with overall increases, yearly varied increments, and payment inequality. Caution is warranted as financial ties may intensify with the continued development of next-generation Alzheimer's disease drugs.

Assistive AI in Lung Cancer Screening: A Retrospective Multinational Study in the United States and Japan.

Purpose To evaluate the impact of an artificial intelligence (AI) assistant for lung cancer screening on multinational clinical workflows. Materials and Methods An AI assistant for lung cancer screening was evaluated on two retrospective randomized multireader multicase studies where 627 (141 cancer-positive cases) low-dose chest CT cases were each read twice (with and without AI assistance) by experienced thoracic radiologists (six U.S.-based or six Japan-based radiologists), resulting in a total of 7524 interpretations. Positive cases were defined as those within 2 years before a pathology-confirmed lung cancer diagnosis. Negative cases were defined as those without any subsequent cancer diagnosis for at least 2 years and were enriched for a spectrum of diverse nodules. The studies measured the readers' level of suspicion (on a 0-100 scale), country-specific screening system scoring categories, and management recommendations. Evaluation metrics included the area under the receiver operating characteristic curve (AUC) for level of suspicion and sensitivity and specificity of recall recommendations. Results With AI assistance, the radiologists' AUC increased by 0.023 (0.70 to 0.72; P = .02) for the U.S. study and by 0.023 (0.93 to 0.96; P = .18) for the Japan study. Scoring system specificity for actionable findings increased 5.5% (57% to 63%; P < .001) for the U.S. study and 6.7% (23% to 30%; P < .001) for the Japan study. There was no evidence of a difference in corresponding sensitivity between unassisted and AI-assisted reads for the U.S. (67.3% to 67.5%; P = .88) and Japan (98% to 100%; P > .99) studies. Corresponding stand-alone AI AUC system performance was 0.75 (95% CI: 0.70, 0.81) and 0.88 (95% CI: 0.78, 0.97) for the U.S.- and Japan-based datasets, respectively. Conclusion The concurrent AI interface improved lung cancer screening specificity in both U.S.- and Japan-based reader studies, meriting further study in additional international screening environments. Keywords: Assistive Artificial Intelligence, Lung Cancer Screening, CT Supplemental material is available for this article. Published under a CC BY 4.0 license.

Categorization of disaster-related deaths in Minamisoma city after the Fukushima nuclear disaster using clustering analysis.

The medical situation during disasters often differs from that at usual times. Disasters can lead to significant mortality that can be difficult to monitor. The types of disaster-related deaths are largely unknown. In this study, we conducted a survey to categorize the disaster-related deaths caused by a radiation disaster. A total of 520 people living in Minamisoma City, Fukushima Prefecture, at the time of the Fukushima Daiichi Nuclear Power Plant accident, who were certified to have died due to disaster-related causes were surveyed. We divided the participants into those who were at home at the time of the earthquake and those who were in hospitals or facilities when the disaster struck and conducted a hierarchical cluster analysis of the two groups. Disaster-related deaths could be divided into seven groups for those who were at home at the time of the disaster and five groups for those who were in hospitals or facilities at the time of the disaster. Each group showed different characteristics, such as "the group with disabilities," "the group receiving care," and "the group with depression," and it became evident that not only uniform post-disaster support, but support tailored to the characteristics of each group is necessary.

Japanese physicians' perceptions of conflicts of interest with pharmaceutical companies: Estimating two different questioning approaches.

Despite being one of the world's largest pharmaceutical markets, interactions between Japanese physicians and pharmaceutical companies often remain opaque. Importantly, potential conflicts of interest associated with these interactions can compromise patient care and increase costs. We conducted an online survey of Japanese physicians to elucidate perspectives on pharmaceutical company promotional activities and how these influence physician prescribing patterns. Anticipating that physicians might downplay their reliance on, or the value of, pharmaceutical company-provided information, the survey incorporated a direct questioning method and an unmatched count technique (UCT) to identify hidden perceptions on factors likely to influence prescribing. Overall, 1080 eligible physicians participated. Of these, 105 (9.7%) self-identified as hospital directors or managers. Surprisingly, nearly twice as many participants responding to direct questioning (18.9%) versus those responding to the UCT (10.1%) asserted that information provided by pharmaceutical companies was important when prescribing medicine. Hospital directors or managers (adjusted odds ratio [adjOR] 2.56, 95% confidence interval [95% CI]: 1.00-6.54, reference = physician without title) and frequent interactions with pharmaceutical sales representatives (adjOR 5.96, 95% CI: 1.88-18.9, reference = rare interaction) significantly valued the information from sales representatives and sponsored lectures when considering prescribing decisions. Additionally, 77.1% of respondents believed that sales representatives provide fair, neutral, or relatively honest and unbiased information about their products. Few Japanese physicians acknowledged the influence of industry-provided information on prescribing patterns. Our study uniquely applies two distinct question formats, providing a novel approach to understanding the depth of physician-industry relationships and the effectiveness of various survey methodologies.

Is proton-pump inhibitor effective in preventing postoperative bleeding after esophageal endoscopic submucosal dissection?

Although proton-pump inhibitor (PPI) administration was reported to be effective in preventing delayed bleeding after gastric endoscopic submucosal dissection (ESD), its effectiveness in esophageal ESD is still unknown. We assessed whether PPI or vonoprazan administration was effective in preventing posterior hemorrhage after esophageal ESD. This retrospective cohort study used the Japanese Diagnosis Procedure Combination (DPC) database, and patients who underwent esophageal ESD between January 2012 and December 2020 were enrolled. The participants were divided into two groups: patients who were prescribed PPI or vonoprazan (PPI or vonoprazan group) and those who were not prescribed PPI (no acid suppression). Propensity score matching analysis was performed, and the delayed bleeding rate was compared between the groups. We analyzed 54,345 patients, of whom 8237 (15.16%) were in the no acid suppression group and 46,108 (84.84%) in the PPI or vonoprazan group (PPI: 34,380 and vonoprazan: 11,728). Delayed bleeding occurred in 1126 patients (2.07%). A total of 8237 pairs were created after matching. Delayed bleeding was not significantly different between the no acid suppression group and PPI or vonoprazan group, respectively (odds ratio: 1.20, 95% confidential interval: 0.93-1.54, P = 0.227). A sub-analysis according to the dose of PPI or vonoprazan, tumor location, and prescription of antithrombotic or anticoagulant medications was performed, but no significant effects of PPI or vonoprazan administration were found. PPI or vonoprazan did not prevent delayed bleeding; thus, the prescription of PPI and vonoprazan after esophageal ESD may not be recommended for the prevention of delayed bleeding.

Comparison of clinical utility of deep learning-based systems for small-bowel capsule endoscopy reading.

BACKGROUND AND AIM: Convolutional neural network (CNN) systems that automatically detect abnormalities from small-bowel capsule endoscopy (SBCE) images are still experimental, and no studies have directly compared the clinical usefulness of different systems. We compared endoscopist readings using an existing and a novel CNN system in a real-world SBCE setting. METHODS: Thirty-six complete SBCE videos, including 43 abnormal lesions (18 mucosal breaks, 8 angioectasia, and 17 protruding lesions), were retrospectively prepared. Three reading processes were compared: (A) endoscopist readings without CNN screening, (B) endoscopist readings after an existing CNN screening, and (C) endoscopist readings after a novel CNN screening. RESULTS: The mean number of small-bowel images was 14 747 per patient. Among these images, existing and novel CNN systems automatically captured 24.3% and 9.4% of the images, respectively. In this process, both systems extracted all 43 abnormal lesions. Next, we focused on the clinical usefulness. The detection rates of abnormalities by trainee endoscopists were not significantly different across the three processes: A, 77%; B, 67%; and C, 79%. The mean reading time of the trainees was the shortest during process C (10.1 min per patient), followed by processes B (23.1 min per patient) and A (33.6 min per patient). The mean psychological stress score while reading videos (scale, 1-5) was the lowest in process C (1.8) but was not significantly different between processes B (2.8) and A (3.2). CONCLUSIONS: Our novel CNN system significantly reduced endoscopist reading time and psychological stress while maintaining the detectability of abnormalities. CNN performance directly affects clinical utility and should be carefully assessed.

Effect of temperature on the protective efficacy of a live attenuated vaccine against herpesviral haematopoietic necrosis in goldfish.

The live attenuated vaccine P7-P8 strain against herpesviral haematopoietic necrosis, which is caused by cyprinid herpesvirus 2 (CyHV-2), exhibits high protective efficacy in goldfish at 25°C, the predominant temperature for this disease; however, the effect of water temperature during the vaccination period on efficacy has not been determined. In this study, an in vitro experiment revealed that the vaccine strain grew between 15 and 30°C in the goldfish cell line RyuF-2. Subsequent in vivo efficacy tests were conducted with vaccination temperatures ranging from 15 to 30°C. During the vaccination period, organs were sampled to determine the vaccine growth dynamics. Blood plasma was collected to assess anti-CyHV-2 antibody titres. The protective efficacy of the vaccine at 15, 20, 25, and 30°C after subsequent virulent CyHV-2 challenge resulted in a relative percentage survival of 73.3%, 77.8%, 100%, and 77.8%, respectively, which indicated that the vaccine is effective over this temperature range. The vaccine virus load in the spleen was lowest at 15°C (103.7 DNA copies/mg) and highest at 25°C (106.5 DNA copies/mg). This indicates that the vaccine virus load over 104 DNA copies/mg may elicit sufficient acquired immunity. No significant differences in antibody titre were observed between groups, which suggests that cell-mediated immunity can be fundamentally involved in protection.

Long-term Experience on Breast Cancer-related Lymphedema in the Coastal Area of Fukushima, Japan After the 2011 Triple Disaster.

BACKGROUND/AIM: Disasters can jeopardize breast cancer care and Japan's triple disaster in 2011 (earthquake, tsunami, and nuclear accident) is no exception. However, detailed information is lacking regarding the care of breast cancer related lymphedema (BCRL) following the disaster. We aimed to explore the process by which local patients become aware of BCRL, the problems faced, and the support they require. We also aimed to clarify the effects of the 2011 disaster on experiences related to lymphedema in the target population. PATIENTS AND METHODS: Patients who developed BCRL after breast cancer treatment were recruited from Iwaki city, a municipality located in the southern coastal region of Fukushima (N=16). In-depth, semi-structured, face-to-face interviews were conducted, and the obtained data were appraised using thematic analysis. RESULTS: Five themes related to BCRL were identified: 1) the process of becoming aware of BCRL, 2) troubles or worries/concerns due to BCRL, 3) information sources regarding BCRL management, 4) strategies to cope with BCRL, and 5) the adverse impacts of the 2011 disaster on BCRL management. CONCLUSION: Except for the disaster context, the themes are in line with those of previous studies conducted in the non-disaster context. Nonetheless, there were limited but non-negligible adverse effects of the 2011 disaster on long-term local BCRL management. The findings of this study demonstrate the necessity for individualizing coping strategies against BCRL among healthcare professionals in the Fukushima coastal area and beyond.

Idobata-Nagaya: a community housing solution for socially isolated older adults following the great East Japan earthquake.

Introduction: Following the Great East Japan Earthquake, the living environment of socially isolated older adults has become a pressing concern. In response, Nagaya, a collective housing program, was established in Soma City, Fukushima, Japan to address social isolation among older adults and support their long-term health. This study aimed to identify characteristics of individuals in Nagaya and examine the sustainability of this initiative. Methods: We conducted a retrospective analysis of residents who were relocated to Nagaya, emphasizing their characteristics, the continuity of their stay in Nagaya, and their care certification levels, using data up to December 31, 2022. We employed Kaplan-Meier curves to analyze the duration for which residents continued to reside in Nagaya and the time leading up to the requiring care-level certification. Results: Of 65 people who moved to Nagaya after the disaster, 30 people (46.2%) continued to live there, 21 (32.3%) died during their stay, and 14 (21.5%) moved out. The overall duration of occupancy averaged 6.39 years (SD 3.83 years). The proportion of requiring care-level certification occurrences per person-year was 0.0577 for those without care certification and 0.3358 for those with requiring support level at the time of moving in. Conclusion: In summary, Nagaya-style communal housing may offer suitable living environments for older adults with diverse needs during disasters and serve as a valuable tool for developing public policies in aging societies.

Rethinking the Utility of the Audio-Only Encounter: A Case of Herpes Zoster Co-Infection in Asymptomatic SARS-CoV-2.

Background: Telemedicine with video communication has become commonly applied during and after the COVID-19 pandemic. While audio-only encounters are not allowed in Japan after August 2023. The Centers for Medicaid and Medicare Services (CMS) in the United States revised the telehealth policy to make the video visit standard. We present here a case with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and diagnosed her with the Herpes zoster at audio-only encounters followed by an in-person clinic visit. Case Presentation: A 31-year-old woman called our hospital for a complaint of right chest discomfort and a tingling sensation. The SARS-CoV-2 infection was confirmed on her with the polymerase chain reaction (PCR) test 4 days before the symptom onset. A telephone encounter was made for her since the video communication failed to be prepared. The attending physician made a diagnosis of herpes zoster based on her verbal explanation of symptoms and localized skin lesions. An anti-viral medication with amenamevir was given. The photos of skin lesions were sent 3 days after the audio visit, which was consistent with herpes zoster. The patient visited our outpatient clinic and was confirmed for herpes zoster serologically with positive antibodies of both varicella-zoster IgM and IgG. Conclusions: The audio-only visit could help diagnose herpes zoster if the follow-up examinations are performed adequately. Audio-only encounters preserve the flexibility of telemedicine when video communication cannot be prepared promptly.

Association between Conflicts of Interest Disclosure and Quality of Clinical Practice Guidelines in Japan: A Meta-Epidemiological Study.

Accurate disclosure of financial conflicts of interest (COI) among clinical practice guideline (CPG) developers is critical to ensure the quality of CPGs. However, there is limited evidence on the impact of underreporting COIs on the quality of CPGs. This study aimed to examine the proportion of underreported COI disclosures in the development of Japanese CPGs and to estimate the association between underreported COIs and CPG quality using the Appraisal of Guidelines for Research & Evaluation (AGREE) II. Twenty-three Japanese CPGs published in 2019 and their 1114 developers were included in the study. The results show that underreporting of COIs occurred in 52% of the included CPGs and 8% of all CPG developers. Underreporting COI disclosures was negatively associated with low-quality CPG (Odds ratio [OR], 0.57; 95% confidence interval [CI]: 0.11, 3.04). On the other hand, CPGs that had more than 13% of CPG developers with voting rights on recommendation decisions and underreporting of COI disclosures were positively associated with low quality (OR, 1.78; 95% CI: 0.25, 12.45). For individual CPG developers with voting rights for recommendation decisions, the presence of a COI was positively associated with low quality (OR, 1.11; 95% CI: 0.71, 1.75). This study demonstrates that the involvement and underreporting of COIs did not seriously distort the CPG development process. However, the COI-related factors of CPG developers with voting rights for recommendation decisions may be associated with low CPG quality.