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Before and after sound therapy, how does the pitch of the tinnitus change? Determine the change of the tinnitus pitch and THI, VAS, SDS (depression degree), relations with STAI (anxiety degree). Give sound therapy for the chronic tinnitus in our department; 206 patients with chronic tinnitus passed more than 12 months after the start of therapy (127 men, women 79). The age distribution was 15-78 years old, an average of 60.9 years old. We evaluated evaluation, THI of the pitch of the tinnitus by the pitch match test, tinnitus VAS, SDS (depression degree), STAI (anxiety degree) by sound therapy using the following instruments enforcement initiation time and 12 months later. We evaluated the effect of treatment of the sound therapy with five phases of subjective degree of improvement. The tinnitus pitch before and after the sound therapy - 84 patients in decrease group (more than a decrease 1.5 octave: 38, lower than decrease octave: 46), 78 in immutability group, in increase group 44. The tinnitus pitch and the subjective improvement were 59.1% for 90.5% of decrease group, immutability case 75.6%, increase case. Concerning THI, tinnitus VAS, SDS (depression degree), STAI (anxiety degree) and the tinnitus pitch, all showed the percent improvement that was higher than increase group in pitch decrease group. About 206 chronic ringing in the ears cases, we can put it one year after sound therapy. We examined the change of the tinnitus pitch. As for tinnitus pitch one year later, an improvement example was found a lot in the decrease group that was 44 increase (21.4%), decrease 38 (18.4%), mild decrease 46 (22.3%), immutability 78 (37.9%), increase 44 (21.4%). In the decrease group, THI degree of improvement, the SDS score one year after the SDS degree of improvement shop were better than a constant group, and VAS, THI, SDS, THI one year after the degree of improvement shop of STAI (state anxiety), SDS score were better than increase group. [ABSTRACT FROM AUTHOR]

Background: Tri-weekly cisplatin and radiotherapy (CDDP + RT) is a standard of care for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) but is sometimes challenging to complete in older patients. Weekly CDDP + RT has shown mild toxicity compared to tri-weekly CDDP + RT for LA-HNSCC and is a promising option for older adults. We aimed to report the treatment outcomes and prognostic factors in patients with LA-HNSCC treated with weekly CDDP + RT., Methods: We analyzed patients aged ≥ 70 years who started weekly CDDP + RT for LA-HNSCC between July 2006 and October 2022. LA-HNSCC includes cancer in the oropharynx, hypopharynx, or larynx with a clinical stage of 3 or 4 without distant metastases based on the Union for International Cancer Control staging system 8th edition. The radiation dose of 70 Gy was delivered in 35 fractions by 3-dimensional conformal radiotherapy, intensity-modulated radiotherapy, or proton beam therapy. The primary endpoint was the 3-year overall survival (OS), and the secondary endpoints were the 3-year progression-free survival (PFS) and 3-year cause-specific survival (CSS). The Kaplan-Meier method was used to calculate survival rates, and the log-rank test was used to evaluate statistical significance. A Cox proportional hazards model was used for the multivariate analysis of prognostic factors., Results: The median age of the 49 patients was 72 (range: 70-78) years. The median CDDP dose was 200 (40-280) mg/ m 2 , and 47 patients completed scheduled radiotherapy. Forty-eight patients (98.0%) had a performance status of ≥ 1 at the initial visit. The 3-year OS, PFS, and CSS were 80.9% (95% confidence interval [CI]: 64.8-90.7), 68.3% (95% CI 51.8-81.2), and 85.0% (95% CI 68.7-93.4), respectively. In the multivariate analysis, the cumulative CDDP dose (< 200 or ≥ 200 mg/m 2 ) was a significant factor for OS (hazard ratio: 0.29 [95% CI 0.08-0.97], p = 0.044). There was one case of early mortality. Grade 3 or higher late adverse events were observed in four patients (8.2%)., Conclusions: Weekly CDDP + RT in older patients led to good survival outcomes with an acceptable rate of adverse events. CDDP should be administered at a dose of at least 200 mg/m 2 in older patients. Trial registration Retrospectively registered., (© 2023. The Author(s).)

We conducted a charge-charge clustering experiment of positively and negatively charged colloidal particles in aqueous media under a microgravity environment at the International Space Station. A special setup was used to mix the colloid particles in microgravity and then these structures were immobilized in gel cured using ultraviolet (UV) light. The samples returned to the ground were observed by optical microscopy. The space sample of polystyrene particles with a specific gravity ρ (=1.05) close to the medium had an average association number of ~50% larger than the ground control and better structural symmetry. The effect of electrostatic interactions on the clustering was also confirmed for titania particles (ρ ~ 3), whose association structures were only possible in the microgravity environment without any sedimentation they generally suffer on the ground. This study suggests that even slight sedimentation and convection on the ground significantly affect the structure formation of colloids. Knowledge from this study will help us to develop a model which will be used to design photonic materials and better drugs., (© 2023. The Author(s).)

On-site disinfection techniques are beneficial during a pandemic when there is a marked shortage of personal protective equipment (PPE), as experienced during the coronavirus disease 2019 outbreak. Ozone gas has been considered an alternative on-site disinfectant during a pandemic because it has antimicrobial activities, can be produced from air by electricity without the need for storage, and can be easily deactivated after use. However, ozone gas might become distributed at the lower layer because it has a larger molecular weight than air. This study aimed to reveal the applicability of ozone gas for the on-site disinfection of PPE. The lockers meant for changing dresses were used as ozone gas exposure boxes, and the distribution of ozone was assayed. Considering that the determined ozone levels were not consistent in the types of ozone analysers, we studied the chemical and biological activities of ozone, which were evenly detected in the locker. The gown in the locker was also uniformly exposed to ozone. Results showed that ozone gas could be used for the on-site disinfection of PPE in a closed box, such as a locker. This finding is valuable during a pandemic when PPE is in short supply., Competing Interests: The authors declare the following conflict of interests: S.I. received research grants from Tamura Teco Co., Ltd, Osaka, Japan. All other authors have no conflict of interest to declare., (© 2023 The Authors.)

Aims: Hemoglobin A1c (HbA1c) levels are widely employed to diagnose diabetes. However, estimates of the heritability of HbA1c and glucose levels are different. Therefore, we explored HbA1c- and blood glucose-associated loci in a non-diabetic Japanese population., Methods: We conducted a two-stage genome-wide association study (GWAS) on variants associated with HbA1c and blood glucose levels in a Japanese population. In the initial stage, data of 4911 participants of the Japan Multi-Institutional Collaborative Cohort (J-MICC) were subjected to discovery analysis. In the second stage, two datasets from the Tohoku Medical Megabank project, with 8175 and 40,519 participants, were used for the replication study. Association of the imputed variants with HbA1c and blood glucose levels was determined via linear regression analyses adjusted for age, sex, body mass index (BMI), smoking, and genetic principal components (PC1-PC10). Moreover, we performed a BMI-stratified GWAS on HbA1c levels in the J-MICC. The discovery analysis and BMI-stratified GWAS results were validated with re-analyses of normalized HbA1c levels adjusted for site in addition to the above, and blood glucose adjusted for fasting time as an additional covariate., Results: Genetic variants associated with HbA1c levels were identified in KCNQ1 and TMC6 . None of the genetic variants associated with blood glucose levels in the discovery analysis were replicated. Association of rs2299620 in KCNQ1 with HbA1c levels showed heterogeneity between individuals with BMI ≥ 25 kg/m 2 and BMI < 25 kg/m 2 ., Conclusions: The variant rs2299620 in KCNQ1 might affect HbA1c levels differentially based on BMI grouping in the Japanese population., Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00618-0., Competing Interests: Conflict of interestTakuya Sakashita is an employee of Takara Bio, Inc., Japan. Dr. Hachiya is a board member of Genome Analytics Japan Inc. Dr. Nakatochi reports receiving grants from Boehringer Ingelheim outside the submitted work. All other authors declare that they have no conflicts of interest associated with this study., (© The Japan Diabetes Society 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Objective: Both 90 Y and 177 Lu are attractive β-emitters for radionuclide therapy and have been used in clinical practice. Nevertheless, comparative evaluation between 90 Y- and 177 Lu-labeled molecules has not been fully conducted. Thus, in this study, the features of 90 Y and 177 Lu for radionuclide therapy were assessed in tumor-bearing mice., Methods: Two tumor cell lines with different growth rates were used. Biodistribution studies of 177 Lu-labeled antibodies ( 177 Lu-Abs) were conducted in each tumor-bearing mouse model. Subsequently, the therapeutic effect of 90 Y- and 177 Lu-Ab were assessed in tumor-bearing mice. The absorbed radiation dose for the tumor was estimated using the Monte Carlo simulation., Results: 177 Lu-Abs demonstrated high tumor accumulation in both tumor-xerograph. In the fast-growing tumor model, 90 Y-Ab showed a better therapeutic effect than 177 Lu-Ab, reflecting a higher absorbed radiation dose of 90 Y-Ab than that of 177 Lu-Ab. In the slow-growing tumor model, both 90 Y- and 177 Lu-Ab showed an excellent therapeutic effect; however, 177 Lu-Ab had a longer efficacy period than 90 Y-Ab, which could be attributed to the longer half-life and better dose uniformity of 177 Lu than those of 90 Y., Conclusions: To accomplish a maximum therapeutic effect, selecting 90 Y or 177 Lu, to depend on the growth rate of individual cancer, would be helpful., (© 2022. The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine.)

The rearrangement of anaplastic lymphoma kinase (ALK) occurs in 3%-5% of patients with non-small cell lung cancer (NSCLC) and confers sensitivity to ALK-tyrosine kinase inhibitors (TKIs). For the treatment of patients with ALK-rearranged NSCLC, various additional ALK-TKIs have been developed. Ceritinib is a second-generation ALK-TKI and has shown great efficacy in the treatment of patients with both newly diagnosed and crizotinib (a first-generation ALK-TKI)-refractory ALK-rearranged NSCLC. However, tumors can also develop ceritinib resistance. This may result from secondary ALK mutations, but other mechanisms responsible for this have not been fully elucidated. In this study, we explored the mechanisms of ceritinib resistance by establishing ceritinib-resistant, echinoderm microtubule-associated protein-like 4 (EML4)-ALK-positive H3122 cells and ceritinib-resistant patient-derived cells. We identified a mechanism of ceritinib resistance induced by bypass signals that is mediated by the overexpression and activation of fibroblast growth factor receptor 3 (FGFR3). FGFR3 knockdown by small hairpin RNA or treatment with FGFR inhibitors was found to resensitize the resistant cells to ceritinib in vitro and in vivo. FGFR ligands from either human serum or fetal bovine serum were able to activate FGFR3 and induce ceritinib resistance. A detailed analysis of ceritinib-resistant patient-derived specimens confirmed that tyrosine-protein kinase Met (cMET) amplification induces ceritinib resistance. Amplified cMET counteractivated EGFR and/or Her3 and induced ceritinib resistance. These results reveal multiple ceritinib resistance mechanisms and suggest that ceritinib resistance might be overcome by identifying precise resistance mechanisms., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Multilayered approaches to suicide prevention combine universal, selective, and indicated prevention interventions. These approaches may be more successful in reducing suicide rates among older adults if they link these layers more systematically: that is, if the programs are designed so that interventions at a lower level facilitate involvement at a higher level when appropriate. This study aimed to examine the effect on suicide rates of the structure of multilayered approaches, and in particular the types of interventions and the connections or linkages between them. We also wished to consider any different effects by sex. A literature search used PubMed and PsycINFO to identify systematic reviews of interventions in this age group. From the reference lists of these articles, we identified controlled studies assessing the impact of a multilayered program on suicide incidence among older adults. We were particularly interested in initiatives linking different kinds of prevention interventions. We found three relevant systematic reviews, and from these, we identified nine eligible studies. These included seven non-randomized controlled studies from rural areas in Japan (average eligible population: 3,087, 59% women, average duration: 8 years). We also found two cohort studies. The first was from a semi-urban area in Padua, Italy (18,600 service users, 84% women, duration: 11 years). The second was from urban Hong Kong, with 351 participants (57% women) over a 2-year follow-up period. We used a narrative synthesis of these studies to identify five different multilayered programs with different forms of connections or linkages between layers. Two studies/programs (Italy and Hong Kong) involved selective and indicated prevention interventions. One study/program (Yuri, Japan) included universal and selective prevention interventions, and the final six studies (two programs in northern Japan) involved linkages between all three layers. We also found that these linkages could be either formal or informal. Formal linkages were professional referrals between levels. Informal linkages included advice from professionals and self-referrals. Several of the studies noted that during the program, the service users developed relationships with services or providers, which may have facilitated movements between levels. All five programs were associated with reduced suicide incidence among women in the target groups or communities. Two programs were also associated with a reduction among men. The study authors speculated that women were more likely to accept services than men, and that the care provided in some studies did less to address issues that are more likely to affect men, such as suicidal impulsivity. We therefore suggest that it is important to build relationships between levels, especially between selective and indicated prevention interventions, but that these can be both formal and informal. Additionally, to reach older men, it may be important to create systematic methods to involve mental health professionals in the indicated prevention intervention. Universal interventions, especially in conjunction with systematically linked indicated and selective interventions, can help to disseminate the benefits across the community., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sakashita and Oyama.)

Prophylactic elective neck dissection (ND) with navigation surgery using radioisotope-based sentinel lymph node biopsy (SLNB) is non-inferior to elective ND in terms of survival but has an advantage in postoperative functional disability. We conducted a subgroup analysis to identify predictive factors for false-negative (FN)-SLNB in patients with early oral cavity cancer. This study is a supplementary analysis using the dataset of a previously reported randomized clinical trial on SLN navigation surgery for oral cancers. This study investigated the association of clinical and SLN-related factors with false-negative cases in the SLNB group. From 2011 to 2016, 275 patients were enrolled and randomly assigned to the ND and SLNB study groups, with 134 patients assigned to the SLNB group. In the SLNB group, seven cases with negative SLNs and neck recurrences were judged as FN-SLNBs according to the general definition. The number of detected SLNs with and without adjusting for the propensity score was significantly associated with FNs in the logistic analysis. FN-SLNB was associated with the number of identified SLNs, suggesting the need for careful postoperative monitoring for neck recurrence in patients with one or two identified SLNs after acquiring sufficient experience in the identification technique., (© 2022. The Author(s).)

Background: The global point prevalence survey (Global-PPS) is the standard for the surveillance of prescribed antimicrobials among inpatients and provides data for the development of hospital antimicrobial stewardship programs., Aim: To evaluate the prevalence and quality of antimicrobial prescriptions using the universally standardized Global-PPS protocol in a non-acute care hospital in Saitama Prefecture, Japan., Methods: Antimicrobial prescriptions for inpatients, staying at the hospital overnight, were surveyed on three separate week days in November 2018, January 2019, and May 2019. Information on the prescribed antimicrobials on the survey target day was obtained from the in-hospital pharmacy. Survey data were collected by physicians, based on the extracted information. Patient information was anonymized and entered in the Global-PPS Web application by physicians. We report the antimicrobial use prevalence, the indication for prescription, diagnosis, the most prescribed antimicrobials, and a set of quality indicators related to antimicrobial prescribing., Results: In total, 6.7% of the surveyed inpatients (120/1796) were prescribed antimicrobials on the survey day. Sulfamethoxazole/trimethoprim was the most commonly prescribed, with 20.0% of systemic antibiotic prescriptions (ATC J01). Of all antibiotics for systemic use, up to 58.4% were Watch antibiotics, as defined by the World Health Organization AWaRe classification. The most prescribed group of systemic antibiotics was non-penicillin beta-lactam antibiotics (34.4%), followed by penicillin antibiotics in combination with beta-lactamase inhibitors (25.6%), and sulfonamides with trimethoprim (20.8%). Healthcare-associated infections and medical prophylaxis were the most common indications reported in 69.3% and 26.3% of prescriptions, respectively. The most common diagnosis for systemic antibiotic prescriptions was pneumonia (49.6%). Reasons for antimicrobial prescriptions were indicated in the medical records for 67.1% of prescriptions, and the stop/review date was documented to be 50.3%. Compliance with local guidelines reached 66.7%., Conclusions: This study highlights important challenges related to antimicrobial prescription in a highly specific, non-acute care patient population., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Noriomi Ishibashi et al.)

Background: We recently reported a new absorbed dose conversion method, RAP (RAtio of Pharmacokinetics), for 211 At-meta-astatobenzylguanidine ( 211 At-MABG) using a single biodistribution measurement, the percent injected dose/g. However, there were some mathematical ambiguities in determining the optimal timing of a single measurement of the percent injected dose/g. Thus, we aimed to mathematically reconstruct the RAP method and to examine the optimal timing of a single measurement., Methods: We derived a new formalism of the RAP dose conversion method at time t. In addition, we acquired a formula to determine the optimal timing of a single measurement of the percent injected dose/g, assuming the one-compartment model for biological clearance., Results: We investigated the new formalism's performance using a representative RAP coefficient with radioactive decay weighting. Dose conversions by representative RAP coefficients predicted the true [ 211 At]MABG absorbed doses with an error of 10% or less. The inverses of the representative RAP coefficients plotted at 4 h post-injection, which was the optimal timing reported in the previous work, were very close to the new inverses of the RAP coefficients 4 h post-injection. Next, the behavior of the optimal timing was analyzed by radiolabeled compounds with physical half-lives of 7.2 h and 10 d on various biological clearance half-lives. Behavior maps of optimal timing showed a tendency to converge to a constant value as the biological clearance half-life of a target increased. The areas of optimal timing for both compounds within a 5% or 10% prediction error were distributed around the optimal timing when the biological clearance half-life of a target was equal to that of the reference. Finally, an example of RAP dose conversion was demonstrated for [ 211 At]MABG., Conclusions: The RAP dose conversion method renovated by the new formalism was able to estimate the [ 211 At]MABG absorbed dose using a similar pharmacokinetics, such as [ 131 I]MIBG. The present formalism revealed optimizing imaging time points on absorbed dose conversion between two radiopharmaceuticals. Further analysis and clinical data will be needed to elucidate the validity of a behavior map of the optimal timing of a single measurement for targeted alpha-nuclide therapy., (© 2021. The Author(s).)

Radiation damages many cellular components and disrupts cellular functions, and was previously reported to impair locomotion in the model organism Caenorhabditis elegans . However, the response to even higher doses is not clear. First, to investigate the effects of high-dose radiation on the locomotion of C. elegans , we investigated the dose range that reduces whole-body locomotion or leads to death. Irradiation was performed in the range of 0-6 kGy. In the crawling analysis, motility decreased after irradiation in a dose-dependent manner. Exposure to 6 kGy of radiation affected crawling on agar immediately and caused the complete loss of motility. Both γ-rays and carbon-ion beams significantly reduced crawling motility at 3 kGy. Next, swimming in buffer was measured as a motility index to assess the response over time after irradiation and motility similarly decreased. However, swimming partially recovered 6 h after irradiation with 3 kGy of γ-rays. To examine the possibility of a recovery mechanism, in situ GFP reporter assay of the autophagy-related gene lgg-1 was performed. The fluorescence intensity was stronger in the anterior half of the body 7 h after irradiation with 3 kGy of γ-rays. GFP::LGG-1 induction was observed in the pharynx, neurons along the body, and the intestine. Furthermore, worms were exposed to region-specific radiation with carbon-ion microbeams and the trajectory of crawling was measured by image processing. Motility was lower after anterior-half body irradiation than after posterior-half body irradiation. This further supported that the anterior half of the body is important in the locomotory response to radiation.

We present pathology of the peripheral nerves of a patient with Adult-onset Charcot-Marie-Tooth disease 4F caused by periaxin gene mutation p.D651N. The patient was a 72-year-old woman. She had hoarseness and underwent continuous positive airway pressure therapy at night due to sleep apnea. The patient died abruptly. Remarkable demyelination with tomacula formation was found in the phrenic nerve, vagal nerve, recurrent laryngeal nerve, and oculomotor nerves. The cause of death could have been insufficient reactivity to the aspiration or sudden onset of bilateral vocal cord palsy. We must pay attention to respiratory function and cranial nerve palsies in hereditary demyelinating neuropathies., Competing Interests: None., (© 2021 The Authors.)

Tardigrades are microscopic animals of which terrestrial species are capable of tolerating extreme environments by entering a desiccated ametabolic state known as anhydrobiosis. Intriguingly, they survive high dosage gamma rays (>4,000 Gy), possibly through a mechanism known as cross-tolerance. We hypothesized that anhydrobiosis genes are also regulated during cross-tolerance, thus we submitted Ramazzottius varieornatus to 500 Gy 60 Co gamma-ray and conducted time-course low-input RNA-Seq. The gene expression was quantified with RSEM and differential expression was determined with DEseq2. Differentially expressed genes were submitted to gene ontology enrichment analysis with GOStat. The transcriptome dynamically shifted nine hours post-exposure., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships which have or could be perceived to have influenced the work reported in this article., (© 2021 The Author(s). Published by Elsevier Inc.)

Objective: We aimed to estimate in vivo 211 At-labeled meta-benzylguanidine ( 211 At-MABG) absorbed doses by the two dose conversion methods, using 131 I-MIBG biodistribution data from a previously reported neuroblastoma xenograft model. In addition, we examined the effects of different cell lines and time limitations using data from two other works., Methods: We used the framework of the Monte Carlo method to create 3200 virtual experimental data sets of activity concentrations (kBq/g) to get the statistical information. Time activity concentration curves were produced using the fitting method of a genetic algorithm. The basic method was that absorbed doses of 211 At-MABG were calculated based on the medical internal radiation dose formalism with the conversion of the physical half-life time of 131 I to that of 211 At. We have further improved the basic method; that is, a novel dose conversion method, RAP (Ratio of Pharmacokinetics), using percent injected dose/g., Results: Virtual experiments showed that 211 At-MABG and 131 I-MIBG had similar properties of initial activity concentrations and biological components, but the basic method did not simulate the 211 At-MABG dose. Simulated 211 At-MABG doses from 131 I-MIBG using the RAP method were in agreement with those from 211 At-MABG, so that their boxes overlapped in the box plots. The RAP method showed applicability to the different cell lines, but it was difficult to predict long-term doses from short-term experimental data., Conclusions: The present RAP dose conversion method could estimate 211 At-MABG absorbed doses from the pharmacokinetics of 131 I-MIBG with some limitations. The RAP method would be applicable to a large number of subjects for targeted nuclide therapy.

The extracellular adenosine triphosphate (ATP) concentration is highly elevated in the tumor microenvironment (TME) and remains tightly regulated in normal tissues. Using phage display technology, we establish a method to identify an antibody that can bind to an antigen only in the presence of ATP. Crystallography analysis reveals that ATP bound in between the antibody-antigen interface serves as a switch for antigen binding. In a transgenic mouse model overexpressing the antigen systemically, the ATP switch antibody binds to the antigen in tumors with minimal binding in normal tissues and plasma and inhibits tumor growth. Thus, we demonstrate that elevated extracellular ATP concentration can be exploited to specifically target the TME, giving therapeutic antibodies the ability to overcome on-target off-tumor toxicity., Competing Interests: Declaration of Interests All authors except for J.K. and M.I. are employees of Chugai Pharmaceutical Co., Ltd. K. Ohara, K.A., H.K., H.K., T.I., E.T., M.M., Y.A., Y.S., K.H., T.K., T.M., M.N., S.K., S.T., T.B., M.E., and F.M. own stock in the company. H.K., K.T, S.S., M.K., T.I., S.T., H.K., A.H., F.M., T.K., and M.H. are inventors on intellectual property related to this work. J.K. and M.I. receive research support from Chugai Pharmaceutical Co., Ltd. This study was funded by Chugai Pharmaceutical Co., Ltd., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Pharmacokinetics of SN-38 in patients with end-stage kidney disease (ESKD) is partially varied because of fluctuations in transporters expression and/or function by high protein bound-uremic toxins concentration. The fluctuations may induce variations in anticancer drugs sensitivity to cancer cells. We aimed to clarify the variations in sensitivity of SN-38 to cancer patients with ESKD and investigate this mechanism, by human colon cancer cells exposed to uremic serum residue. LS180 cells were exposed to normal or uremic serum residue (LS/NSR or LS/USR cells) for a month. IC 50 values of SN-38 in LS/NSR or LS/USR cells were calculated from viability of each cells treated SN-38. mRNA expression and intracellular SN-38 accumulation was evaluated by RT-PCR and HPLC-fluorescence methods, respectively. The IC 50 value in LS/USR cells was higher than that in LS/NSR cells. Organic anion transporter polypeptide (OATP) 2B1 mRNA expression was lower in LS/USR cells than in LS/NSR cells, and SN-38 accumulation in LS/USR cells was lower than that in LS/NSR cells. Only co-treatment baicalin, which is OATP2B1 inhibitor, almost negated the difference in SN-38 accumulation between LS/NSR and LS/USR. Anticancer effects of substrates of OATP2B1, such as SN-38, were reduced in ESKD patients at the same plasma substrate concentration.

Cataracts have long been known, but a biomathematical model is still unavailable for cataratogenesis. There has been a renewed interest in ionizing radiation cataracts because the recent international recommendation of the reduced lens dose limit stimulated the discussion toward its regulatory implementation in various countries. Nevertheless, a relationship between radiation (dose and dose rate) and response (e.g., incidence, onset and progression) remains incompletely understood, raising the need for a risk-predictive mathematical model. We here report for the first time an in silico model for cataractogenesis. First, a simplified cell proliferation model was developed for human lens growth based on stem and progenitor cell proliferation as well as epithelial-fiber cell differentiation. Then, a model for spontaneous cataractogenesis was developed to reproduce the human data on a relationship between age and cataract incidence. Finally, a model for radiation cataractogenesis was developed that can reproduce the human data on a relationship between dose and cataract onset at various ages, which was further applied to estimate cataract incidence following chronic lifetime exposure. The model can serve as the foundation for further development of the risk-predictive model for cataractogenesis along with additional considerations of various biological mechanisms and epidemiological datasets., Competing Interests: The authors have declared that no competing interests exist.

Suicide prevention is an increasingly important issue, especially among older people. Recent work on improving its effectiveness has focused on developing a framework aligning interventions with key risk factors and stages of the suicide process. We have developed this further, by integrating psycho-behavioral components associated with suicide, existing guidelines for identifying critical points of intervention, and the previous preventive strategies framework. Our schematic diagram shows the relationship between the suicide process and prevention strategies, combined with initiatives for linking different types of strategies, from universal strategies at population level, through selective strategies focusing on groups at risk, to indicated strategies, aimed at specific high-risk individuals. We tested our framework using previous studies assessing the impact of suicide prevention interventions on suicide rates in older adults. It was possible to place all identified interventions within the framework. Examining effectiveness within the framework suggests that some interventions may be more successful in reducing suicide rates because they developed systematic linkages between universal, selective, and indicated prevention interventions. Other studies, however, show that interventions can be successful without these linkages, so other factors may also be important. The main weakness of our framework is a lack of evidence about critical intervention points within the suicide process, which may limit its practical application. However, the framework may help to improve the linkages between types of interventions, and support practitioners in developing a wide range of strategies across different areas and stages of the suicide process.