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Because of the advent of genome-editing technology, gene knockout (KO) hamsters have become attractive research models for diverse diseases in humans. This study established a new KO model of diabetes by disrupting the insulin receptor substrate-2 (Irs2) gene in the golden (Syrian) hamster. Homozygous KO animals were born alive but with delayed postnatal growth until adulthood. They showed hyperglycemia, high HbA1c, and impaired glucose tolerance. However, they normally responded to insulin stimulation, unlike Irs2 KO mice, an obese type 2 diabetes (T2D) model. Consistent with this, Irs2 KO hamsters did not increase serum insulin levels upon glucose administration and showed β-cell hypoplasia in their pancreas. Thus, our Irs2 KO hamster provide a unique T2D animal model that is distinct from the obese T2D models. This model may contribute to a better understanding of the pathophysiology of human non-obese T2D with β-cell dysfunction, the most common type of T2D in East Asian countries, including Japan., (© 2024. The Author(s).)

Since the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident, great attention has been paid to the impact of chronic low-dose-rate (LDR) radiation exposure on biological systems. The reproductive system is sensitive to radiation, with implications connected to infertility. We investigated the testis ultrastructure of the wild large Japanese field mouse ( Apodemus speciosus ) from three areas contaminated after the FDNPP accident, with different levels of LDR radiation (0.29 µSv/h, 5.11 µSv/h, and 11.80 µSv/h). Results showed good preservation of the seminiferous tubules, comparable to the unexposed animals (controls), except for some ultrastructural modifications. Increases in the numerical density of lipid droplet clusters in spermatogenic cells were found at high levels of LDR radiation, indicating an antioxidant activity rising due to radiation recovery. In all groups, wide intercellular spaces were found between spermatogenic cells, and cytoplasmic vacuolization increased at intermediate and high levels and vacuolated mitochondria at the high-level. However, these findings were also related to the physiological dynamics of spermatogenesis. In conclusion, the testes of A. speciosus exposed to LDR radiation associated with the FDNPP accident showed a normal spermatogenesis, with some ultrastructural changes. These outcomes may add information on the reproductive potential of mammals chronically exposed to LDR radiation.

CD8+ T cells can recognize tumor antigens displayed by HLA class I molecules and eliminate tumor cells. Despite their low tumor mutation burden, immune checkpoint blockade (ICB) is often beneficial in patients with renal cell carcinoma (RCC). Here, using a proteogenomic approach, we directly and comprehensively explored the HLA class I-presenting peptidome of RCC tissues and demonstrated that the immunopeptidomes contain a small subset of peptides derived from human endogenous retroviruses (hERV). A comparison between tumor and normal kidney tissues revealed tumor-associated hERV antigens, one of which was immunogenic and recognized by host tumor-infiltrating lymphocytes (TIL). Stimulation with the hERV antigen induced reactive CD8+ T cells in healthy donor-derived (HD-derived) peripheral blood mononuclear cells (PBMC). These results highlight the presence of antitumor CD8+ T cell surveillance against hERV3895 antigens, suggesting their clinical applications in patients with RCC.

Bladder cancer is a major and fatal urological disease. Cisplatin is a key drug for the treatment of bladder cancer, especially in muscle-invasive cases. In most cases of bladder cancer, cisplatin is effective; however, resistance to cisplatin has a significant negative impact on prognosis. Thus, a treatment strategy for cisplatin-resistant bladder cancer is essential to improve the prognosis. In this study, we established a cisplatin-resistant (CR) bladder cancer cell line using an urothelial carcinoma cell lines (UM-UC-3 and J82). We screened for potential targets in CR cells and found that claspin (CLSPN) was overexpressed. CLSPN mRNA knockdown revealed that CLSPN had a role in cisplatin resistance in CR cells. In our previous study, we identified human leukocyte antigen (HLA)-A*02:01-restricted CLSPN peptide by HLA ligandome analysis. Thus, we generated a CLSPN peptide-specific cytotoxic T lymphocyte clone that recognized CR cells at a higher level than wild-type UM-UC-3 cells. These findings indicate that CLSPN is a driver of cisplatin resistance and CLSPN peptide-specific immunotherapy may be effective for cisplatin-resistant cases., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Few studies have examined the prescribing patterns of orexin receptor antagonists (ORAs) in the real-world clinical setting in Japan., Objective: We sought to analyze the factors associated with ORA prescriptions for patients with insomnia in Japan., Methods: Outpatients (aged ≥ 20 to < 75 years old) prescribed one or more hypnotic for insomnia between April 1, 2018 and March 31, 2020 with continuous enrollment for ≥ 12 months were extracted from the JMDC Claims Database. We performed multivariable logistic regression to identify factors (patient demographics and psychiatric comorbidities) associated with ORA prescription in new or non-new users of hypnotics (patients without or with hypnotics prescription history, respectively)., Results: Of 58,907 new users, 11,589 (19.7%) were prescribed ORA at the index date. Male sex (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.12-1.22) and presence of bipolar disorders (OR 1.36, 95% CI 1.20-1.55) were associated with greater odds of ORA prescription. Among 88,611 non-new users, 15,504 (17.5%) were prescribed ORA at the index date. Younger age and several psychiatric comorbidities, such as neurocognitive disorders (OR 1.64, 95% CI 1.15-2.35), substance use disorders (OR 1.19, 95% CI 1.05-1.35), bipolar disorders (OR 1.14, 95% CI 1.07-1.22), schizophrenia spectrum disorders (OR 1.07, 95% CI 1.01-1.14), and anxiety disorders (OR 1.05, 95% CI 1.00-1.10), were associated with greater odds of ORA prescription., Conclusion: This is the first study to determine the factors associated with ORA prescriptions in Japan. Our findings could help guide appropriate insomnia treatment using ORAs., (© 2023. The Author(s).)

Background: There is limited consensus regarding the optimal treatment of insomnia. The recent introduction of orexin receptor antagonists (ORA) has increased the available treatment options. However, the prescribing patterns of hypnotics in Japan have not been comprehensively assessed. We performed analyses of a claims database to investigate the real-world use of hypnotics for treating insomnia in Japan., Methods: Data were retrieved for outpatients (aged ≥ 20 to < 75 years old) prescribed ≥ 1 hypnotic for a diagnosis of insomnia between April 1 st , 2009 and March 31 st , 2020, with ≥ 12 months of continuous enrolment in the JMDC Claims Database. Patients were classified as new or long-term users of hypnotics. Long-term use was defined as prescription of the same mechanism of action (MOA) for ≥ 180 days. We analyzed the trends (2010-2019) and patterns (2018-2019) in hypnotics prescriptions., Results: We analyzed data for 130,177 new and 91,215 long-term users (2010-2019). Most new users were prescribed one MOA per year (97.1%-97.9%). In 2010, GABA A -receptor agonists (benzodiazepines [BZD] or z-drugs) were prescribed to 94.0% of new users. Prescriptions for BZD declined from 54.8% of patients in 2010 to 30.5% in 2019, whereas z-drug prescriptions remained stable (~ 40%). Prescriptions for melatonin receptor agonist increased slightly (3.2% to 6.3%). Prescriptions for ORA increased over this time from 0% to 20.2%. Prescriptions for BZD alone among long-term users decreased steadily from 68.3% in 2010 to 49.7% in 2019. Prescriptions for ORA were lower among long-term users (0% in 2010, 4.3% in 2019) relative to new users. Using data from 2018-2019, multiple (≥ 2) MOAs were prescribed to a higher proportion of long-term (18.2%) than new (2.8%) users. The distribution of MOAs according to psychiatric comorbidities, segmented by age or sex, revealed higher proportions of BZD prescriptions in elderly (new and long-term users) and male (new users) patients in all comorbidity segments., Conclusion: Prescriptions for hypnotics among new and long-term users in Japan showed distinct patterns and trends. Further understanding of the treatment options for insomnia with accumulating evidence for the risk-benefit balance might be beneficial for physicians prescribing hypnotics in real-world settings., (© 2023. Merck & Co., Inc., Rahway, NJ, USA and its affiliates.)

Background: Inhaled corticosteroids (ICS) are a safe treatment for asthma. However, at higher doses, ICS use has been reported to inhibit adrenocortical function., Objective: This study aimed to evaluate the effect of ICS on bone mineral density (BMD) in adult patients with asthma., Methods: Ultrasonic bone densitometry was performed in 40 patients (14 men, 26 women, mean age 61.2 years, mean duration of asthma 6.19 years) who were receiving ICS for asthma, and the whole bone density, thickness of cortical bone, and density of cancellous bone of the radius was measured. The age-matched mean was set as 100%. Lifetime cumulative dose of ICS was calculated using all past prescriptions., Results: No significant correlations were observed between lifetime cumulative ICS dose and whole bone density (r² = 0.011), cortical bone thickness (r² = 0.022), and cancellous bone density (r² = 0.004). No significant differences were observed between lower and higher lifetime cumulative ICS dose among these BMD parameters (104% vs 97%, 103% vs 99%, and 106% vs 91%, respectively). No significant correlations or differences in lifetime cumulative ICS dose were observed by asthma severity, asthma duration, and pulmonary function. Also, serum markers of bone metabolism showed no significant correlations or differences with lifetime cumulative ICS dose., Conclusions: In the entire study population, long-term ICS use was safe and was not associated with an increased risk of osteoporosis.

Objectives: Delirium is a neuropsychiatric disorder that commonly occurs in elderly patients with cognitive impairment. The economic burden of delirium in Japan has not been well characterised. In this study, we assessed incremental medical costs of delirium in hospitalised elderly Japanese patients with cognitive impairment., Design: Retrospective, cross-sectional, observational study., Setting: Administrative data collected from acute care hospitals in Japan between April 2012 and September 2020., Participants: Hospitalised patients ≥65 years old with cognitive impairment were categorised into groups-with and without delirium. Delirium was identified using a delirium identification algorithm based on the International Classification of Diseases 10 th Revision codes or antipsychotic prescriptions., Outcome Measures: Total medical costs during hospitalisation were compared between the groups using a generalised linear model., Results: The study identified 297 600 hospitalised patients ≥65 years of age with cognitive impairment: 39 836 had delirium and 257 764 did not. Patient characteristics such as age, sex, inpatient department and comorbidities were similar between groups. Mean (SD) unadjusted total medical cost during hospitalisation was 979 907.7 (871 366.4) yen for patients with delirium and 816 137.0 (794 745.9) yen for patients without delirium. Adjusted total medical cost was significantly greater for patients with delirium compared with those without delirium (cost ratio=1.09, 95% CI: 1.09 to 1.10; p<0.001). Subgroup analyses revealed significantly higher total medical costs for patients with delirium compared with those without delirium in most subgroups except patients with hemiplegia or paraplegia., Conclusions: Medical costs during hospitalisation were significantly higher for patients with delirium compared with those without delirium in elderly Japanese patients with cognitive impairment, regardless of patient subgroups such as age, sex, intensive care unit admission and most comorbidities. These findings suggest that delirium prevention strategies are critical to reducing the economic burden as well as psychological/physiological burden in cognitively impaired elderly patients in Japan., Competing Interests: Competing interests: MI, KO, NU, HS, KT, ST and SO are employees of MSD KK, Tokyo, Japan, a subsidiary of Merck & Co, Inc, Rahway, New Jersey, USA, and may own stock and/or stock options in Merck & Co, Inc, Rahway, New Jersey, USA. ZPQ was an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, New Jersey, USA, at the time of the study and may have owned stock and/or stock options in Merck & Co, Inc, Rahway, New Jersey, USA. AO and YO have received funding from MSD KK, Tokyo, Japan, for research consulting., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A 253 J with 26 ns at 0.2 Hz laser performance was demonstrated using a LD pumped cryogenically cooled Yb:YAG ceramics laser amplifier. A high energy storage of 344 J was achieved with a stored energy density of 0.58 J/cm 3 using a 1 kJ output multidirectional-pumping system. High energy-extraction efficiency of 56.5% was achieved with high energy fluence of 4.63 J /cm 2 . To the best of our knowledge, this is the highest output energy obtained with a repetitive nanosecond pulse by LD pumped solid-state laser. This paper presented a design of 1 kJ amplifier based on experimentally proven numerical data.

Introduction: To present longitudinal data from the Real-world Observational Study on Patient Outcomes in Diabetes (RESPOND) in Japan., Research Design and Methods: In this multicenter, prospective, observational cohort study, patients with type 2 diabetes mellitus (T2DM) newly initiated on monotherapy were followed up for 2 years. Primary outcomes included changes in treatment pattern over time, target hemoglobin A1c (HbA1c) attainment and treatment satisfaction per Oral Hypoglycaemic Agent Questionnaire (OHA-Q)., Results: Among 1474 enrolled patients (male, 62.1%; mean age, 59.7 years; HbA1c, 8.08%), the oral antidiabetic drug (OAD) monotherapy prescription rate decreased to 47.2% and that of 2 and ≥3 OADs increased to 14.8% and 5.4% at 24 months, respectively. Switch/add-on OAD was associated with higher HbA1c and body mass index (BMI), baseline OAD being non-dipeptidyl peptidase-4 inhibitor (DPP-4i)/non-sodium glucose cotransporter-2 inhibitor (SGLT2i), diabetes complications, no comorbidities and consulting a diabetes specialist. The mean (SD) HbA1c (%) was 6.73 (0.85) at 24 months. Higher HbA1c, diabetes complications, cardiovascular disease, being employed, no hypertension and younger treating physician were associated with ≥2 OAD classes prescription or target HbA1c non-attainment at 24 months. OHA-Q subscale scores were significantly higher in patients achieving (vs not achieving) target HbA1c and in those continuing monotherapy (vs combination therapy). Baseline age (<65 years), sex (female), HbA1c, alcohol use, use of non-‍DPP-4i OADs or non-T2DM drugs, diabetes complications and cardiovascular disease had a significant negative impact, while EuroQol five-dimensional five-level and Summary of Diabetes Self-Care Activities-specific diet scores, BMI and unemployment had a significant positive impact on OHA-Q scores at 24 months., Conclusions: Primary outcomes show real-world treatment patterns and glycemic control over 2 years in patients with T2DM newly initiated on OAD monotherapy in Japan. Key factors associated with durability of initial monotherapy, target achievement or treatment satisfaction included baseline HbA1c, comorbidity and initial OAD choice., Competing Interests: Competing interests: AT, KT, JE and ST are employees of MSD K.K., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock and/or hold stock options in the company. HO has received personal fees from MSD during the conduct of the study. HW has received grants and personal fees from MSD during the conduct of the study. His relevant financial activities outside the submitted work are grants and personal fees from Astellas, Daiichi Sankyo, Eli Lilly, Mitsubishi Tanabe, Nippon Boehringer Ingelheim, Novartis, Novo Nordisk, Ono, Sanofi, Sanwa Kagaku, Sumitomo Dainippon and Takeda; grants from Johnson & Johnson, Teijin, Yakult, Kissei, Kowa, Kyowa Hakko Kirin, Pfizer and Taisho Toyama and personal fees from Fujifilm, Terumo and AstraZeneca. IS has received personal fees from MSD during the conduct of the study. His relevant financial activities outside the submitted work are grants and personal fees from Kowa, Novo Nordisk and Takeda; grants from Kobayashi, Daiichi Sankyo, Kyowa Kirin, Mitsubishi Tanabe, Mochida, Rohto, Sanofi, Sumitomo Dainippon and Teijin; and personal fees from Ono, Taisho and Eli Lilly. TK has received honoraria (e.g., lecture fees) from MSD K.K., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Astellas Pharma Inc., Teijin Pharma Ltd., Ono Pharmaceutical Co., Ltd., AstraZeneca K.K., Sumitomo Dainippon Pharma Co., Ltd., Sanofi K.K., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co., Ltd., Novo Nordisk Pharma Ltd., Novartis Pharma K.K., Daiichi Sankyo Co., Ltd., FUJIFILM Toyama Chemical Co., Ltd., Kowa Co., Ltd. and Kyowa Kirin Co., Ltd.; received research grants from Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly Japan K.K., Kyowa Kirin Co., Ltd., MSD K.K., Daiichi Sankyo Co., Ltd., Novo Nordisk Pharma Ltd., Sanofi K.K., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation and Sumitomo Dainippon Pharma Co., Ltd.; received consulting fees from Abbott Japan LLC, Medtronic Japan Co., Ltd. and Novo Nordisk Pharma Ltd. and endowed departments by commercial entities (Asahi Mutual Life Insurance Company)., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Combined chemoradiotherapy (CRT) and programmed cell death-ligand 1 (PD-L1) blockade is a new care standard for unresectable stage III non-small-cell lung cancer (NSCLC). Although this consolidation therapy has improved the overall survival of patients with NSCLC, the synergistic action mechanisms of CRT and immunotherapy on T cells remain unclear. In addition, there is a paucity of reliable biomarkers to predict clinical responses to therapy. In this study, we analyzed T-cell receptor (TCR) sequences in the peripheral blood of five patients with NSCLC. T-cell receptor analysis was undertaken before treatment, after CRT, and after PD-L1 blockade. Notably, we observed the expansion and alteration of the dominant T-cell clonotypes in all cases with a complete response. In contrast, neither expansion nor alteration of the TCR repertoire was observed in cases with progressive disease. T cell expansion was initiated after CRT and was further enhanced after PD-L1 blockade. Our findings suggest the systemic effect of CRT on circulating T cells in addition to the curative effect on limited tumor sites. Dynamic changes in circulating T-cell clonotypes could have a prognostic significance for combined CRT and PD-L1 blockade., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Although unmet medical needs for better care of patients with chronic cough exist in Japan, epidemiological information about these patients and their treatments is very limited., Objectives: To describe patient characteristics, underlying cough-related diseases and drug utilisation patterns in patients with chronic cough, and their changes over time., Methods: This large retrospective claims database study enrolled subjects with chronic cough, identified either by a specific diagnostic cough code for chronic cough (Population 1) or by multiple cough-related diagnostic codes spanning > 8 weeks (Population 2). Within Population 2, patients with each of the three most frequent diagnostic cough codes were analysed as subgroups. Patient characteristics, underlying cough-related diseases and utilisation patterns for drugs used for cough were documented at the index date, during the 6-month pre-index period and during the 12-month post-index period., Results: 6,038 subjects were enrolled in the cohort (Population 1: N = 3,500; Population 2: N = 2,538). The mean age was 43.7 ± 12.2 years and 61.8% were women. The largest cough diagnosis subgroups in Population 2 were 'other coughs' (N = 1,444), 'cough-variant asthma' (N = 1,026) and 'atopic/allergic cough' (N = 105). At the index date, the most frequent underlying cough-related diseases were allergic rhinitis/nasal inflammation (N = 3,132; 51.9%), asthma (N = 2,517; 41.7%) and gastro-esophageal reflux disease (N = 829; 13.7%). At the index date, 4,860 participants (80.5%) were prescribed at least one cough-related treatment. 194 participants (4.0% of medication users) were prescribed central antitussives alone, principally in Population 1, and 2,331 (48.0%) were prescribed expectorants. Other frequently prescribed medications were antiallergic drugs (N = 2,588; 53.3%), antimicrobials (N = 1,627; 34.4%) and inhaled corticosteroids with long-acting beta-agonists (N = 1,404; 28.9%). Over time, cough diagnoses tended to be lost, with only 470 participants in Population 1 retaining a diagnostic code for chronic cough one year later. The frequency of underlying cough-related diseases was stable over time., Conclusions: Patients in this cohort with chronic cough are most frequently identified by a diagnostic cough code for chronic cough, followed by codes for other coughs, cough-variant asthma and atopic cough. Chronic cough frequently presents with an underlying cough-related disease, most frequently allergic rhinitis/nasal inflammation, asthma or GERD. Medication prescription for the underlying cough-related diseases was generally appropriate., (© 2022. The Author(s).)

Background: Chronic cough lasting for > 8 weeks is a common medical condition that burdens patients. This study aimed to qualitatively describe knowledge, awareness, experiences, and subtypes of burdens (physical, social, psychological) among Japanese patients with refractory chronic cough (refractory to treatment of underlying relevant medical conditions) and unexplained chronic cough (symptoms of unexplained origin)., Methods: This non-interventional, cross-sectional study was conducted between February and March 2021 among patients (aged ≥ 20 years) with self-reported refractory or unexplained chronic cough. Subjects with a history of comorbid respiratory conditions were excluded. Eligible subjects participated in a 60-min online semi-structured interview. Verbatim terms from interviews were qualitatively transcribed and generated into word clouds, followed by a clustering analysis in which meaningful clusters were chosen, manually coded, and utterances and burdens categorized., Results: A total of 21 participants (95.2% with refractory chronic cough, mean age 53.5 years, and 76.2% being males) with Leicester Cough Questionnaire mean ± standard deviation scores of physical 4.8 ± 1.1, psychological 4.4 ± 1.3, social 4.9 ± 1.4, and total 14.1 ± 3.5 were included. The word cloud identified the most frequently used word ('cough'); etiology ('asthma'); and words associated with change in states ('influence,' 'changing,' 'change') and expressions ('tough,' 'pain,' 'hard,' 'terrible,' 'unpleasant'). The patients experienced 'mental/social burden,' 'physical burden,' 'impact on sleep and meals,' 'impact on work and housework,' 'impact on communication,' 'impact on hobbies and leisure,' and 'economic burden.' By closed coding analysis, the situations or types of burden patients experienced from the cough were ordered sequentially as emotion, working style, acquaintanceship, hobbies and leisure, and sleeping pattern., Conclusions: The present study indicated that there were two types of participant clusters, in which one showed mainly the burdens in the social communications such as work-related communication and another one showed the burdens of relationships with others. Also, some participants highlighted 'mental burden,' on social life due to the current pandemic. To relieve these burdens, disease awareness and knowledge should be improved for patients with refractory and unexplained chronic cough. Trial registration The trial was registered under UMIN-CTR as UMIN000042772, on 17/12/2020. The study was approved by the Medical Corporation Toukeikai Kitamachi Clinic (IRB registration number: 11001110)., (© 2022. The Author(s).)

Objectives: Delirium commonly occurs during hospitalisation and is associated with increased mortality, especially in elderly patients. This study aimed to determine the demographic and clinical characteristics of patients with delirium in the Japanese real-world clinical setting using a nationwide database comprising claims and discharge abstract data., Design: This was an observational, cross-sectional, retrospective study in hospitalised patients with an incident delirium identified by a diagnosis based on International Classification of Diseases, 10th Revision codes or initiating antipsychotics recommended for delirium treatment in Japan during their hospitalisation., Setting: Patients from the Medical Data Vision database including more than 400 acute care hospitals in Japan were evaluated from admission to discharge., Participants: Of the 32 910 227 patients who were included in the database between April 2012 and September 2020, a total of 145 219 patients met the criteria for delirium., Primary and Secondary Outcome Measures: Demographic and baseline characteristics, comorbidities, clinical profiles and pharmacological treatments were evaluated in patients with delirium., Results: The mean (SD) patient age was 76.5 (13.8) years. More than half of the patients (n=82 159; 56.6%) were male. The most frequent comorbidities were circulatory system diseases, observed in 81 954 (56.4%) patients. Potentially inappropriate medications (PIMs) with risk of delirium including benzodiazepines and opioids were prescribed to 76 798 (52.9%) patients. Approximately three-fourths of these patients (56 949; 74.2%) were prescribed ≥4 PIMs. The most prescribed treatment for delirium was injectable haloperidol (n=82 490; 56.8%). Mean (SD) length of hospitalisation was 16.0 (12.1) days., Conclusions: The study results provide comprehensive details of the clinical characteristics of patients with delirium and treatment patterns with antipsychotics in the Japanese acute care setting. In this patient population, the prescription rate of injectable haloperidol and PIMs was high, suggesting the need for improved understanding among healthcare providers about the appropriate management of delirium, which may benefit patients., Competing Interests: Competing interests: NU, MI, KO, HS, KT, ST and SO are employees of MSD KK, Tokyo, Japan, a subsidiary of Merck & Co Inc, Rahway, New Jersey, USA, and may own stock and/or hold stock options in Merck & Co Inc, Rahway, New Jersey, USA. ZPQ is an employee of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc, Kenilworth, New Jersey, USA, and may own stock and/or hold stock options in Merck & Co Inc, Kenilworth, New Jersey, USA. AO and YO have received funding from MSD KK, Tokyo, Japan for research consulting., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

CD8 + T cells recognize peptides displayed by HLA class I molecules and monitor intracellular peptide pools. It is known that the proteasome splices two short peptide fragments. Recent studies using mass spectrometry (MS) and bioinformatics analysis have suggested that proteasome-generated spliced peptides (PSPs) may account for a substantial proportion of HLA class I ligands. However, the authenticity of the PSPs identified using bioinformatics approaches remain ambiguous. In this study, we employed MS-based de novo sequencing to directly capture cryptic HLA ligands that were not templated in the genome. We identified two PSPs originating from the same protein in a human colorectal cancer line with microsatellite instability. Healthy donor-derived CD8 + T cells readily responded to the two PSPs, showing their natural HLA presentation and antigenicity. Experiments using minigene constructs demonstrated proteasome-dependent processing of two PSPs generated by standard and reverse cis splicing, respectively. Our results suggest a broader diversity of HLA class I Ag repertoires generated by proteasomal splicing, supporting the advantage of MS-based approaches for the comprehensive identification of PSPs., (Copyright © 2022 by The American Association of Immunologists, Inc.)

High energy density physics is the field of physics dedicated to the study of matter and plasmas in extreme conditions of temperature, densities and pressures. It encompasses multiple disciplines such as material science, planetary science, laboratory and astrophysical plasma science. For the latter, high energy density states can be accompanied by extreme radiation environments and super-strong magnetic fields. The creation of high energy density states in the laboratory consists in concentrating/depositing large amounts of energy in a reduced mass, typically solid material sample or dense plasma, over a time shorter than the typical timescales of heat conduction and hydrodynamic expansion. Laser-generated, high current-density ion beams constitute an important tool for the creation of high energy density states in the laboratory. Focusing plasma devices, such as cone-targets are necessary in order to focus and direct these intense beams towards the heating sample or dense plasma, while protecting the proton generation foil from the harsh environments typical of an integrated high-power laser experiment. A full understanding of the ion beam dynamics in focusing devices is therefore necessary in order to properly design and interpret the numerous experiments in the field. In this work, we report a detailed investigation of large-scale, kilojoule-class laser-generated ion beam dynamics in focusing devices and we demonstrate that high-brilliance ion beams compress magnetic fields to amplitudes exceeding tens of kilo-Tesla, which in turn play a dominant role in the focusing process, resulting either in a worsening or enhancement of focusing capabilities depending on the target geometry., (© 2022. The Author(s).)

Immune checkpoint inhibitors (ICIs) are used in cancer immunotherapy to block programmed death-1 and cytotoxic T-lymphocyte antigen 4, but the response rate for ICIs is still low and tumor cell heterogeneity is considered to be responsible for resistance to immunotherapy. Tumor-infiltrating lymphocytes (TILs) have an essential role in the anti-tumor effect of cancer immunotherapy; however, the specificity of TILs in renal cell carcinoma (RCC) is elusive. In this study, we analyzed a 58-year-old case with clear cell RCC (ccRCC) with the tumor showing macroscopic and microscopic heterogeneity. The tumor was composed of low-grade and high-grade ccRCC. A tumor cell line (1226 RCC cells) and TILs were isolated from the high-grade ccRCC lesion, and a TIL clone recognized a novel neoantigen peptide (YVVPGSPCL) encoded by a missense mutation of the tensin 1 (TNS1) gene in a human leukocyte antigen-C*03:03-restricted fashion. The TNS1 gene mutation was not detected in the low-grade ccRCC lesion and the TIL clone did not recognized low-grade ccRCC cells. The missense mutation of TNS1 encoding the S1309Y mutation was found to be related to cell migration by gene over-expression. These findings suggest that macroscopically and microscopically heterogenous tumors might show heterogenous gene mutations and reactivity to TILs., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Recent studies have revealed that treatment-resistant cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) can be targeted by cytotoxic T lymphocytes (CTLs). CTLs recognize antigenic peptides derived from tumor-associated antigens; thus, the identification of tumor-associated antigens expressed by CSCs/CICs is essential. Human leucocyte antigen (HLA) ligandome analysis using mass spectrometry enables the analysis of naturally expressed antigenic peptides; however, HLA ligandome analysis requires a large number of cells and is challenging for CSCs/CICs. In this study, we established a novel bladder CSC/CIC model from a bladder cancer cell line (UM-UC-3 cells) using an ALDEFLUOR assay. CSCs/CICs were isolated as aldehyde dehydrogenase (ALDH)-high cells and several ALDH high clone cells were established. ALDH high clone cells were enriched with CSCs/CICs by sphere formation and tumorigenicity in immunodeficient mice. HLA ligandome analysis and cap analysis of gene expression using ALDH high clone cells revealed a distinctive antigenic peptide repertoire in bladder CSCs/CICs, and we found that a glutamate receptor, ionotropic, kainite 2 (GRIK2)-derived antigenic peptide (LMYDAVHVV) was specifically expressed by CSCs/CICs. A GRIK2 peptide-specific CTL clone recognized GRIK2-overexpressing UM-UC-3 cells and ALDH high clone cells, indicating that GRIK2 peptide can be a novel target for bladder CSC/CIC-targeting immunotherapy., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

To develop combination immunotherapies for gastric cancers, immunologically well-characterized preclinical models are crucial. Here, we leveraged two transplantable murine gastric cancer cell lines, YTN2 and YTN16, derived from the same parental line but differing in their susceptibility to immune rejection. We established their differential sensitivity to immune checkpoint inhibitors (ICI) and identified neoantigens. Although anti-CTLA-4 mAbs eradicated YTN16 tumors in 4 of 5 mice, anti-PD-1 and anti-PD-L1 mAbs failed to eradicate YTN16 tumors. Using whole-exome and RNA sequencing, we identified two and three neoantigens in YTN2 and YTN16, respectively. MHC class I ligandome analysis detected the expression of only one of these neoantigens, mutated Cdt1, but the exact length of MHC binding peptide was determined. Dendritic cell vaccine loaded with neoepitope peptides and adoptive transfer of neoantigen-specific CD8 + T cells successfully inhibited the YTN16 tumor growth. Targeting mutated Cdt1 had better efficacy for controlling the tumor. Therefore, mutated Cdt1 was the dominant neoantigen in these tumor cells. More mCdt1 peptides were bound to MHC class I and presented on YTN2 surface than YTN16. This might be one of the reasons why YTN2 was rejected while YTN16 grew in immune-competent mice.

Wild large Japanese field mice ( Apodemus speciosus ) responses to cyclic seasonal changes are associated with physiological and behavioral changes. However, the detailed regulation of oogenesis in the ovary during the seasonal reproductive cycle in wild large Japanese field mice has not been studied. We assessed the dynamics and changes in ovarian morphology and hormone concentrations associated with reproductive seasonality throughout the year. The stages of the ovarian morphological breeding cycle of wild large Japanese field mice were classified as breeding, transition, and non-breeding periods during the annual reproductive cycle. Measurement of blood estradiol concentrations throughout the year showed that the levels in September and October were higher than those in other months. It is presumed that follicle development starts from a blood estradiol concentration of 38.4 ± 27.1 pg/mL, which marks a shift from the transitional season to the breeding season, followed by the transition to the non-breeding season at 26.1 ± 11.6 pg/mL. These results suggest that seasonal follicle development in wild rodents is correlated with estradiol regulation. We consider this species to be an alternative animal model for studying seasonal reproductive changes and the effects of environmental changes., Competing Interests: Conflict of interest: The authors have no conflict of interest to declare.

Palladium (Pd) is a widely used metal and extremely important biomaterial for the reconstruction of occlusions during dental restorations. However, metallic biomaterials can cause serious allergic reactions, such as Pd-related oral mucositis seen in dentistry. Metal allergy is categorized as a type IV allergy and we demonstrated that CD8 T cells play an important role in Pd allergy previously. As TCR of CD8 T cells recognizes MHC class I/peptide complex, the antigen specificity to this complex seems to be generated during Pd allergy. However, it remains unknown if Pd affects the MHC class I/peptide complex. In this study, we investigated the behavior of the MHC class I/peptide complex in response to Pd treatment. We found that PdCl 2 treatment altered peptide presentation on MHC class I and that co-culture with Pd-treated DC2.4 cells induced activation of Pd-responsive TCR-expressing T cell line. Furthermore, PdCl 2 treatment induced temporal MHC class I internalization and inhibition of membrane movement suppressed Pd-induced T cell-mediated antigenicity. These data suggest that Pd-induced MHC class I internalization is critical for generation of antigenicity through a mechanism including differential peptide loading on MHC class I, which results in Pd allergy., 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. The reviewer N.S has declared a shared affiliation with some of the authors KI, NH, KO to the handling editor at the time of review., (Copyright © 2021 Ito, Kanaseki, Tokita, Torigoe, Hirasawa and Ogasawara.)

CD8 + T cells recognize peptides displayed by HLA class I molecules on cell surfaces, monitoring pathologic conditions such as cancer. Advances in proteogenomic analysis of HLA ligandomes have demonstrated that cells present a subset of cryptic peptides derived from noncoding regions of the genome; however, the roles of cryptic HLA ligands in tumor immunity remain unknown. In the current study, we comprehensively and quantitatively investigated the HLA class I ligandome of a set of human colorectal cancer and matched normal tissues, showing that cryptic translation products accounted for approximately 5% of the HLA class I ligandome. We also found that a peptide encoded by the long noncoding RNA (lncRNA) PVT1 was predominantly enriched in multiple colorectal cancer tissues. The PVT1 gene is located downstream of the MYC gene in the genome and is aberrantly overexpressed across a variety of cancers, reflecting its oncogenic property. The PVT1 peptide was recognized by patient CD8 + tumor-infiltrating lymphocytes, as well as peripheral blood mononuclear cells, suggesting the presence of patient immune surveillance. Our findings show that peptides can be translated from lncRNAs and presented by HLA class I and that cancer patient T cells are capable of sensing aberrations in noncoding regions of the genome., (©2021 American Association for Cancer Research.)

Background: The role of anti-elastin antibody (Ab) in the lung is unclear, although they may be involved in chronic obstructive pulmonary disease (COPD). Recently, increased anti-elastin Ab levels were reported in asthma., Objective: To elucidate the role of anti-elastin Ab in asthma, we created a murine asthma model. Anti-elastin Ab in the airway was neutralized by intratracheal administration of elastin peptide, and the inhibitory effects of anti-elastin Ab on airway remodeling were evaluated., Methods: BALB/c mice were immunized with ovalbumin (OVA) on days 0 and 14. After immunization, the mice received booster OVA via inhalation twice per week for 9 weeks, and bronchoalveolar lavage fluid (BALF) and lung tissues were evaluated., Results: In lung tissues, airway remodeling occurred after 9 weeks of OVA sensitization. Peak levels of anti-elastin Ab and eosinophils in BALF were detected after 3 weeks of OVA sensitization. Anti-elastin Ab and eosinophil levels in BALF were significantly reduced after 3 weeks by the neutralization of anti-elastin Ab. Peak transforming growth factor-β1 levels in BALF were detected at 3 weeks after OVA sensitization and were significantly reduced by the neutralization of anti-elastin Ab. Airway remodeling in lung tissues was also significantly inhibited by the neutralization of anti-elastin Ab., Conclusions: In our murine asthma model, anti-elastin Ab was recruited to the airway by OVA-induced allergic inflammation. Airway remodeling was inhibited by the neutralization of anti-elastin Ab. Anti-elastin Ab may contribute to the progression of airway remodeling.

Aims: To investigate the prevalence of comorbid conditions/complications among Japanese patients with type 2 diabetes mellitus (T2DM) in a real-world setting., Methods: We performed retrospective analyses of a large-scale database directly linked to electronic medical records, J-DREAMS (Japan Diabetes compREhensive database project based on an Advanced electronic Medical record System), to determine the prevalence of clinically significant comorbid conditions/complications among Japanese patients with T2DM aged ≥ 20 years with ≥ 1 clinical encounter at a referral center between April 1, 2017 and March 31, 2019., Results: Data were available for 10,151 patients (39.2% female). The mean age and T2DM duration were 66.0 years and 16.1 years, respectively. Only 0.5% had isolated T2DM, 6.6% had one comorbid condition/complication, and the remainder had multiple comorbid conditions/complications. Dyslipidemia (84.7%) and hypertension (75.1%) were the most common, followed by chronic kidney disease (35.4%), retinopathy (23.1%), and cardiovascular diseases (22.1%). Overall, 36.0% of patients were overweight/obese (body mass index ≥ 25 kg/m 2 ) and 18.6% had a history of neoplasms. The prevalence of comorbid conditions/complications tended to increase with advancing age and duration of T2DM., Conclusions: We revealed a high prevalence of comorbid conditions/complications, including chronic kidney and cardiovascular diseases, in Japanese patients with T2DM., (Copyright © 2021 Merck Sharp & Dohme Corp., The Author(s). Published by Elsevier B.V. All rights reserved.)

Although CD8+ T cells recognize neoantigens that arise from somatic mutations in cancer, only a small fraction of nonsynonymous mutations give rise to clinically relevant neoantigens. In this study, HLA class I ligandomes of a panel of human colorectal cancer (CRC) and matched normal tissues were analyzed using mass spectrometry-based proteogenomic analysis. Neoantigen presentation was rare; however, the analysis detected a single neoantigen in a mismatch repair-deficient CRC (dMMR-CRC) tissue sample carrying 3967 nonsynonymous mutations, where abundant tumor-infiltrating lymphocytes (TILs) and inflamed gene expression status were observed in the tumor microenvironment (TME). Using the HLA class I ligandome data and gene expression profiles, a set of nonmutated tumor-associated antigen (TAA) candidates was concomitantly identified. Interestingly, CD8+ TILs predominantly recognized the detected neoantigen over the array of TAA candidates. Neoantigen-reactive CD8+ TILs showed PD-1 positivity and exhibited functional and specific responses. Moreover, T cell receptor (TCR) profiling identified the sequence of the neoantigen-reactive TCR clonotype and showed its expansion in the TME. Transduction of the sequenced TCR conferred neoantigen specificity and cytotoxicity to peripheral blood lymphocytes. The proteogenomic approach revealed the antigenic and reactive T cell landscape in dMMR-CRC, demonstrating the presence of an immunogenic neoantigen and its potential therapeutic applications.

Aims: The current study evaluated patient demographics and clinical characteristics that associated with HbA1c reduction following addition of one oral antidiabetic drug (OAD) to DPP4i monotherapy., Methods: A retrospective study was conducted using CoDiC database. Adult T2DM patients treated with sitagliptin monotherapy for ≥ 6 months and adding one OAD were extracted. Association between patient characteristics at the time of add-on OAD and following HbA1c reduction was assessed., Results: Of 444 included patients, mean age was 62 years and 33% were female. All add-on OAD classes demonstrated further HbA1c reduction ( p  < 0.05). The majority received biguanide (BG; 61%) or sulfonylurea (SU; 25%) add-on therapy. BG and SU groups showed a significant association between higher baseline HbA1c categories and greater HbA1c reductions (BG: - 0.24 to - 1.75%, p  < 0.0001; SU: - 0.15 to - 2.11%, p  < 0.0001). Lower HDL-cholesterol/higher non-HDL-cholesterol (BG), male gender (SU), and lower SBP (SU) were associated with larger HbA1c reductions. The results for baseline HbA1c (BG and SU) and gender (SU) were also confirmed by multivariate analysis., Conclusion: The majority of Japanese T2DM patients on sitagliptin monotherapy who require an add-on OAD utilized BG or SU. There were 2 determinants of glycemic response: baseline HbA1c with BG and SU and gender with SU during add-on OAD therapy., Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-021-00514-5., Competing Interests: Conflict of interestKoichi Kawai., Azuma Kanatsuka., Shinobu Motohashi, and Katsuya Yamazaki have no potential conflicts of interest to declare. Hiroshi Maegawa has received lecture fees from MSD K.K., Nippon Boehringer Ingelheim Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Sanofi K.K., Astellas Pharma Inc., Takeda Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Novo Nordisk Pharma Ltd., Eli Lilly Japan K.K. Sumitomo Dainippon Pharma Co. Ltd., and Astra Zeneca K.K.; research supports from Astellas Pharma Inc., Astra Zeneca K.K., Nippon Boehringer Ingelheim Co. Ltd., Sunstar Inc., Mitsubishi Tanabe Pharma Corporation, Kyowa Hakko Kirin Co. Ltd., Nissan Chemical Corporation and MIKI Corporation; grants from Takeda Pharmaceutical Co. Ltd., Astellas Pharma Inc., MSD K.K., Nippon Boehringer Ingelheim Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Taisho Pharma Co. Ltd., Kowa Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation, Sanwa Kagaku Kenkyusho Co. Ltd., Eli Lilly Japan K.K., Sumitomo Dainippon Pharma Co. Ltd., Novo Nordisk Pharma Ltd., Bayer Yakuhin Ltd., Teijin Pharma Limited, Shionogi & Co. Ltd.,, Novartis Pharma K.K. and Nipro Corporation. Jun-ichi Eiki, Akira Wakana, Ai Hayashi, Kristy Iglay and Shigeru Tokita are current or former employees of MSD K.K., Tokyo, Japan or Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock and/or hold stock options in Merck & Co., Inc., Kenilworth, NJ, USA., (© The Japan Diabetes Society 2021, corrected publication 2021.)

Background: It is often difficult to differentiate between asthma and chronic obstructive pulmonary disease (COPD), and useful biomarkers are needed for accurate diagnosis., Objective: We evaluated anti-elastin antibody to identify useful biomarkers for differentiating between a diagnosis of asthma and COPD., Methods: Patients with asthma (male to female ratio = 10/13; mean age, 67.3 years), COPD (16/0; 74.8 years) and controls (8/4; 72.3 years) were enrolled. Samples from sputum and serum were collected and levels of anti-elastin Ab were measured., Results: The levels of anti-elastin Ab in sputum were significantly higher in asthma (11.4 ± 7.16 μg/mL) than in COPD (5.82 ± 5.16 μg/mL; P < 0.01), and serum levels in asthma (67.4 ± 29.7 μg/mL) were also significantly higher than in COPD or controls (45.0 ± 12.8 μg/mL; P < 0.05, 38.6 ± 10.4 μg/mL; P < 0.01, respectively). Anti-elastin Ab in sputum showed a positive correlation with smoking in asthma (r2 = 0.218, P < 0.05). However, no significant differences were observed in the levels of anti-elastin Ab and eosinophils, asthma phenotypes, inhaled corticosteroids, or severity in patients with asthma. Elastin was strongly expressed under the airway basement membrane in asthma compared with COPD or the healthy control., Conclusions: Anti-elastin Ab in sputum could be a useful biomarker for COPD and asthma in ever-smokers. In asthma, anti-elastin Ab was recruited to the airways by both airway allergic inflammation and smoking, and it may contribute to the progression of airway remodeling via autoimmune inflammation, but not emphysema, in COPD.

Background: Cough lasting 3-8 weeks and more than 8 weeks are defined as subacute/prolonged cough and chronic cough, respectively. Japanese chronic cough population has not been well studied. This study aimed to describe the prevalence and characteristics of chronic cough and subacute cough patients in Japan. This study also sought to compare between chronic cough patients who were not greatly satisfied with treatment effectiveness for resolving cough and other chronic cough patients., Methods: Data from a cross-sectional online 2019 Japan National Health and Wellness Survey and a supplemental chronic cough survey were used to understand respondents' chronic cough status and their cough-specific characteristics and experience. The prevalence, patient characteristics and cough-specific characteristics were summarised descriptively. Patients who were not greatly satisfied with treatment effectiveness and other chronic cough patients were compared for their characteristics and cough severity., Results: The point prevalence of chronic cough was 2.89% and 12-month period prevalence was 4.29%. Among all chronic cough patients analysed, the average age was 56 years old, 61.1% were males and 29.4% were current smokers. Patients were most frequently told by a physician that cough was related to allergic rhinitis, asthma and cough variant asthma. Only 44.2% of chronic cough patients had spoken with a physician about their cough, and half of chronic cough patients did not use any medications. Patients who were not greatly satisfied with treatment effectiveness had significantly greater cough severity during past 2 weeks compared with other chronic cough patients (Visual Analogue Scale 45.34 vs 39.63)., Conclusions: This study described the prevalence and patient characteristics information of chronic cough patients in Japan. Furthermore, the study highlighted an unmet need for better diagnosis and treatments for chronic cough patients, especially among patients who were not greatly satisfied with treatment effectiveness and reported significantly worse cough severity., Competing Interests: Competing interests: KT, TK, KO, MK, MA and ST are employees at MSD K.K, Tokyo, Japan. YC is an employee at Kantar, Health Division, Singapore. Kantar received funding from MSD K.K., Tokyo, Japan for conduction of the study, analysis and manuscript development. JS is an employee at Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, New Jersey, USA., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Er 3+ /Dy 3+ co-doped double-clad ZBLAN optical fiber has been used to obtain amplified spontaneous emission (ASE) broadband light sources cladding-pumped by 980-nm multimode laser diode (LD) sources. It has been demonstrated that mid-infrared broadband emission extending from 2515 to 3735 nm was obtained by energy transfer between Er 3+ and Dy 3+ . We experimentally investigated the optimum design of Er 3+ /Dy 3+ co-doped ZBLAN fiber in terms of ion concentration, fiber length, pumping configuration, and pumping power. The ASE output power was more than 2.5 mW when the LD pump power was set at 5 W. To assess its potential for gas sensing applications, the fabricated ASE light source was used to successfully detect methane gas with concentrations at 1% and 5%. The simple and stable construction of our ASE light source is suitable for practical purposes.

Background: Cough lasting 3-8 and >8 weeks are defined as subacute/prolonged cough and chronic cough (CC), respectively. Studies have revealed that CC negatively impact patients' quality of life (QoL). In Japan, there is limited data on the impact of CC on health-related quality of life (HRQoL), work productivity and activity impairment (WPAI) and healthcare resource utilisation (HRU) using validated instruments. This study aimed to estimate the burden of CC and to compare the burden among patients with CC between subgroups., Methods: Data from two cross-sectional online surveys conducted between September and November 2019 were combined for the analysis. Eligible patients with cough were propensity score matched to non-cough respondents. Comparisons of general HRQoL, WPAI, HRU and other symptoms experienced were conducted between matched non-cough respondents and patients with cough. Among patients with CC, subgroup comparisons were performed to understand general HRQoL, WPAI, HRU, cough-related QoL (Leicester Cough Questionnaire and Hull Airway Reflux Questionnaire) between patients with CC of different severities, patients with refractory CC and patients with non-refractory CC and patients with CC whose underlying diseases were unknown and others., Results: Patients with CC (n=568) in Japan reported significantly poorer HRQoL, increased WPAI, more HRU and higher proportion of psychological and sleep problems, compared with matched non-cough respondents selected from 21 415 non-cough respondents. More patients with severe CC reported significantly poorer HRQoL, increased WPAI and worse cough-related QoL. Patients with refractory CC experienced significantly greater burden measured by cough-related QoL. No significant differences were observed between patients with CC whose underlying diseases were unknown and other patients with CC in terms of general HRQoL and cough-related QoL., Conclusions: This study showed that patients with CC in Japan experienced significant burden compared with non-cough respondents. Patients with more severe cough and refractory CC experienced worse cough-related QoL. These results highlighted the unmet need for better interventions and treatments to reduce the burden among patients with CC., Competing Interests: Competing interests: TK, KT, KO, MK, MA, ST are employees at MSD KK, Tokyo, Japan. JS is an employee at Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, USA. YC is an employee at Kantar, Health Division, Singapore. Kantar received funding from MSD KK, Tokyo, Japan for conduction of the study, analysis and manuscript development., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We report, to the best of our knowledge, the highest power conductive-cooled active-mirror amplifier (CcAMA) using Yb:YAG with a pulse energy of 10 J. By using four liquid-nitrogen circulating cooled laser heads, we achieved a repetition rate, pulse energy, and average power of 33.3 Hz, 9.3 J, and 310 W, respectively. The problem of wavefront distortion, which is difficult to solve with a large-aperture active-mirror laser, is suppressed by using reinforcing materials with the same thermal expansion coefficient. We have confirmed that the wavefront distortion is small (0.15 λ P-V per head) at 100 Hz operation, which paves the way for 100 Hz operation with the CcAMA concept.

CD8 + T cells are capable of recognizing mutation-derived neoantigens displayed by HLA class I molecules, thereby exhibiting the ability to distinguish between cancer and normal cells. However, accumulating evidence has shown that only a small fraction of nonsynonymous somatic mutations give rise to clinically relevant neoantigens. The properties of such neoantigens, which must be presented by HLA and immunogenic to induce a T-cell response, remain elusive. In this study, we explored the HLA class I ligandome of a human cancer cell line with microsatellite instability using a proteogenomic approach. The results demonstrated that neoantigens accounted for only 0.34% of the HLA class I ligandome, and most neoantigens were encoded by genes with abundant expression. Thereafter, T-cell responses were prioritized, and immunodominant neoantigens were defined using naive CD8 + T cells derived from healthy donors. AKF9, an immunogenic neoantigen with a mutation at a non-anchor position, formed a stable peptide-HLA complex. T-cell responses were analyzed against a panel of AKF9 variants with single amino-acid substitutions, in which mutations did not alter the high HLA-binding affinity and stability. The responses varied across individuals, demonstrating the impact of heterogeneous T-cell repertoires in this human cancer model. Moreover, responses were biased toward a variant group with large structural changes compared to the wild-type peptide. Thus, naive T-cell induction can be attributed to multiple determinants. Combining structural dissimilarity with gene-expression levels, HLA-binding affinity, and stability may further help prioritize the immunogenicity of non-anchor-type neoantigens., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Introduction: To investigate factors affecting glycemic control, oral antidiabetic drug (OAD) treatment distribution and self-care activities among patients with type 2 diabetes mellitus (T2DM) who newly initiate OAD monotherapy in a real-world setting in Japan., Research Design and Methods: A Real-world Observational Study on Patient Outcomes in Diabetes (RESPOND) is an ongoing, prospective, observational cohort study with follow-up at 6, 12, 18 and 24 months. Primary objectives include OAD treatment patterns (cross-sectional and longitudinal) among diabetes specialists versus non-specialists; adherence to diabetes self-care activities; quality of life; treatment satisfaction among patients and target attainment rates of parameters, including glycated hemoglobin. Here, we present the study design and baseline data., Results: Of 1506 patients enrolled (June 2016-May 2017; 174 sites in Japan), 1485 were included in the baseline analysis (617 treated by specialists, 868 by non-specialists). Most patients were prescribed dipeptidyl peptidase-4 inhibitors (DPP-4Is) (specialist vs non-specialist, 54.1% vs 57.1%), then sodium-glucose cotransporter 2 inhibitors (13.9% vs 22.2%), metformin (20.3% vs 12.9%) and other OADs (<5% individually in both groups). Regardless of age, body mass index and glycated hemoglobin, DPP-4Is were the most commonly prescribed OADs by both specialists and non-specialists. About one-fifth and one-third of patients visiting specialists and non-specialists, respectively, received no advice on diet and exercise. The proportion of patients following self-care recommendations for diet and exercise (2/5 items on the Summary of Diabetes Self-Care Activities) was significantly higher among those visiting specialists than non-specialists., Conclusion: The use of newer OAD was common across a broad range of clinical characteristics in patients with T2DM who newly initiated monotherapy in Japan. However, patient-related and physician-related factors could affect the treatment changes during the following course of treatment. In addition, treatment outcome could vary with the observed difference in the level of patient education provided by diabetes specialists versus non-specialists., Competing Interests: Competing interests: DY has received personal fees from MSD during the conduct of the study. His relevant financial activities outside the submitted work are grants and personal fees from Nippon Boehringer Ingelheim and Novo Nordisk and grants from Ono, Taisho Toyama, Takeda, Terumo and Arkray. HH has received personal fees and non-financial support from MSD during the conduct of the study and grants from Novartis outside the submitted work. TK has received consulting fees from MSD for the work under consideration for publication. His relevant financial activities outside the submitted work are contract research funds from AstraZeneca and Takeda; joint research funds from Daiichi Sankyo; grants from Astellas, Daiichi Sankyo, Eli Lilly, Kissei, Mitsubishi Tanabe, MSD, Novo Nordisk, Ono, Sanofi, Sumitomo Dainippon, Taisho and Takeda and fees for consulting and/or lectures from Abbott, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Cosmic, Daiichi Sankyo, Eli Lilly, Fujifilm, Johnson & Johnson, Kissei, Kowa, Kyowa Hakko Kirin, Medical Review, Medical View, Medscape Education, Medtronic Sofamor Danek, Mitsubishi Tanabe, MSD, Musashino Foods, Nipro, Novartis, Novo Nordisk, Ono, Sanofi, Sanwa Kagaku, Sumitomo Dainippon, Taisho, Takeda and Terumo. He has also been an Endowed Chair for Asahi Mutual Life Insurance, Boehringer Ingelheim, Kowa, Mitsubishi Tanabe, MSD, Novo Nordisk, Ono and Takeda. HO has received personal fees from MSD during the conduct of the study. IS has received grants and personal fees from MSD during the conduct of the study. His relevant financial activities outside the submitted work are grants and personal fees from Astellas, AstraZeneca, Mitsubishi Tanabe, Eli Lilly, Novo Nordisk, Ono, Sanofi and Takeda; grants from Daiichi Sankyo, Kissei, Kowa, Kyowa Hakko Kirin, Mochida, Novartis, Rohto, Shionogi, Sumitomo Dainippon, Teijin and Terumo and personal fees from Kowa, Nippon Boehringer Ingelheim and Sanwa Kagaku. HW has received grants and personal fees from MSD during the conduct of the study. His relevant financial activities outside the submitted work are grants and personal fees from Astellas, Daiichi Sankyo, Eli Lilly, Mitsubishi Tanabe, Nippon Boehringer Ingelheim, Novartis, Novo Nordisk, Ono, Sanofi, Sanwa Kagaku, Sumitomo Dainippon and Takeda; grants from Johnson & Johnson, Teijin, Yakult, Kissei, Kowa, Kyowa Hakko Kirin, Pfizer and Taisho Toyama and personal fees from Fujifilm, Terumo and AstraZeneca. KI was employed by Merck & Co., Inc., Kenilworth, New Jersey, USA, during the conduct of this study and owns stock. YS has received personal fees from MSD during the conduct of the study. His relevant financial activities outside the submitted work are grants and personal fees from Novo Nordisk and Taisho Toyama; grants from Arkray Marketing, Bayer, Boehringer Ingelheim, Ono, Sumitomo Dainippon and Terumo and personal fees from Kao, Nippon Becton Dickinson, Nippon Boehringer Ingelheim, Taisho and Takeda. KT and ST are employees of MSD K.K. and own stock., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

An actively Q -switched mid-infrared Fe:ZnSe laser pumped by a continuous wave fluoride fiber laser has been developed. Stable operation with a pulse duration of 20 ns and a repetition rate of 40 kHz at 4 µm was achieved. The maximum peak power was 1.1 kW. The high-repetition rate, high-peak power nanosecond pulsed laser, which has been created for the first time, to the best of our knowledge, in an actively Q -switched Fe:ZnSe laser, should prove a suitable light source for laser processing and molecular sensing.

We report, for the first time, to the best of our knowledge, a femtosecond mode-locked Fe:ZnSe laser. Passive mode locking is implemented using graphene as a saturable absorber. The laser operates at 4.4 µm with a repetition frequency of 100 MHz and 415 mW output power pumped by a fiber 7 W Er:ZBLAN laser. The pulse duration of about 732 fs is retrieved from the first-order autocorrelation function. Additionally, we observe pulsed nanosecond oscillation under continuous-wave pumping and strong amplitude modulation caused by Kerr self-focusing. This Letter fills the gap in operating regimes of Fe:ZnSe lasers and paves the way for the development of powerful ultrafast high-repetition-rate mid-IR sources for the most advanced fields of science.

Fast isochoric laser heating is a scheme to heat matter with a relativistic intensity (>10^{18}  W/cm^{2}) laser pulse for producing an ultrahigh-energy-density (UHED) state. We have demonstrated an efficient fast isochoric heating of a compressed dense plasma core with a multipicosecond kilojoule-class petawatt laser and an assistance of externally applied kilotesla magnetic fields for guiding fast electrons to the dense plasma. A UHED state of 2.2 PPa is achieved experimentally with 4.6 kJ of total laser energy that is one order of magnitude lower than the energy used in the conventional implosion scheme. A two-dimensional particle-in-cell simulation confirmed that diffusive heating from a laser-plasma interaction zone to the dense plasma plays an essential role to the efficient creation of the UHED state.

A fluoride-fiber-based master oscillator power amplifier (MOPA) for 30-W class continuous-wave (cw) operation at 2.8-μm wavelength has been demonstrated. To overcome the low durability of ZBLAN fibers, various novel technologies for using fluoride glass with a ZBLAN-fiber-based side-pump combiner have been adopted in the system. A maximum cw output power of 33 W and stable operation under 23-W output have been demonstrated. We suggest that such fiber MOPA systems will open up advanced fluoride fiber technology for next-generation high-power mid-IR lasers.

Objective: We implemented a stepwise antimicrobial stewardship program (ASP). This study evaluated the effect of each intervention and the overall economic impact on carbapenem (CAR) use., Method: Carbapenem days of therapy (CAR-DOT) were calculated to assess the effect of each intervention, and antipseudomonal DOT were calculated to assess changes in use of broad-spectrum antibiotics. We carried out segmented regression analysis of studies with interrupted time series for 3 periods: Phase 1 (infectious disease [ID] consultation service only), Phase 2 (adding monitoring and e-mail feedback), and Phase 3 (adding postprescription review and feedback [PPRF] led by ID specialist doctors and pharmacists). We also estimated cost savings over the study period due to decreased CAR use., Results: The median monthly CAR-DOT, per month per 100 patient-days, during Phase 1, Phase 2, and Phase 3 was 5.46, 3.69, and 2.78, respectively. The CAR-DOT decreased significantly immediately after the start of Phase 2, but a major decrease was not observed during this period. Although the immediate change was not apparent after Phase 3 started, CAR-DOT decreased significantly over this period. Furthermore, the monthly DOT of 3 alternative antipseudomonal agents also decreased significantly over the study period, but the incidence of antimicrobial resistance did not decrease. Cost savings over the study period, due to decreased CAR use, was estimated to be US $150 000., Conclusions: Adding PPRF on the conventional ASP may accelerate antimicrobial stewardship. Our CAR stewardship program has had positive results, and implementation is ongoing., (© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Host T cells infiltrate the cancer lesion and contribute to patient survival. T cells recognize antigen peptides displayed by the cancer cell human leukocyte antigen (HLA) system. Cancer antigens constitute an essential element of T-cell discrimination and play an indispensable role in anti-cancer responses. HLA ligandome analysis directly and comprehensively detects the peptides that are naturally presented by HLA of given cells, leading to discovery of cancer antigens. A proteogenomic approach, which combines conventional proteomics with genomic information, has further deciphered the landscape of the cancer HLA ligandome. Neoantigens that arise from somatic mutations are arguably the major type of peptides patient T cells recognize. Moreover, cancer cells present peptides derived from alleged noncoding regions, which also elicit T-cell responses thereby serving as cancer antigens. The diversity of newly discovered antigen sources implies that T cells are capable of sensing a variety of genomic aberrations in cancer., (© 2019 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

The prognosis of advanced pancreatic adenocarcinoma is still extremely poor. This study sought to determine the efficacy of, and immunological response to, peptide vaccination therapy in patients with this disease. In this multicenter randomized phase II study, patients with advanced pancreatic adenocarcinoma after gemcitabine and/or tegafur/gimeracil/oteracil were randomly assigned to 3 groups that each received a 2-step treatment course. In Step 1, the groups received treatments of: (i) survivin 2B peptide (SVN-2B) plus interferon-β (IFNβ); (ii) SVN-2B only; or (iii) placebo until the patients show progression. In Step 2, all patients who consented to participate received 4 treatments with SVN-2B plus IFNβ. The primary endpoint was progression-free survival (PFS) after initiation of Step 1 treatment. Secondary endpoints included immunological effects assessed by analysis of PBMCs after Step 1. Eighty-three patients were randomly assigned to receive SVN-2B plus IFNβ (n = 30), SVN-2B (n = 34), or placebo (n = 19). No significant improvement in PFS was observed. Survivin 2B-specific CTLs were found to be increased in the SVN-2B plus IFNβ group by tetramer assay. Among patients who participated in Step 2, those who had received SVN-2B plus IFNβ in Step 1 showed better overall survival compared with those who had received placebo in Step 1. Patients vaccinated with SVN-2B plus IFNβ did not have improved PFS, but showed significant immunological reaction after vaccination. Subgroup analysis suggested that a longer SVN-2B plus IFNβ vaccination protocol might confer survival benefit. (Clinical trial registration number: UMIN 000012146)., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: This study aimed to identify potential predictors of medication adherence and persistence with statin-ezetimibe combinational lipid-lowering therapy (LLT) as a separate pill combination in a real-world setting in Japan.Methods and Results:Patients newly switched to statin-ezetimibe combinational LLT from statin monotherapy were identified within a Japanese national pharmacy claims database during January 2015 to April 2018. Adherence and persistence were measured by the proportion of days covered (PDC), time to treatment discontinuation and persistence rate at 1 year. A stepwise multivariate logistic regression model and Cox proportional hazards regression model were used to explore potential predictors associated with adherence and persistence, respectively. Among 6,921 patients, 71.9% were adherent (PDC ≥80%), and 83.6% were persistent at 1 year after initiation. Patients aged ≤54 years and ≥75 years were prone to be more non-adherent. Secondary prevention was associated with better adherence and longer persistence. Concomitant use of medications for depression/anxiety was associated with shorter persistence, whereas use of antihypertensive drugs was associated with better adherence and persistence., Conclusions: Age, concomitant use of certain classes of medications (or the existence of these diseases) and secondary prevention were associated with adherence and persistence of statin-ezetimibe combinational LLT. Given that dyslipidemia is a chronic disease requiring life-long control, active interventions are required for patients with poor adherence and persistence.

Increasing the laser energy absorption into energetic particle beams represents a longstanding quest in intense laser-plasma physics. During the interaction with matter, part of the laser energy is converted into relativistic electron beams, which are the origin of secondary sources of energetic ions, γ-rays and neutrons. Here we experimentally demonstrate that using multiple coherent laser beamlets spatially and temporally overlapped, thus producing an interference pattern in the laser focus, significantly improves the laser energy conversion efficiency into hot electrons, compared to one beam with the same energy and nominal intensity as the four beamlets combined. Two-dimensional particle-in-cell simulations support the experimental results, suggesting that beamlet interference pattern induces a periodical shaping of the critical density, ultimately playing a key-role in enhancing the laser-to-electron energy conversion efficiency. This method is rather insensitive to laser pulse contrast and duration, making this approach robust and suitable to many existing facilities.

Background: Sleep disturbance in Alzheimer's disease (AD) patients may have a negative impact not only on patients themselves but also on the physical and mental health of their caregivers. Detailed analysis of these issues is lacking., Objective: This study investigated the association between sleep disturbance in AD patients and the burden on, and health status of, their caregivers in Japan., Methods: We conducted a cross-sectional web-based questionnaire survey among caregivers of AD patients with insomnia symptoms in Japan. Demographic data and Sleep Disorders Inventory (SDI) scores for patients, caregiver burden (Burden Index of Caregivers-11 [BIC-11]) and health status, including Pittsburgh Sleep Quality Index, Patient Health Questionnaire-9, and 12-Item Short Form Health Survey v2, were collected. Multivariate analysis was used to examine the association between the burden and health status of caregivers and sleep disturbance in their care recipients with AD., Results: A total of 496 caregivers of AD patients with insomnia symptoms were examined in this study. We found that the BIC-11 total score increased as the SDI score increased, indicating a significant positive association, even after adjusting for confounding factors. We also found an association between sleep disturbances of AD patients and health of caregivers (sleep quality, depression, and physical/mental quality of life)., Conclusion: This study demonstrated that sleep disturbance in AD patients was associated with an increased burden and poorer health status of caregivers. Our findings highlight the importance of sleep management in AD patients.

Cytotoxic CD8 + T lymphocytes (CTLs) recognize peptides displayed by HLA class I molecules on cell surfaces, monitoring pathological conditions such as cancer. Difficulty in predicting HLA class I ligands is attributed to the complexity of the Ag processing pathway across the cytosol and the endoplasmic reticulum. By means of HLA ligandome analysis using mass spectrometry, we collected natural HLA class I ligands on a large scale and analyzed the source-protein sequences flanking the ligands. This comprehensive analysis revealed that the frequency of proline at amino acid positions 1-3 upstream of the ligands was selectively decreased. The depleted proline signature was the strongest among all the upstream and downstream profiles. Experiments using live cells demonstrated that the presence of proline at upstream positions 1-3 attenuated CTL responses against a model epitope. Other experiments, in which N-terminal-flanking Ag precursors were confined in the endoplasmic reticulum, demonstrated an inability to remove upstream prolines regardless of their positions, suggesting a need for synergistic action across cellular compartments for making the proline signature. Our results highlight, to our knowledge, a unique role and position of proline for inhibiting downstream epitope presentation, which provides a rule for defining natural peptide-HLA class I repertoire formation and CTL responses., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Aims/introduction: The present study aimed to describe hospital utilization and examine actual medical costs for severe hypoglycemic events in patients with type 2 diabetes mellitus in Japan., Materials and Methods: Medical resource utilization associated with severe hypoglycemia was evaluated using a receipt database of acute-care hospitals in Japan. Patients with type 2 diabetes treated with antihyperglycemic agents were included. Severe hypoglycemic events were identified and divided into two groups: with or without hospitalization. Total and attributable medical costs per event were calculated based on the actual medical treatment after severe hypoglycemic events. Attributable costs were estimated from the receipt codes directly associated with the treatment of severe hypoglycemia., Results: In the hospitalized patients, the median length of hospital stay was 11 days, and the median total and attributable medical costs were ¥402,081 and ¥302,341, respectively. The majority of the hospitalized patients underwent a radiographic examination and general blood tests. Apart from the hospitalization costs, the costs associated with diagnosis accounted for 29.6% of the total medical costs. In the outpatients, 60.6% visited hospitals only once for the severe hypoglycemic event, whereas 11.4% visited hospitals daily for a week after the severe hypoglycemic event. The mean number of hospital visits of the outpatient after a severe hypoglycemic event was 2.7 ± 2.6 days. The median total and attributable medical costs were ¥265,432 and ¥4,628, respectively., Conclusions: Significant medical resources are used for the treatment of severe hypoglycemic events of patients with type 2 diabetes in Japan., (© 2018 Merck Sharp & Dohme Corp. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

A method of 2-dimensional (2-D) space-scanned (in the x-y plane) spatiotemporal double-slit interference is used to reconstruct the 2-D pulse-front (in the x-y-t domain) of a femtosecond pulsed beam. While comparing with recent other methods, the method possesses two advantages: no reference pulse/beam is required anymore, and an arbitrarily distorted pulse-front, not just pulse-front tilt and pulse-front curvature, could be detected. Meanwhile, the influence of different factors of unknown pulsed beams and optical elements on the measurement reliability is also analyzed for engineering applications.

Background: Type 2 Diabetes Mellitus (T2DM) is undertreated in Japan. We sought to understand the potential factors associated with reluctance to initiate/continue oral antihyperglycemic agents (OAHA) treatment in Japan., Methods: A two-phase study was conducted which included cognitive interviews in the first phase (N = 12) to ensure retrieval from memory of relevant information to respond to questions. The second phase included recruitment of respondents from an internet re-contact survey (N = 560) using NHWS or other Lightspeed panels. Patients' self-reported measures were collected to identify the potential barriers to T2DM treatment initiation or continuation. All measured variables were summarized descriptively using means and standard deviations for continuous variables, and frequencies and percentages for categorical variables., Results: A total of 560 respondents were assessed. Of those who were drug-naïve and ever been recommended prescription medication, only 17.3% were satisfied with how physicians presented the treatment options compared to current users or those who discontinued treatment (47.2% and 47.6% respectively). More than 50% of respondents did not realize neuropathic pain and end organ damage as potential consequences of untreated T2DM. 34.8% and 47.6% of drug-naïve and T2DM respondents who discontinued treatment were likely to start/restart treatment after realizing potential complications. Among those who discontinued treatment, 23.1% were extremely dissatisfied with their dosing frequency and less than 15% reported that their physicians discussed the importance of staying on medication long-term., Conclusion: The potential barriers addressed in this study should be considered when planning intervention strategies targeted at T2DM patients to promote their treatment in Japan., (Copyright © 2019 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

The prospect for developing a passively Q-switched Yb:YAG/Cr:YAG monolithic microchip laser that operates at cryogenic temperature is theoretically analyzed. It is concluded that such a system has the potential to deliver laser pulses with improved energy and increased peak power in comparison with composite Yb:YAG/Cr:YAG or Nd:YAG/Cr:YAG devices that are operated at room temperature. Consequently, a cryogenically cooled Yb:YAG/Cr:YAG system is built and the emission performances are investigated. Laser pulses with 3.2 mJ energy, 6.1 MW peak power and high beam quality of M 2 = 1.8 are achieved. By increasing the pump beam diameter, laser pulses with higher energy 32 mJ are obtained at 25 MW peak power with M 2 = 5.4. To our knowledge, these are the best results obtained from passively Q-switched composite Yb:YAG/Cr:YAG monolithic microchip lasers.

To investigate medication adherence to oral antihyperglycemic agents and its associated factors in Japanese type 2 diabetic patients, a questionnaire survey was conducted in 983 adult patients receiving once-daily (QD) or twice-daily (BID) dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitor) or BID biguanides (BG) as monotherapy at 502 pharmacies in Japan. The percentage of patients with good adherence (the proportion of days in which patients took all pills as prescribed in the past 7 days ≥80%) was high (≥90%) in any dosing regimen with no significant difference among the groups. The following factors were identified as associating with good adherence: the longer duration of type 2 diabetes (≥1 year) (p=0.002), "Feeling your disease gets worse if you don't take medications" (p=0.031), "Not forgetting to bring along your medicine when you leave home" (p=0.007), "Feeling anxiety on taking medications for long period of time" (p=0.042), "Neither feeling nor not feeling anxiety on taking medications for a long period of time" (p=0.004), "Never run out of your medicine because you get a refill on time" (p=0.035), and the lower MMAS-4 score (p<0.001). Subgroup analyses revealed that adherence of younger patients (<65 years) with BG (BID) was lower than those with DPP-4 inhibitor (QD) (p=0.021). Additionally, around 60% of patients currently prescribed with QD preferred QD regimen, and ≥80% patients prescribed with BID equally preferred once-weekly or QD regimen, suggesting a large discrepancy exists between their preference and the actual regimen in patients on BID.

In this Letter, we report a compact and robust coherent source, operating in mid-infrared (IR) and based on the Fe:ZnSe chalcogenide gain medium, optically pumped by an Er:ZBLAN fiber laser. The output power of 2.1 W with a 59% slope efficiency with respect to the absorbed pump power at liquid nitrogen cooling is achieved. We show that strong re-absorption at a high pump power and iron ion doping concentrations leads to a continuous tuning of central wavelength from 4012 to 4198 nm. The robustness of a high-power Er:ZBLAN fiber laser combined with prominent spectroscopic properties of Fe:ZnSe media pave the way for the development of a reliable tunable continuous-wave mid-IR sources for scientific and industrial purposes.