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Background: Prioritization for novel coronavirus disease 2019 (COVID-19)-related health policies usually considers age and certain other characteristics, but sex is rarely included, despite the higher risk of severe disease in men. The aim of this study was to compare the impact of sex and age on the severity of COVID-19 by estimating the age difference in years for which the risk for men versus women is the same., Methods: We analyzed 23,414 Japanese COVID-19 inpatients aged 20-89 years (13,360 men and 10,054 women). We graded the severity of COVID-19 (0 to 5) according to the most intensive treatment required during hospitalization. The risk of grade 2/3/4/5 (non-invasive positive pressure ventilation/invasive mechanical ventilation/extracorporeal membrane oxygenation/death), grade 3/4/5, and separately grade 5 was analyzed using a multiple logistic regression model., Results: The odds ratio (OR) of grades 2/3/4/5, 3/4/5 (primary outcome), and 5 for men relative to women was 2.76 (95% CI, 2.44-3.12), 2.78 (95% CI, 2.42-3.19), and 2.60 (95% CI, 2.23-3.03), respectively, after adjustment for age and date of admission. These risks for men were equivalent to those for women 14.1 (95% CI, 12.3-15.8), 11.2 (95% CI, 9.7-12.8), and 7.5 (95% CI, 6.3-8.7) years older, respectively., Conclusion: The risks of worse COVID-19 prognosis (grades 3/4/5) in men were equivalent to those of women 11.2 years older. Reanalyzing data extracted from four previous studies also revealed a large impact of sex difference on the severity of COVID-19. We should pay more attention to sex differences to predict the risk of COVID-19 severity and to formulate public health policy accordingly.

Purpose: Acoustic analysis has recently been applied to cementless total hip arthroplasty (THA). The aim of this study was to develop a machine learning algorithm to predict post-operative subsidence with high accuracy., Methods: The acoustic parameters of the hammering sounds during a broaching procedure for 62 hips in 55 patients who underwent THAs with cementless taper-wedged stem were analysed. The patient's basic background such as age, sex, height, weight and body mass index, the femoral morphological parameters and the hammering sound characteristics of 24 features of normalised sound pressure (nSP) in 24 frequency ranges were applied to binary classification using a support vector machine using the following models with different features: model A, nSP only; model B, nSP + patients' basic background features; model C, nSP + patients' basic background features + femoral morphological parameters., Results: In 62 hips with 310 hammering sounds, 12 hips (19.4%) showed ≥ 3 mm of post-operative subsidence; hence, 60 hammering sounds were set as positive examples and 250 hammering sounds were set as negative examples. The AUC was very high in all models. The accuracy (AUC/sensitivity/specificity/positive predictive value/negative predictive value/accuracy rate) of each model was as follows: model A, 0.963/0.656/0.996/0.980/0.925/0.934; model B, 0.9866/0.675/1.000/1.000/0.928/0.937 and model C, 0.998/0.750/1.000/1.000/0.950/0.957., Conclusion: In this study, we developed a high-accuracy machine learning algorithm for post-operative subsidence using acoustic parameters and additional pre-operative features. Our results represent a step toward the realisation of acoustic monitoring to avoid the complication in cementless THA., (© 2022. The Author(s) under exclusive licence to SICOT aisbl.)

Background: Ventilator-associated pneumonia (VAP) has emerged as a critical issue in the intensive care unit (ICU) because of its high burden on patients and medical staff. Here, we examined the potential for reducing VAP incidence through physical oral care interventions without any medication., Methods: This prospective interventional study compared VAP incidence during an 8-month baseline period (usual oral care) and a 9-month intervention period (physical oral care with sponge brush) among patients who received mechanical ventilation for >48 h in a tertiary care hospital in Vietnam from 2017 to 2019. Physical oral care was provided by general ICU nurses who had been trained by dentists and infection control nurses. VAP was diagnosed using the Clinical Pulmonary Infection Score., Results: In total, 423 patients were enrolled in the baseline group and 454 patients were enrolled in the intervention group; 303 and 300 patients, respectively, were included in the analysis. Two hundred thirty-eight VAP episodes were identified: 135 (44.6%) during the baseline period and 103 (34.3%) during the intervention period. Univariate analysis revealed significant reduction of VAP occurrence in the intervention period (odds ratio = 0.65; 95% confidence interval = 0.47-0.90; P = 0.010). The incidences of VAP per 1000 ventilator-days were 63.4 (135/2128) during the baseline period and 48.4 (103/2128) during the intervention period (P = 0.038)., Conclusions: Physical oral care without any medication (e.g., chlorhexidine) reduced VAP incidence in the ICU. This method could be used to reduce VAP incidence, particularly in countries with limited medical resources., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Typical amorphous aerogels pose great potential for CO 2 adsorbents with high surface areas and facile diffusion, but they lack well-defined porosity and specific selectivity, inhibiting utilization of their full functionality. To assign well-defined porous structures to aerogels, a hierarchical metal-organic aerogel (HMOA) is designed, which consists of well-defined micropores ( d ∼ 1 nm) by coordinative integration with chromium(III) and organic ligands. Due to its hierarchical structure with intrinsically flexible coordination, the HMOA has excellent porous features of a high surface area and a reusable surface with appropriate binding energy for CO 2 adsorption. The HMOA features high CO 2 adsorption capacity, high CO 2 /N 2 IAST selectivity, and vacuum-induced surface regenerability (100% through 20 cycles). Further, the HMOA could be prepared via simple ambient drying methods while retaining the microporous network. This unique surface-tension-resistant micropore formation and flexible coordination systems of HMOA make it a potential candidate for a CO 2 adsorbent with industrial scalability and reproducibility.

Background: The role of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) in the pandemic context of coronavirus disease 2019 (COVID-19) continues to be debated. Patients with hypertension, diabetes mellitus, chronic renal failure, cerebro-cardiovascular disease, or chronic obstructive pulmonary disease (COPD), who often use ACEi/ARB, may be at risk of severe COVID-19. However, there are no data available on the association of ACEi/ARB use with COVID-19 severity in this population., Methods: This study is an observational study of patients with a positive severe acute respiratory syndrome coronavirus 2 test and inpatient treatment at a healthcare facility, using the registry information of COVIREGI-JP. Our primary outcomes were in-hospital death, ventilator support, extracorporeal membrane oxygenation support, and intensive care unit admission. Out of the 6055 patients, 1921 patients with preexisting hypertension, diabetes mellitus, chronic renal failure, cerebro-cardiovascular disease, or COPD were enrolled., Results: Factors associated with an increased risk of the primary outcomes were aging, male sex, COPD, severe renal impairment, and diabetes mellitus. No correlations were observed with ACEi/ARB, cerebro-cardiovascular diseases, or hypertension. Associated factors in male patients were aging, renal impairment, hypertension, and diabetes. In female patients, factors associated with an increased risk were aging, ACEi/ARB, renal impairment, and diabetes, whereas hypertension was associated with a lower risk of the primary outcomes., Conclusions: Independent factors for the primary outcomes were aging, male sex, COPD, severe renal impairment, and diabetes, but not ACEi/ARB. Based on this registry data analysis, more detailed data collection and analysis is needed with the cooperation of multiple healthcare facilities., Competing Interests: Declaration of competing interest There is no conflict of interest in the present study., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aim: We investigated the relationship between small dense low-density cholesterol (sdLDL-C) and risk of major adverse cardiovascular events (MACE) in patients treated with high- or low-dose statin therapy., Methods: This was a prospective case-cohort study within the Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study, a randomized trial of high- or low-dose (4 or 1 mg/d pitavastatin, respectively) statin therapy, in patients with stable coronary artery disease (CAD). Serum sdLDL-C was determined using an automated homogenous assay at baseline (randomization after a rule-in period, ＞1 month with 1 mg/d pitavastatin) and 6 months after randomization, in 497 MACE cases, and 1543 participants randomly selected from the REAL-CAD study population., Results: High-dose pitavastatin reduced sdLDL-C by 20% than low-dose pitavastatin (p for interaction ＜0.001). Among patients receiving low-dose pitavastatin, baseline sdLDL-C demonstrated higher MACE risk independent of LDL-C (hazard ratio [95% confidence interval], 4th versus 1st quartile, 1.67 [1.04-2.68]; p for trend=0.034). High-dose (versus low-dose) pitavastatin reduced MACE risk by 46% in patients in the highest baseline sdLDL-C quartile (＞34.3 mg/dL; 0.54 [0.36-0.81]; p=0.003), but increased relative risk by 40% in patients with 1st quartile (≤ 19.5 mg/dL; 1.40 [0.94-2.09]; p=0.099) and did not alter risk in those in 2nd and 3rd quartiles (p for interaction=0.002)., Conclusions: These findings associate sdLDL-C and cardiovascular risk, independent of LDL-C, in statin-treated CAD patients. Notably, high-dose statin therapy reduces this risk in those with the highest baseline sdLDL-C.

Self-complementary assembly is one of the most promising phenomena for the formation of discrete assemblies, e.g., proteins and capsids. However, self-complementary assembly based on multiple host-guest systems has been scarcely reported due to the difficulty in controlling each assembly. Herein, we report a dual interaction system in which the key assembly direction is well regulated by both π-π stacking and hydrogen bonding to construct a self-complementary macrocycle. Continuous host-guest behavior of anthracene-based molecular tweezers during crystallization leads to successful construction of a cyclic hexamer, which is reminiscent of Kekulé's monkey model. Furthermore, the cyclic hexamer in a tight and triple-layered fashion shows hierarchical assembly into cuboctahedron and rhombohedral assemblies in the presence of trifluoroacetic acid. Our findings would be potentially one of metal-free strategies for constructing anthracene-based supramolecular assemblies with higher-order structure., (© 2022. The Author(s).)

We demonstrated the synthesis of a conductive two-dimensional metal-organic framework (MOF) thin film by single-step all-vapor-phase chemical vapor deposition (CVD). The synthesized large-area thin film of Cu 3 (C 6 O 6 ) 2 has an edge-on-orientation with high crystallinity. Cu 3 (C 6 O 6 ) 2 thin film-based microdevices were fabricated by e-beam lithography and had an electrical conductivity of 92.95 S/cm. Synthesis of conductive MOF thin films by the all-vapor-phase CVD will enable fundamental studies of physical properties and may help to accomplish practical applications of conductive MOFs.

In condensed matter, phase separation is strongly related to ferroelasticity, ferroelectricity, ferromagnetism, electron correlation, and crystallography. These ferroics are important for nano-electronic devices such as non-volatile memory. However, the quantitative information regarding the lattice (atomic) structure at the border of phase separation is unclear in many cases. Thus, to design electronic devices at the molecular level, a quantitative electron-lattice relationship must be established. Herein, we elucidated a Pd II -Pd IV /Pd III -Pd III phase transition and phase separation mechanism for [Pd(cptn) 2 Br]Br 2 (cptn = 1 R ,2 R -diaminocyclopentane), propagated through a hydrogen-bonding network. Although the Pd···Pd distance was used to determine the electronic state, the differences in the Pd···Pd distance and the optical gap between Mott-Hubbard (MH) and charge-density-wave (CDW) states were only 0.012 Å and 0.17 eV, respectively. The N-H···Br···H-N hydrogen-bonding network functioned as a jack, adjusting the structural difference dynamically, and allowing visible ferroelastic phase transition/separation in a fluctuating N 2 gas flow. Additionally, the effect of the phase separation on the spin susceptibility and electrical conductivity were clarified to represent the quasi-epitaxial crystals among CDW-MH states. These results indicate that the phase transitions and separations could be controlled via atomic and molecular level modifications, such as the addition of hydrogen bonding.

Background: The aim of this study was to identify associations between smoking status and the severity of COVID-19, using a large-scale data registry of hospitalized COVID-19 patients in Japan (COVIREGI-JP), and to explore the reasons for the inconsistent results previously reported on this subject., Methods: The analysis included 17 666 COVID-19 inpatients aged 20-89 years (10 250 men and 7416 women). We graded the severity of COVID-19 (grades 0 to 5) according to the most intensive treatment required during hospitalization. The smoking status of severe grades 3/4/5 (invasive mechanical ventilation/extracorporeal membrane oxygenation/death) and separately of grade 5 (death) were compared with that of grade 0 (no oxygen, reference group) using multiple logistic regression. Results were expressed as odds ratios (OR) and 95% confidence intervals (CI) adjusted for age and other factors considering the potential intermediate effects of comorbidities., Results: Among men, former smoking significantly increased the risk of grade 3/4/5 and grade 5, using grade 0 as a reference group, with age- and admission-date-adjusted ORs (95% CI) of 1.51 (1.18-1.93) and 1.65 (1.22-2.24), respectively. An additional adjustment for comorbidities weakened the ORs. Similar results were seen for women. Current smoking did not significantly increase the risk of grade 3/4/5 and grade 5 in either sex., Conclusions: The severity of COVID-19 was not associated with current or former smoking per se but with the comorbidities caused by smoking. Thus, smoking cessation is likely to be a key factor for preventing smoking-related disease and hence for reducing the risk of severe COVID-19., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Objective: Adjuvant chemotherapy with trastuzumab improves the postoperative life expectancy of women with early-stage breast cancer. Although trastuzumab is reportedly cardiotoxic, quantification based on real-world evidence is lacking. Therefore, in this study, we aimed to analyse trastuzumab cardiotoxicity using a nationwide claim-based database., Methods: In this retrospective study, we used data from a nationwide claims database (Japan Medical Data Center, Tokyo, Japan) under the universal healthcare system. Women with breast cancer who underwent initial surgery were included. Patients with recurrent or advanced-stage breast cancer, with a history of heart failure, receiving neoadjuvant chemotherapy or a preoperative history of less than 6 months were excluded. Propensity score (PS) was calculated using logistic regression based on age, cardiovascular risk factors, radiotherapy and concomitant anthracyclines (AC)., Results: We identified 12 060 eligible patients (mean age 50.8±8.56 years) between January 2010 and December 2019. After 1:2 PS matching (trastuzumab users, TZ, n=1005; non-users, NT, n=2010), Cox proportional hazards model analysis showed that the rate of heart failure development within 18 months postoperative was significantly higher in the TZ group than in the NT group (adjusted HR 2.28, 95% CI 1.38 to 3.77). Baseline cardiac evaluation in the combined AC/TZ cases was 27.2% preoperative, 66.0% pre-AC and 86.6% pre-TZ, respectively., Conclusion: Trastuzumab cardiotoxicity remained relevant in the claim-based analysis adjusted for AC effects. Further collaborative studies in cardio-oncology with real-world data are warranted to improve the rate of baseline cardiovascular risk assessment in patients with cancer scheduled for cardiotoxic cancer treatment., Competing Interests: Competing interests: AS received lecture fees from Chugai and Eli-Lilly and received research grant from Chugai, AstraZeneca, Daiichi Sankyo, Eisai and Taiho. NY is an employee and a shareholder of Pfizer. SU received grants from Kowa, Bayer, Bristol-Myers Squibb, Pfizer, Daiichi Sankyo, and Takeda and received lecture fees from Eisai, Novartis, MSD, and Boelinger Ingelheim. CS received research grant from Eli-Lilly. KS received lecture fees from Daiichi Sankyo. All of the above are unrelated to the submitted work. All other authors have no conflicts with any industry., (© 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.)

Background: Depression during pregnancy is relatively undertreated; however, the relationship between prenatal exposure to antidepressants and neonatal outcomes remains controversial., Methods: This retrospective cohort study used a Japanese nationwide claims database. Data of 114,359 singletons born between January 2005 and November 2019 were used to evaluate the relationship between prenatal exposure to antidepressants and neonatal morbidity., Results: Of 2892 mothers with a history of depression before delivery, 352 (12.1%) received prescriptions within three months before delivery (MP3), and 2540 did not (non-MP3). The participants were propensity score matched (PSM) in a ratio of 1:3 using logistic regression (MP3_PSM [n = 351] vs non-MP3_PSM [n = 1052]), and maternal prescriptions of antidepressants within three months before delivery were associated with neonatal morbidity indicators, including admission to the neonatal intensive care unit (NICU) (15.7 vs. 9.1%, odds ratio (OR) 1.9 [95% confidence interval (CI): 1.3-2.6]), poor neonatal adaptation syndrome (6.0 vs 1.0%, OR 6.6 [95% CI: 3.1-14.2]), transient tachycardia (15.7 vs. 6.7%, OR 2.6 [95% CI: 1.8-3.8]), and meconium aspiration syndrome (3.1 vs 0.7%, OR 4.8 [95% CI, 1.9-12.5]). There were no significant differences in the long-term duration of stay at the NICU (>15 days)., Limitations: Confounding factors may remain even after the propensity matching., Conclusion: Maternal prescription of antidepressants within three months before delivery was associated with increased admission to the NICU. However, the absolute risk of severe neonatal morbidity was low. Therefore, collaborative care for prenatal depression and the neonatal intensive care is warranted., (Copyright © 2022. Published by Elsevier B.V.)

This investigator-initiated, phase 2, single-arm trial primarily assessed the efficacy of G47∆, a triple-mutated, third-generation oncolytic herpes simplex virus type 1, in 19 adult patients with residual or recurrent, supratentorial glioblastoma after radiation therapy and temozolomide (UMIN-CTR Clinical Trial Registry UMIN000015995). G47Δ was administered intratumorally and repeatedly for up to six doses. The primary endpoint of 1-yr survival rate after G47∆ initiation was 84.2% (95% confidence interval, 60.4-96.6; 16 of 19). The prespecified endpoint was met and the trial was terminated early. Regarding secondary endpoints, the median overall survival was 20.2 (16.8-23.6) months after G47∆ initiation and 28.8 (20.1-37.5) months from the initial surgery. The most common G47∆-related adverse event was fever (17 of 19) followed by vomiting, nausea, lymphocytopenia and leukopenia. On magnetic resonance imaging, enlargement of and contrast-enhancement clearing within the target lesion repeatedly occurred after each G47∆ administration, which was characteristic to this therapy. Thus, the best overall response in 2 yr was partial response in one patient and stable disease in 18 patients. Biopsies revealed increasing numbers of tumor-infiltrating CD4 + /CD8 + lymphocytes and persistent low numbers of Foxp3 + cells. This study showed a survival benefit and good safety profile, which led to the approval of G47∆ as the first oncolytic virus product in Japan., (© 2022. The Author(s).)

Objectives: Endovascular aortic repair (EVAR) evolved through competition with open aortic repair (OAR) as a safe and effective treatment option for appropriately selected patients with abdominal aortic aneurysm (AAA). Although endoleaks are the most common reason for post-EVAR reintervention, compliance with lifelong regular follow-up imaging remains a challenge., Design: Retrospective data analysis., Setting: The Japan Medical Data Center (JMDC), a claims database with anonymous data linkage across hospitals, consists of corporate employees and their families of ≤75 years of age., Participants: The analysis included participants in the JMDC who underwent EVAR or OAR for intact (iAAA) or ruptured (rAAA) AAA. Patients with less than 6 months of records before the aortic repair were excluded., Main Outcome Measures: Overall survival and reintervention rates., Results: We identified 986 cases (837 iAAA and 149 rAAA) from JMDC with first aortic repairs between January 2015 and December 2020. The number of patients, median age (years (IQR)), follow-up (months) and post-procedure CT scan (times per year) were as follows: iAAA (OAR: n=593, 62.0 (57.0-67.0), 26.0, 1.6, EVAR: n=244, 65.0 (31.0-69.0), 17.0, 2.2), rAAA (OAR: n=110, 59.0 (53.0-59.0), 16.0, 2.1, EVAR: n=39, 62.0 (31.0-67.0), 18.0, 2.4). Reintervention rate was significantly higher among EVAR than OAR in rAAA (15.4% vs 8.2%, p=0.04). In iAAA, there were no group difference after 5 years (7.8% vs 11.0%, p=0.28), even though EVAR had initial advantage. There were no differences in mortality rate between EVAR and OAR for either rAAA or iAAA., Conclusions: Claims-based analysis in Japan showed no statistically significant difference in 5-year survival rates of the OAR and EVAR groups. However, the reintervention rate of EVAR in rAAA was significantly higher, suggesting the need for regular post-EVAR follow-up with imaging. Therefore, international collaborations for long-term outcome studies with real-world data are warranted., Competing Interests: Competing interests: YK received a fee from the Pharmaceuticals and Medical Devices Agency. HO received a consultant fee from EPS International, outside the submission work. NY is an employee and shareholder of Pfizer. KS has received lecture fees from Diichi Sankyo, Novartis, Pfizer, and Bristol-Myers Squibb, outside the submitted work., (© 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.)

The detection of other pathogens in patients with hospitalized coronavirus disease (COVID-19) are not frequent. Considering that data from Japan are limited, we conducted an observational study including patients with hospitalized COVID-19 at the National Center for Global Health and Medicine from January to September 2020. In total, 247 patients with COVID-19 were included in the study. Rapid diagnostic tests, such as immunochromatography, were performed in 31 patients (12.6%). The Film Array Respiratory Panel was performed in 18 (7.3%) patients, and none of the tests were positive for pathogens other than severe acute respiratory syndrome coronavirus 2. Respiratory bacterial culture was performed in 66 (26.7%) patients, with gram-positive bacteria, gram-negative bacteria and normal flora being detected in eight (12.1%), seven (10.6%), and 63 (95.5%) patients, respectively. Patients for whom cultures were performed were older, more severely ill, and more likely to have radiological evidence of pneumonia on admission. Culture was performed more frequently in the early than in the later period of the epidemic, without any differences being observed in bacterial detection rates. The proportion of viral and bacterial detection among hospitalized patients with COVID-19 in tertiary care hospitals in Japan was low. A larger cohort study is necessary to evaluate the effect of each pathogen on the clinical course of COVID-19.

Here, we report the results of a phase I/II, single-arm study (UMIN-CTR Clinical Trial Registry UMIN000002661) assessing the safety (primary endpoint) of G47∆, a triple-mutated oncolytic herpes simplex virus type 1, in Japanese adults with recurrent/progressive glioblastoma despite radiation and temozolomide therapies. G47Δ was administered intratumorally at 3 × 10 8  pfu (low dose) or 1 × 10 9  pfu (set dose), twice to identical coordinates within 5-14 days. Thirteen patients completed treatment (low dose, n = 3; set dose, n = 10). Adverse events occurred in 12/13 patients. The most common G47Δ-related adverse events were fever, headache and vomiting. Secondary endpoint was the efficacy. Median overall survival was 7.3 (95%CI 6.2-15.2) months and the 1-year survival rate was 38.5%, both from the last G47∆ administration. Median progression-free survival was 8 (95%CI 7-34) days from the last G47∆ administration, mainly due to immediate enlargement of the contrast-enhanced area of the target lesion on MRI. Three patients survived >46 months. One complete response (low dose) and one partial response (set dose) were seen at 2 years. Based on biopsies, post-administration MRI features (injection site contrast-enhancement clearing and entire tumor enlargement) likely reflected tumor cell destruction via viral replication and lymphocyte infiltration towards tumor cells, the latter suggesting the mechanism for "immunoprogression" characteristic to this therapy. This study shows that G47Δ is safe for treating recurrent/progressive glioblastoma and warrants further clinical development., (© 2022. The Author(s).)

Background: Venous thromboembolism (VTE) is a well-known type of cancer-associated thrombosis and a common complication of malignancy. However, the incidence of VTE associated with lung cancer and the effectiveness of direct oral anticoagulants remain unclear. This study aimed to identify the incidence of VTE associated with lung cancer at the time of diagnosis or during treatment, the efficacy and safety of edoxaban, and associated risk factors., Methods: The Rising-VTE/NEJ037 study was a multicenter prospective observational study. Altogether, 1021 patients with lung cancer who were unsuitable for radical resection or radiation were enrolled and followed up for 2 years. Patients with VTE at the time of lung cancer diagnosis started treatment with edoxaban. The primary endpoint of this trial was the rate of newly diagnosed VTE after enrollment or recurrence rate 6 months after treatment initiation., Results: Data were available for 1008 patients. The median age was 70 years (range: 30-94 years), and 70.8% were men. Sixty-two patients had VTE at the time of lung cancer diagnosis, and 38 (9.9%) developed VTE at follow-up. No cases of VTE recurrence were recorded 6 months after treatment initiation with edoxaban. Major and clinically relevant non-major bleeding events occurred in 4.9% of patients and increased to 22.7% in the edoxaban treatment group., Conclusions: VTE occurrence should be monitored during lung cancer treatment. Although treatment with edoxaban was highly effective in preventing VTE recurrence, its administration should be cautiously considered because of the high bleeding rate., Trial Registration: jRCTs061180025., Competing Interests: Competing Interests: Yukari Tsubata received grant and personal fees from Daiichi Sankyo Co., Ltd. and AstraZeneca K.K. and personal fees from Chugai Pharmaceuticals Inc. outside the submitted work. Naoki Furuya received personal fees from AstraZeneca K.K., Chugai Pharmaceutical, Nippon Boehringer Ingelheim Co. Ltd., Bristol-Myers Squibb Company, Eli Lilly Japan K.K., MSD K.K., Pfizer Japan Inc., Taiho Pharmaceutical, and Novartis Pharma K.K. outside the submitted work. Toshihide Yokoyama received personal fees from Eli Lilly Japan K.K., Merck Sharp & Dohme K.K., and Takeda Pharmaceutical outside the submitted work. Atsushi Nakamura received grant and personal fees from AstraZeneca K.K., Thermo Fisher Scientific Inc., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Novartis Pharma K.K., Pfizer Japan Inc., and Nippon Kayaku Co., Ltd. and personal fees from Taiho Pharmaceutical Co., Ltd. outside the submitted work. Takeshi Masuda received personal fees from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Eli Lilly Japan, Nippon Boehringer Ingelheim Co., Ltd., Kyowa Kirin Co., Ltd., and Ono Pharmaceutical Co., Ltd. outside the submitted work. Kazunori Fujitaka received personal fees from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Bristol-Myers Squibb Company, MSD K.K., Pfizer Japan Inc., Daiichi Sankyo Co., Ltd., Eli Lilly Japan, and Nippon Boehringer Ingelheim Co., Ltd. outside the submitted work. Hiroshi Ohtsu received personal fees from EPS International outside the submitted work. Kunihiko Kobayashi received personal fees from AstraZeneca K.K. and Takeda Pharmaceutical outside the submitted work. Takeshi Isobe received grant and personal fees from Daiichi Sankyo Co., Ltd.; personal fees from AstraZeneca K.K., Pfizer Japan Inc., and Nippon Boehringer Ingelheim Co., Ltd.; and grants from Pearl Therapeutics Inc. and Janssen Pharmaceutical K.K. outside the submitted work., (© The Author(s), 2022.)

An N-Fmoc and C-tBu-protected glutamate (1) bearing a phenanthrene moiety at the side residue crystalizes and gels to afford hetero- and homochiral assemblies, respectively, depending on its optical purity or solvent. When a non-stoichiometric mixture of enantiomers of 1 in acetonitrile was treated with the conditions that leave a mixture of gel and supernatant, it exhibited the self-disproportionation of enantiomers with an enrichment of the major enantiomer in the gel. Under similar conditions, a racemic mixture of 1 also provided a gel/supernatant mixture, where the gel was enriched in either of L or D-form of 1 stochastically as the result of macroscopic chiral symmetry breaking in its gelation process., (© 2022 Wiley-VCH GmbH.)

Background: The epidemiology and risk of coronavirus disease 2019 (COVID-19) among travelers at international borders remain unclear., Methods: We conducted descriptive and individually matched case-control studies using a nationwide register for COVID-19 testing of travelers from 3 August to 31 October 2020 at airport/port quarantine stations across Japan. Case patients, defined as travelers positive for COVID-19 on arrival, were individually matched with 4 controls for arrival date and airport or port. We assessed associations between test positivity and traveler characteristics using conditional logistic regression analysis., Results: Overall, 157 507 travelers arriving from 146 countries/areas at 17 quarantine stations across Japan were tested for COVID-19. The percentage of test positivity during the study period was 0.35%. In the case-control study, with 536 case patients and 2144 controls, we found evidence of lower test positivity in travelers aged 3-19 years, female travelers, and travel corridor users (adjusted odds ratio [95% confidence interval], 0.36 [.22-.60], 0.71 [.56-.89], and 0.48 [.30-.77], respectively), whereas higher positivity was associated with arrival from South-East Asia (1.88 [1.33-2.65]) or lower-middle- or low-income countries (2.46 [1.69-3.58] and 7.25 [2.22-23.66], respectively), any symptom (4.08 [1.43-11.65]), and nasopharyngeal compared with saliva sampling (2.75 [1.85-4.09]). A higher 14-day average incidence in the countries of stay was also associated with higher test positivity (1.64 [1.16-2.33] and 3.13 [1.88-5.23] for those from countries and areas where the 14-day average incidence was from 10 to <100 and ≥100 cases per million, respectively)., Conclusions: These findings justify travel restrictions based on the epidemic situation in countries of stay, although underestimation of the epidemic in lower-income countries should be considered. A strict travel corridor could also reduce the risk of COVID-19 importation., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

To prevent falls in the elderly, it is essential to evaluate their gait stability and identify factors that negatively affect it. Although one of the probable factors is a decrease in propulsive force of walking, the relationship between the force and the gait stability has not been fully clarified. To this end, two simple walking models were used to investigate the relationship between the propulsive force and the number of steps required to stop, denoted N. N was calculated as the number of steps required for the rimless wheel to stop and was treated as a variable which is an indirect indicator of stability. A lower N corresponds to the gait being closer to a stopped state. The propulsive force was calculated using the push-off impulse applied to the simplest walking model during the step-to-step transition. To account for the effects of the double support phase in human walking, the gravitational impulse, which is the integral of the body weight (gravitational force) over the double support time, was applied to the step-to-step transition equation of the models. The models revealed that the propulsive force is reduced by two factors: the reduction in step length and the reduction in walking speed. In the former, N increases; in the latter, N decreases. The former is consistent with previous experimental results on human gait, whereas the latter has not been experimentally investigated. These results may provide important insights in clarifying the relationship between the stability and the propulsive force in human gait., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Before widespread coronavirus disease (COVID-19) vaccinations, Japan experienced three COVID-19 epidemic waves. This study aimed to evaluate the characteristics of hospitalised COVID-19 patients and reveal temporal changes., Methods: This study included 33,554 hospitalised patients with COVID-19 from 553 healthcare facilities. Data were analysed by age group and epidemic wave (first wave, 01/01/2020-05/31/2020; second wave, 06/01/2020-10/31/2020; and third wave, 11/01/2020-03/31/2021)., Findings: By age group, 3% (under 18), 22% (young), 34% (middle-aged), and 41% (older patients) were aged 0-17, 18-39, 40-64, and >65 years; while 16%, 35%, and 49% were in the first, second, and third wave, respectively. The patients' overall median age (58 years; interquartile range, 39-74) was lowest and highest during the second and third waves, respectively. The frequency of any comorbidity was lowest and highest during the second (44·5%) and third (63·6%) waves, respectively. The symptoms at admission and exposure history differed considerably with age. The overall case fatality rate (5%) was highest among older patients (11·4%). Case fatality rate was highest and lowest during the first (7·3%) and second (2·8%) waves, respectively. Medication use changed over time., Interpretation: Although the overall case fatality rate remained relatively low, it was more than twice as high among older patients. After adjusting for age and comorbidities, the risk of death was highest in the first wave., Funding: This work was supported by the Ministry of Health, Labour and Welfare "Research on Emerging and Re-emerging Infectious Diseases and Immunization" 19HA1003]., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Author(s).)

Background: Cardiovascular complications of coronavirus disease 2019 (COVID-19) are critical for prognosis but have not been elucidated in Japan., Methods and results: The COVID-19 Registry Japan, which included data from 19,853 individuals at the end of 2020, was analyzed. The incidences of cardiovascular complications were 0.098% for myocarditis/pericarditis/cardiomyopathy, 0.48% for ventricular tachycardia/fibrillation, 0.17% for myocardial ischemia, 0.062% for endocarditis, 0.59% for deep vein thrombosis, 0.19% for pulmonary embolism, and 0.37% for cerebral infarction/hemorrhage. Excluding endocarditis, all complications were associated with increased in-hospital mortality., Conclusions: Cardiovascular complications of COVID-19 were infrequent in Japan but were associated with poor prognosis.

Introduction: We aimed to analyze the clinical characteristics and outcomes of immunosuppressed inpatients with coronavirus disease 2019 (COVID-19)., Methods: In this observational study, we utilized a large nationwide registry of hospitalized patients with COVID-19 in Japan. Patients' baseline characteristics and outcomes were compared according to the immunosuppressed states of the patients. The impact of different therapeutic agents on the clinical courses of the patients was evaluated., Results: Data of 14,760 patients were included, and 887 (5.9%) were immunosuppressed. The immunosuppressed state of the patient resulted from solid tumor (43.3%, n = 384), chemotherapy within 3 months (15.6%, n = 138), collagen disease (16.9%, n = 150), use of immunosuppressive agents (16.0%, n = 142), and metastatic solid tumor (13.5%, n = 120). Immunosuppressed patients were older and had a higher severity of illness at admission and during hospitalization than non-immunosuppressed patients. The mortality rates for major diseases causing immunosuppression were as follows: solid tumor, 12.5% (48/384; P < 0.001; relative risk [RR], 3.41); metastatic solid tumor, 31.7% (38/120; P < 0.001; RR, 8.43); leukemia, 23.1% (9/39; P < 0.001; RR, 5.87); lymphoma, 33.3% (20/60; P < 0.001; RR, 8.63); and collagen disease, 15.3% (23/150; P < 0.001; RR 3.97). Underlying diseases with high mortality rates were not necessarily associated with high rates of invasive supportive care., Conclusions: The prognosis of immunosuppressed COVID-19 inpatients varied according to the different immunosuppressed states. Multiple factors, including the severity of the underlying diseases, might have affected their invasive supportive care indications., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Introduction: Old age is an independent risk factor (RF) for severe COVID-19; evidence for clinico-epidemiological characteristics among elderly COVID-19 patients is scarce. We aimed to analyze clinical and epidemiological characteristics and comorbidities associated with COVID-19 inpatients in age-stratified populations of an elderly COVID-19 cohort., Methods: We conducted a retrospective cohort study, using nationwide registry data of COVID-19 patients hospitalized before October 31, 2020 (major information entered in the registry as of December 28, 2020). Participants were divided by age according to the Japan Geriatrics Society and the Japan Gerontological Society: pre-old (65-74 years), old (75-89 years), and super-old (≥90 years). Multivariable logistic regression (MLR) analyses were conducted to identify stratified risk and relationships with comorbidities associated with worse outcomes in different age-groups of elderly patients. Demographics and supportive care were evaluated by category., Results: Data of 4,701 patients from 444 hospitals were included. Most patients (79.3%) had at least one comorbidity; the proportion of patients with hypertension was high in all categories. The proportion of patients with dementia, cardiovascular disease, and cerebrovascular disease increased with age. The percentage of patients who underwent invasive mechanical ventilation/extracorporeal membrane oxygenation was lower in the super-old group. In total, 11.5% of patients died (5.3%, pre-old; 15.2%, old; and 22.4%, super-old). MLR showed that the risk of critical illness differed among age-groups. Male sex was a significant RF in all ages. Collagen disease, moderate to severe renal disorder, and dialysis were significant RFs in older patients, while hematological malignancies and metastatic tumors were more important RFs for severe disease in relatively younger patients. Most of the RFs for critical illnesses were associated with death., Conclusion: Differences in the epidemiological and clinical characteristics among the different age-groups were found., (© 2022 S. Karger AG, Basel.)

Aim: The association between high-density lipoprotein cholesterol (HDL-C) level after statin therapy and cardiovascular events in patients with stable coronary artery disease (CAD) remains unclear. Thus, in this study, we sought to determine how HDL-C level after statin therapy is associated with cardiovascular events in stable CAD patients., Methods: From the REAL-CAD study which had shown the favorable prognostic effect of high-dose pitavastatin in stable CAD patients with low-density lipoprotein cholesterol (LDL-C) ＜120 mg/dL, 9,221 patients with HDL-C data at baseline and 6 months, no occurrence of primary outcome at 6 months, and reported non-adherence for pitavastatin, were examined. The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission after 6 months of randomization. Absolute difference and ratio of HDL-C levels were defined as (those at 6 months-at baseline) and (absolute difference/baseline)×100, respectively., Results: During a median follow-up period of 4.0 (IQR 3.2-4.7) years, the primary outcome occurred in 417 (4.5%) patients. The adjusted risk of all HDL-C-related variables (baseline value, 6-month value, absolute, and relative changes) for the primary outcome was not significant (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.91-1.08, HR 1.03, 95% CI 0.94-1.12, HR 1.05, 95% CI 0.98-1.12, and HR 1.08, 95% CI 0.94-1.24, respectively). Furthermore, adjusted HRs of all HDL-C-related variables remained non-significant for the primary outcome regardless of on-treatment LDL-C level at 6 months., Conclusions: After statin therapy with modestly controlled LDL-C, HDL-C level has little prognostic value in patients with stable CAD.

Layer flexibility in two-dimensional coordination polymers (2D-CPs) contributes to several functional materials as it results in anisotropic structural response to external stimuli. Chemical modification is a common technique for modifying layer structures. This study demonstrates that crystal morphology of a cyanide-bridged 2D-CP of type [Mn(salen)] 2 [ReN(CN) 4 ] (1) consisting of flexible undulating layers significantly impacts the layer configuration and assembly. Nanoplates of 1 showed an in-plane contraction of layers with a longer interlayer distance compared to the micrometer-sized rod-type particles. These effects by crystal morphology on the structure of the 2D-CP impacted the structural flexibility, resulting in dual-functional changes: the enhancement of the sensitivity of structural transformation to water adsorption and modification of anisotropic thermal expansion of 1. Moreover, the nanoplates incorporated new adsorption sites within the layers, resulting in the uptake of an additional water molecule compared to the micrometer-sized rods., (© 2021 Wiley-VCH GmbH.)

For the first time, an NAD + -type earth-abundant metal complex [Zn(pbn) 2 (H 2 O)](ClO 4 ) 2 (1) was found to exhibit photo-induced oxidizing ability to convert various primary and secondary alcohols to the corresponding aldehyde and ketone compounds. In addition, a two-electron-reduced Zn(II) complex [Zn(pbnH-pbnH)(ClO 4 ) 2 ] (1red) comprising the novel C-C coupling ligand, obtained by the photo-induced oxidation of alcohols by 1, was successfully isolated and completely characterized. We clarified that the photochemical oxidation of alcohols by 1 to produce 1red proceeds via an electron transfer followed by proton transfer mechanism as elucidated by kinetic analysis on the basis of absorption spectroscopic measurements.

A tridentate 3-pyridyl-based ligand containing a hexaazaphenalene skeleton (3-TPHAP - ) with topologically isolated p orbitals was prepared by a one-pot reaction. It was successfully reacted with a Co 2+ salt and a 1,4-benzenedicarboxylic acid co-ligand to give a porous coordination network. In the structure, the hexaazaphenalene skeleton interacts with water to form an internal hydrogen bonding network, allowing the entire pore space to be revealed by single-crystal X-ray diffraction (SXRD). The network structure consists of dimeric Co clusters featuring labile sites occupied by solvent molecules. Several guest molecules, namely, anthracene, triphenylene, and iodine, were incorporated inside the network. The resultant encapsulated structures were elucidated by SXRD, revealing unusual host-guest interactions with a subtle structural modulation.

Background: There is limited understanding of the characteristics of patients with coronavirus disease 2019 (COVID-19) requiring hospitalization in Japan., Methods: This study included 2638 cases enrolled from 227 healthcare facilities that participated in the COVID-19 Registry Japan (COVIREGI-JP). The inclusion criteria for enrollment of a case in COVIREGI-JP are both (1) a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test and (2) inpatient treatment at a healthcare facility., Results: The median age of hospitalized patients with COVID-19 was 56 years (interquartile range [IQR], 40-71 years). More than half of cases were male (58.9%, 1542/2619). Nearly 60% of the cases had close contact to confirmed or suspected cases of COVID-19. The median duration of symptoms before admission was 7 days (IQR, 4-10 days). The most common comorbidities were hypertension (15%, 396/2638) and diabetes without complications (14.2%, 374/2638). The number of nonsevere cases (68.2%, n = 1798) was twice the number of severe cases (31.8%, n = 840) at admission. The respiratory support during hospitalization includes those who received no oxygen support (61.6%, 1623/2636) followed by those who received supplemental oxygen (29.9%, 788/2636) and invasive mechanical ventilation/extracorporeal membrane oxygenation (8.5%, 225/2636). Overall, 66.9% (1762/2634) of patients were discharged home, while 7.5% (197/2634) died., Conclusions: We identified the clinical epidemiological features of COVID-19 in hospitalized patients in Japan. When compared with existing inpatient studies in other countries, these results demonstrated fewer comorbidities and a trend towards lower mortality., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Objective: This study was conducted to investigate the effects of restriction of forefoot rocker (FFR) functions by immobilisation of unilateral metatarsophalangeal joints (MPJs) on kinematic and kinetic factors during walking., Methods: Eighteen healthy young adults participated in this study. To immobilise the MPJs of the right leg, an aluminium sole plate (AS) was fixed on the sole of the foot. Kinematic and kinetic data were collected while each subject walked at a comfortable speed with the AS and without., Results: In the AS condition, the walking speed and contralateral step length were significantly decreased, and an asymmetrical centre of mass (COM) movement was observed. The range of plantarflexion motion and positive work by the ankle joint were decreased markedly during the late stance of the AS limb. In contrast, maximum hip and knee flexion angles in the swing phase of the AS limb and positive work by the bilateral hip joints over the gait cycle were increased., Conclusions: The results suggested that MPJ immobilisation may result in marked motion limitation of ankle plantarflexion and inhibition of push-off by the ankle joint despite no restrictions on the ankle joint. These changes may interfere with gait speed and a smooth and symmetrical COM shift during walking., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: To determine whether anticoagulation therapy improves outcomes in patients with coronavirus disease 2019 (COVID-19) in Japan given their lower risk of thrombosis compared with Western cohorts., Methods: The efficacy of anticoagulation therapy in hospitalized patients with COVID-19 was evaluated using a nationwide registry: the COVID-19 Registry Japan. The inverse probability of weight treatment method was used to adjust for baseline confounders in the anticoagulation and non-anticoagulation groups., Results: Of the 1748 patients included, anticoagulants were used in 367 patients (treatment group). The patients in the anticoagulant group were older, predominantly male, and often presented with obesity, hyperlipidaemia, hypertension, diabetes and elevated D-dimer levels. Twenty-nine-day mortality was 7.6% in the whole cohort (treatment group, 11.2%; no treatment group, 6.6%), 6% in patients who were not treated with steroids (treatment group, 12.3%; no treatment group, 5.2%), and 11.2% in patients treated with steroids (treatment group, 10.5%; no treatment group, 11.8%). Mortality in the whole cohort was similar between the treatment and no treatment groups (P=0.99), and an insignificant decreasing trend in mortality was observed in patients treated with steroids (P=0.075)., Conclusions: Anticoagulants may be beneficial in Asians, in whom comorbidities and risk of thrombosis may differ from other ethnic groups., Competing Interests: Declaration of Competing Interest H. Ohtsu reports personal fees as a statistician and as an external consultant for clinical trials from EPS International, outside the submitted work. S. Saito reports grants from Shionogi, outside the submitted work. The other authors report no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: The optimal management for acute traumatic cervical spinal cord injury (SCI) is unknown., Objective: To determine whether early surgical decompression results in better motor recovery than delayed surgical treatment in patients with acute traumatic incomplete cervical SCI associated with preexisting canal stenosis but without bone injury., Design, Setting, and Participants: This multicenter randomized clinical trial was conducted in 43 tertiary referral centers in Japan from December 2011 through November 2019. Patients aged 20 to 79 years with motor-incomplete cervical SCI with preexisting canal stenosis (American Spinal Injury Association [ASIA] Impairment Scale C; without fracture or dislocation) were included. Data were analyzed from September to November 2020., Interventions: Patients were randomized to undergo surgical treatment within 24 hours after admission or delayed surgical treatment after at least 2 weeks of conservative treatment., Main Outcomes and Measures: The primary end points were improvement in the mean ASIA motor score, total score of the spinal cord independence measure, and the proportion of patients able to walk independently at 1 year after injury., Results: Among 72 randomized patients, 70 patients (mean [SD] age, 65.1 [9.4] years; age range, 41-79 years; 5 [7%] women and 65 [93%] men) were included in the full analysis population (37 patients assigned to early surgical treatment and 33 patients assigned to delayed surgical treatment). Of these, 56 patients (80%) had data available for at least 1 primary outcome at 1 year. There was no significant difference among primary end points for the early surgical treatment group compared with the delayed surgical treatment group (mean [SD] change in ASIA motor score, 53.7 [14.7] vs 48.5 [19.1]; difference, 5.2; 95% CI, -4.2 to 14.5; P = .27; mean [SD] SCIM total score, 77.9 [22.7] vs 71.3 [27.3]; P = .34; able to walk independently, 21 of 30 patients [70.0%] vs 16 of 26 patients [61.5%]; P = .51). A mixed-design analysis of variance revealed a significant difference in the mean change in ASIA motor scores between the groups (F1,49 = 4.80; P = .03). The early surgical treatment group, compared with the delayed surgical treatment group, had greater motor scores than the delayed surgical treatment group at 2 weeks (mean [SD] score, 34.2 [18.8] vs 18.9 [20.9]), 3 months (mean [SD] score, 49.1 [15.1] vs 37.2 [20.9]), and 6 months (mean [SD] score, 51.5 [13.9] vs 41.3 [23.4]) after injury. Adverse events were common in both groups (eg, worsening of paralysis, 6 patients vs 6 patients; death, 3 patients vs 3 patients)., Conclusions and Relevance: These findings suggest that among patients with cervical SCI, early surgical treatment produced similar motor regain at 1 year after injury as delayed surgical treatment but showed accelerated recovery within the first 6 months. These exploratory results suggest that early surgical treatment leads to faster neurological recovery, which requires further validation., Trial Registration: ClinicalTrials.gov Identifier: NCT01485458; umin.ac.jp/ctr Identifier: UMIN000006780.

Introduction: Many articles have reported that the coronavirus disease 2019 (COVID-19) causes coagulation abnormalities and pulmonary thrombosis, contributing to a poorer prognosis. The study aimed to evaluate whether pre-admission anticoagulation and antiplatelet therapy prevented severe COVID-19 illness or not., Materials and Methods: We conducted a study to determine whether taking antiplatelet or anticoagulation agents before admission affected the severity on admission using a large nationwide cohort of hospitalized COVID-19 patients in Japan. We analyzed a large nationwide cohort of hospitalized COVID-19 patients in Japan from February 9 to July 31, 2020., Results and Conclusion: A total of 4265 patients from 342 facilities in Japan were included. Their use was associated with a slight reduction in the disease severity on admission in a propensity score-matched analysis which controlled for underlying diseases. However, this difference was not statistically significant., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Type 1 diabetes (T1D) is classified into three subtypes: acute-onset, slowly progressive, and fulminant T1D, according to the heterogeneity of clinical course in Japan. Although several cross-sectional databases of T1D have been reported, prospective longitudinal databases to investigate clinical outcomes are lacking in our country. Therefore, we herein construct multi-center prospective longitudinal database of the three subtypes of T1D, accompanied with genetic information and biobanking, which is named Japanese Type 1 Diabetes Database Study (TIDE-J). Inclusion criteria of this study are as follows: (1) the duration of T1D was less than 5 years, (2) the patients had one or more islet-related autoantibodies and/or fasting serum C-peptide levels were less than 1.0 ng/mL, (3) the patients could clearly understand the study consent in writing. In the TIDE-J, clinical data, including glycemic control, endogenous insulin secretion, islet-related autoantibodies, diabetic complications, and treatment, are collected annually using electric data collection system, which is named REDCap. Furthermore, HLA genotypes of each participant were analyzed at entry and the blood samples were stored for assessing exploratory markers and further genetic analysis annually. The TIDE-J certainly helps in revealing distinct clinical course of each T1D subtype. Moreover, this database may help in identifying novel markers for diagnosing each subtype of T1D and predicting clinical outcomes (including pancreatic beta cell function and disease severity) in patients., Competing Interests: Conflict of interestDaisuke Chujo received honorarium for lectures from Eli Lilly and Company; research funding from Novo Nordisk Pharma Ltd., and Sanofi K.K.; Akihisa Imagawa received honorarium for lectures from Astellas Pharma Inc.; clinical commissioned/joint research grant from Astra Zeneca, Soiken Inc., Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Merck KGaA, and Parexel International Inc.; research grant from Shionogi Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company, and Ono Pharmaceutical Co., Ltd.; Norio Abiru received honorarium for lectures from Novo Nordisk Pharma Ltd., Astellas Pharma Inc., and Eli Lilly and Company; research funding from Ono Pharmaceutical Co. Ltd., Bristol Myers Squibb, Taisho Pharmaceutical Co., Ltd., and Astellas Pharma Inc.; Takuya Awata received honorarium for lectures from Astellas Pharma Inc.; Hiroshi Ikegami received honorarium for lectures from Astellas Pharma Inc., Eli Lilly and Company, MSD K.K., Novo Nordisk Pharma Ltd., Novartis Pharma K.K., Sumitomo Dainippon Pharma Co., Ltd., and Terumo Corporation; donations from Abbott Japan Co., Ltd., LifeScan Japan K.K., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Pharma Ltd., Otsuka Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company. Akira Shimada received honorarium for lectures from Novo Nordisk Pharma Ltd., Eli Lilly and Company, and Sanofi K.K.; Other authors have no conflict of interest to declare., (© The Japan Diabetes Society 2021.)

We created dual interactive sites in a porous coordination network using a CuI cluster and a rotation-restricted ligand, tetra(3-pyridyl)phenylmethane (3-TPPM). The dual interactive sites of iodide and Cu ions can adsorb I 2 via four-step processes including two chemisorption processes. Initially, one I 2 molecule was physisorbed in a pore and successively chemisorbed on iodide sites of the pore surface, and then the next I 2 molecule was physisorbed and chemisorbed on Cu ions to form a cross-linked network. We revealed the four-step I 2 diffusion process by single-crystal X-ray structure determination and spectroscopic kinetic analysis.

Antihistamine medications have been suggested to elicit clinical features of restless legs syndrome. The available data are limited, particularly concerning periodic leg movements during sleep, which are common in restless legs syndrome and involve bursts of tibialis anterior electromyogram. Here, we tested whether the occurrence of tibialis anterior electromyogram bursts during non-rapid eye movement sleep is altered in histidine decarboxylase knockout mice with congenital histamine deficiency compared with that in wild-type control mice. We implanted six histidine decarboxylase knockout and nine wild-type mice to record neck muscle electromyogram, bilateral tibialis anterior electromyogram, and electroencephalogram during the rest (light) period. The histidine decarboxylase knockout and wild-type mice did not differ significantly in terms of sleep architecture. In both histidine decarboxylase knockout and wild-type mice, the distribution of intervals between tibialis anterior electromyogram bursts had a single peak for intervals < 10 s. The total occurrence rate of tibialis anterior electromyogram bursts during non-rapid eye movement sleep and the occurrence rate of the tibialis anterior electromyogram bursts separated by intervals < 10 s were significantly lower in histidine decarboxylase knockout than in wild-type mice. These data do not support the hypothesis that preventing brain histamine signalling may promote restless legs syndrome. Rather, the data suggest that limb movements during sleep, including those separated by short intervals, are a manifestation of subcortical arousal requiring the integrity of brain histamine signalling., (© 2020 European Sleep Research Society.)

Predicting the need for hospitalisation of patients with coronavirus disease 2019 (COVID-19) is important for preventing healthcare disruptions. This observational study aimed to use the COVID-19 Registry Japan (COVIREGI-JP) to develop a simple scoring system to predict respiratory failure due to COVID-19 using only underlying diseases and symptoms. A total of 6873 patients with COVID-19 admitted to Japanese medical institutions between 1 June 2020 and 2 December 2020 were included and divided into derivation and validation cohorts according to the date of admission. We used multivariable logistic regression analysis to create a simple risk score model, with respiratory failure as the outcome for young (18-39 years), middle-aged (40-64 years) and older (≥65 years) groups, using sex, age, body mass index, medical history and symptoms. The models selected for each age group were quite different. Areas under the receiver operating characteristic curves for the simple risk score model were 0.87, 0.79 and 0.80 for young, middle-aged and elderly derivation cohorts, and 0.81, 0.80 and 0.67 in the validation cohorts. Calibration of the model was good. The simple scoring system may be useful in the appropriate allocation of medical resources during the COVID-19 pandemic.

We prepared coordination networks that show relatively strong emission with through-space charge-transfer (TSCT) transitions. Thermolysis of a kinetically assembled network with Cu 2 Br 2 dimer connectors, which was assembled from a CuBr cluster and the T d ligand 4-4-tetrapyridyltetraphenylmethane (4-TPPM), generated a highly luminescent network composed of Cu + connectors and 4-TPPM linkers with CuBr 2 - guests. We clarified that the electronic transitions in this network include TSCT in addition to the typical metal-ligand charge transfer (MLCT) observed in conventional Cu complexes.

Introduction: Most of the currently used prognostic models for COVID-19 are based on Western cohorts, but it is unknown whether any are applicable to patients with COVID-19 in Japan., Methods: This retrospective cohort study included 160 patients with COVID-19 who were admitted to the National Center for Global Health and Medicine between January 26, 2020 and July 25, 2020. We searched PubMed for prognostic models for COVID-19. The predicted outcome was initiation of respiratory support or death. Performance of the candidate models was evaluated according to discrimination and calibration. We recalibrated the intercept of each model with our data. We also updated each model by adding β2-microglobulin (β2MG) to the model and recalculating the intercept and the coefficient of β2MG., Results: Mean patient age was 49.8 years, 68% were male, 88.7% were Japanese. The study outcomes occurred in 15 patients, including two deaths. Two-hundred sixty-nine papers were screened, and four candidate prognostic models were assessed. The model of Bartoletti et al. had the highest area under receiver operating characteristic curve (AUC) (0.88; 95% confidence interval 0.81-0.96). All four models overestimated the probability of occurrence of the outcome. None of the four models showed statistically significant improvement in AUCs by adding β2MG., Conclusions: Our results suggest that the existing prediction models for COVID-19 overestimate the probability of occurrence of unfavorable outcomes in a Japanese cohort. When applying a prediction model to a different cohort, it is desirable to evaluate its performance according to the prevalent health situation in that region., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: To investigate the risk factors contributing to severity on admission. Additionally, risk factors of worst severity and fatality were studied. Moreover, factors were compared based on three points: early severity, worst severity and fatality., Design: An observational cohort study using data entered in a Japan nationwide COVID-19 inpatient registry, COVIREGI-JP., Setting: As of 28 September 2020, 10480 cases from 802 facilities have been registered. Participating facilities cover a wide range of hospitals where patients with COVID-19 are admitted in Japan., Participants: Participants who had a positive test result on any applicable SARS-CoV-2 diagnostic tests were admitted to participating healthcare facilities. A total of 3829 cases were identified from 16 January to 31 May 2020, of which 3376 cases were included in this study., Primary and Secondary Outcome Measures: Primary outcome was severe or nonsevere on admission, determined by the requirement of mechanical ventilation or oxygen therapy, SpO2 or respiratory rate. Secondary outcome was the worst severity during hospitalisation, judged by the requirement of oxygen and/orinvasive mechanical ventilation/extracorporeal membrane oxygenation., Results: Risk factors for severity on admission were older age, men, cardiovascular disease, chronic respiratory disease, diabetes, obesity and hypertension. Cerebrovascular disease, liver disease, renal disease or dialysis, solid tumour and hyperlipidaemia did not influence severity on admission; however, it influenced worst severity. Fatality rates for obesity, hypertension and hyperlipidaemia were relatively lower., Conclusions: This study segregated the comorbidities influencing severity and death. It is possible that risk factors for severity on admission, worst severity and fatality are not consistent and may be propelled by different factors. Specifically, while hypertension, hyperlipidaemia and obesity had major effect on worst severity, their impact was mild on fatality in the Japanese population. Some studies contradict our results; therefore, detailed analyses, considering in-hospital treatments, are needed for validation., Trial Registration Number: UMIN000039873. https://upload.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000045453., Competing Interests: Competing interests: HO reports personal fees as a statistician and as an external consultant for clinical trials from EPS International, outside the submitted work., (© 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.)

The loss of hypothalamic neurons that produce wake-promoting orexin (hypocretin) neuropeptides is responsible for narcolepsy type 1 (NT1). While the number of histamine neurons is increased in patients with NT1, results on orexin-deficient mouse models of NT1 are inconsistent. On the other hand, the effect of histamine deficiency on orexin neuron number has never been tested on mammals, even though histamine has been reported to be essential for the development of a functional orexin system in zebrafish. The aim of this study was to test whether histamine neurons are increased in number in orexin-deficient mice and whether orexin neurons are decreased in number in histamine-deficient mice. The hypothalamic neurons expressing L-histidine decarboxylase (HDC), the histamine synthesis enzyme, and those expressing orexin A were counted in four orexin knock-out mice, four histamine-deficient HDC knock-out mice, and four wild-type C57BL/6J mice. The number of HDC-positive neurons was significantly higher in orexin knock-out than in wild-type mice (2,502 ± 77 vs. 1,800 ± 213, respectively, one-tailed t -test, P = 0.011). Conversely, the number of orexin neurons was not significantly lower in HDC knock-out than in wild-type mice (2,306 ± 56 vs. 2,320 ± 120, respectively, one-tailed t -test, P = 0.459). These data support the view that orexin peptide deficiency is sufficient to increase histamine neuron number, supporting the involvement of the histamine waking system in the pathophysiology of NT1. Conversely, these data do not support a significant role of histamine in orexin neuron development in mammals., 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 © 2021 Berteotti, Lo Martire, Alvente, Bastianini, Bombardi, Matteoli, Ohtsu, Lin, Silvani and Zoccoli.)

Histidine decarboxylase (HDC), histamine synthase, is expressed in hematopoietic stem cells and in lineage-committed progenitors in the bone marrow (BM). However, the role of histamine in hematopoiesis is not well described. To evaluate the role of histamine in hematopoiesis, we analyzed the changes in HDC expression at hematopoietic sites, the BM, spleen, and liver of 2-, 3-, and 6-week-old wild-type mice. We also performed morphological analyses of the hematopoietic sites using HDC-deficient (HDC-KO) mice. In wild-type adults, HDC expression in the BM was higher than that in the spleen and liver and showed an age-dependent increase. Histological analysis showed no significant change in the adult BM and spleen of HDC-KO mice compared to wild-type mice. In the liver, HDC expression was temporarily increased at 3 weeks and decreased at 6 weeks of age. Morphological analysis of the liver revealed more numerous hematopoietic colonies and megakaryocytes in HDC-KO mice compared to wild-type mice at 2 and 3 weeks of age, whereas no changes were observed in adults. Most of these hematopoietic colonies consisted of B220-positive B-lymphocytes and TER119-positive erythroblasts and were positive for the cell proliferation marker PCNA. Notably, these hematopoietic colonies declined in HDC-KO mice upon N-acetyl histamine treatment. A significant increase in the expression of hematopoiesis-related cytokines, Il3, Il7, Epo, Gcsf, and Cxcl12 mRNA was observed in the liver of 3-week-old HDC-KO mice compared to wild-type mice. These results suggest that histamine-deficiency may maintain an microenvironment suitable for hematopoiesis by regulating hematopoiesis-related cytokine expression in the liver of postnatal mice., (© 2021 American Association for Anatomy.)

Background: Wearing slippers may increase the risk of tripping while crossing obstacles, regardless of age. This is because slippers are more likely to leave the feet and come into contact with obstacles. However, how wearing slippers affects the movement strategy while crossing over an obstacle has not been clarified., Research Question: How does wearing slippers affect the movement strategy while crossing over an obstacle?, Methods: Thirty healthy young adults crossed over an obstacle using a comfortable speed under two conditions: barefoot and wearing slippers. The moment when the leading or trailing limb was crossing the obstacle was defined as obstacle lead (OL) or obstacle trail (OT), respectively. The margin of stability (MoS) as a measure of stability was measured at OL and OT. Toe clearance and lower limb joint angles of the leading limb were measured at OL, and those of the trailing limb were measured at OT., Results: Wearing slippers increased toe clearance and flexed the hip and knee joints, regardless of the crossing event (OL, OT). However, the ankle joint angle did not change between footwear conditions at OL and was significantly dorsiflexed in the slippered condition at OT. In addition, the MoS did not change between footwear conditions at OL and increased significantly in the slippered condition at OT., Significance: The increase of the MoS at OT when wearing slippers is probably a conservative strategy to reduce the risk of falling forward when a trip occurs. More attention to avoiding tripping likely caused the ankle to dorsiflex and increased toe clearance. This conservative strategy and increased attention are most likely due to the slippers coming off easily. Since these strategies are probably safety measures to prevent tripping, slippers may not be appropriate footwear in terms of tripping risk., (Copyright © 2021 Elsevier B.V. All rights reserved.)

One-dimensional (1D) organic chiral supramolecules have received a great deal of attention for their promising applications in chiral recognition systems, chemical sensors, catalysts, and optoelectronics. Compared to modifications at the imide position of a perylene diimide (PDI), few studies have explored bay substitution of chiral PDIs and their self-assemblies into 1D nanomaterials. Herein, we describe the synthesis of three bay-substituted PDIs and explore the effects of bay substitution on supramolecular chirality by examining circular dichroism spectra and the optoelectronic performance of chiral PDI nanomaterials in phototransistors. Among the three fabricated self-assemblies, nanomaterials based on ( R )-CN-CPDI-Ph exhibited the highest electron mobility of 0.17 cm 2 V -1 s -1 , a low threshold voltage of -1 V, and enhanced optoelectronic performance. For example, the photoresponsivity and external quantum efficiency of ( R )-CN-CPDI-Ph assemblies were 4-fold higher than those of ( R )-2Br-CPDI-Ph and ( R )-2F-CPDI-Ph. All three nanomaterials exhibited fast switching speeds compared with previously reported N-substituted PDIs, suggesting that bay substitution can be an effective means of achieving rapid photoswitching. A comprehensive study using density functional theory calculations and crystal analyses revealed that the enhanced optoelectronic performance of ( R )-CN-CPDI-Ph nanomaterials is related to the substitution of CN at the bay position of PDI. This minor change provides simultaneous improvements in electron injectability and structural order. Our findings demonstrate that bay substitution can significantly impact the self-assembly, supramolecular chirality, and optoelectronic properties of PDI nanomaterials.

Histidine decarboxylase (HDC), a histamine synthase, is expressed in various hematopoietic cells and is induced by hematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF). We previously showed that nitrogen-containing bisphosphonate (NBP)-treatment induces extramedullary hematopoiesis via G-CSF stimulation. However, the function of HDC in NBP-induced medullary and extramedullary hematopoiesis remains unclear. Here, we investigated changes in hematopoiesis in wild-type and HDC-deficient (HDC-KO) mice. NBP treatment did not induce anemia in wild-type or HDC-KO mice, but did produce a gradual increase in serum G-CSF levels in wild-type mice. NBP treatment also enhanced Hdc mRNA expression and erythropoiesis in the spleen and reduced erythropoiesis in bone marrow and the number of vascular adhesion molecule 1 (VCAM-1)-positive macrophages in wild-type mice, as well as increased the levels of hematopoietic progenitor cells and proliferating cells in the spleen and enhanced expression of bone morphogenetic protein 4 (Bmp4), CXC chemokine ligand 12 (Cxcl12), and hypoxia inducible factor 1 (Hif1) in the spleen. However, such changes were not observed in HDC-KO mice. These results suggest that histamine may affect hematopoietic microenvironments of the bone marrow and spleen by changing hematopoiesis-related factors in NBP-induced extramedullary hematopoiesis.

Luminescent silver(I) coordination polymers having a {Ag 2 (μ-X) 2 } rhombic core (X = I, Br) were prepared using pyrazine (pyz), methylpyrazine (Mepyz), and aminopyrazine (ampyz) as bridging ligands. Photophysical measurements show that the complexes were strongly luminescent in the solid state at room temperature; further, the emissive excited state of the pyz and Mepyz complexes was a triplet charge-transfer ( 3 CT) excited state, similar to that of their copper(I) congeners, whereas that of the ampyz complex was a intraligand ( 3 IL) excited state. The energy of the 3 CT excited state of a silver halogenido complex was revealed to be ca. 5000 cm -1 higher than that of the corresponding copper complex.

The aim of this study was to evaluate the effects of dietary brown rice on the growth performance, systemic oxidative status, and splenic inflammatory responses of broiler chickens under both thermo-neutral and chronic heat stress conditions. Forty 12-day-old male broiler chickens (ROSS 308) were randomly assigned to two groups and fed either a control diet (corn-based) or a brown rice-based diet. After seven days (19 days old), both groups were randomly divided into two sub-groups ( n =10), one of which was exposed to heat stress (33°C for 14 days), while the other was maintained at 24°C. Heat exposure reduced the body weight gain and feed intake ( p <0.01) of both groups. In terms of oxidative plasma states, heat exposure reduced the glutathione peroxidase activity and increased the ceruloplasmin content, while the 2-thiobarbituric acid reactive substance and reduced glutathione levels were not affected adversely. Heat exposure activated the immune responses, as evidenced by increased plasma immunoglobin levels, and altered splenic immune-related gene expressions including heat shock proteins, toll-like receptor 4, and interleukin-12. Under both thermo-neutral and heat stress conditions, dietary brown rice improved the growth performance, decreased the immunoglobulin levels, and down-regulated the expression of splenic immune-related genes of broilers, although their systemic oxidative status was not affected. Dietary brown rice should be considered as a valuable component of broiler chicken feeds subjected to both thermo-neutral and heat stress conditions. The positive effects of brown rice on bird performance may be associated with the modulation of the immune responses, as reflected by the decreased production of immunoglobulins and altered splenic immune-related gene expression., Competing Interests: The authors declare no conflict of interest.