Exploring the genetic diversity of the Japanese population: Insights from a large-scale whole genome sequencing analysis.

The Japanese archipelago is a terminal location for human migration, and the contemporary Japanese people represent a unique population whose genomic diversity has been shaped by multiple migrations from Eurasia. We analyzed the genomic characteristics that define the genetic makeup of the modern Japanese population from a population genetics perspective from the genomic data of 9,287 samples obtained by high-coverage whole-genome sequencing (WGS) by the National Center Biobank Network. The dataset comprised populations from the Ryukyu Islands and other parts of the Japanese archipelago (Hondo). The Hondo population underwent two episodes of population decline during the Jomon period, corresponding to the Late Neolithic, and the Edo period, corresponding to the Early Modern era, while the Ryukyu population experienced a population decline during the shell midden period of the Late Neolithic in this region. Haplotype analysis suggested increased allele frequencies for genes related to alcohol and fatty acid metabolism, which were reported as loci that had experienced positive natural selection. Two genes related to alcohol metabolism were found to be 12,500 years out of phase with the time when they began to increase in the allele frequency; this finding indicates that the genomic diversity of Japanese people has been shaped by events closely related to agriculture and food production.

Characteristics of hospitalized COVID-19 patients with other respiratory pathogens identified by rapid diagnostic test.

Rapid diagnostic tests (RDTs) significantly impact disease treatment strategy. In Japan, information on the use of RDTs for patients with COVID-19 is limited. Here, we aimed to investigate the RDT implementation rate, pathogen detection rate, and clinical characteristics of patients positive for other pathogens by using COVIREGI-JP, a national registry of hospitalized patients with COVID-19. A total of 42,309 COVID-19 patients were included. For immunochromatographic testing, influenza was the most common (n = 2881 [6.8%]), followed by Mycoplasma pneumoniae (n = 2129 [5%]) and group A streptococcus (GAS) (n = 372 [0.9%]). Urine antigen testing was performed for 5524 (13.1%) patients for S. pneumoniae and for 5326 patients (12.6%) for L. pneumophila. The completion rate of M. pneumonia loop-mediated isothermal amplification (LAMP) testing was low (n = 97 [0.2%]). FilmArray RP was performed in 372 (0.9%) patients; 1.2% (36/2881) of patients were positive for influenza, 0.9% (2/223) for the respiratory syncytial virus (RSV), 9.6% (205/2129) for M. pneumoniae, and 7.3% (27/372) for GAS. The positivity rate for urine antigen testing was 3.3% (183/5524) for S. pneumoniae and 0.2% (13/5326) for L. pneumophila. The positivity rate for LAMP test was 5.2% (5/97) for M. pneumoniae. Five of 372 patients (1.3%) had positive FilmArray RP, with human enterovirus being the most frequently detected (1.3%, 5/372). The characteristics of patients with and without RDTs submission and positive and negative results differed for each pathogen. RDTs remain an important diagnostic tool in patients with COVID-19 in whom coinfection with other pathogens needs to be tested based on clinical evaluation.

Comorbidities as Risk Factors for Severe Disease in Hospitalized Elderly COVID-19 Patients by Different Age-Groups in Japan.

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.

Predicting respiratory failure for COVID-19 patients in Japan: a simple clinical score for evaluating the need for hospitalisation.

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.

Serum Lactate Dehydrogenase Level One Week after Admission Is the Strongest Predictor of Prognosis of COVID-19: A Large Observational Study Using the COVID-19 Registry Japan.

Clinical features of COVID-19 are diverse, and a useful tool for predicting clinical outcomes based on clinical characteristics of COVID-19 is needed. This study examined the laboratory values and trends that influence mortality in hospitalised COVID-19 patients. Data on hospitalised patients enrolled in a registry study in Japan (COVID-19 Registry Japan) were obtained. Patients with records on basic information, outcomes, and laboratory data on the day of admission (day 1) and day 8 were included. In-hospital mortality was set as the outcome, and associated factors were identified by multivariate analysis using the stepwise method. A total of 8860 hospitalised patients were included. The group with lactate dehydrogenase (LDH) levels >222 IU/L on day 8 had a higher mortality rate compared to the group with LDH levels ≤222 IU/L. Similar results were observed in subgroups formed by age, body mass index (BMI), underlying disease, and mutation type, except for those aged <50 years. When age, sex, BMI, underlying disease, and laboratory values on days 1 and 8 were tested for factors strongly associated with in-hospital mortality, LDH on day 8 was most strongly associated with mortality. LDH level on day 8 was the strongest predictor of in-hospital mortality in hospitalised COVID-19 patients, indicating its potential usefulness in post-treatment decision-making in severe COVID-19 cases.

Evaluation of the representativeness of data in the COVID-19 Registry Japan during the first six waves of the epidemic.

The COVID-19 Registry Japan (COVIREGI-JP), a registry of patients hospitalized with coronavirus disease (COVID-19), contains the largest national COVID-19 inpatient population. Since COVIREGI-JP invites voluntary participation by facilities, selection bias is inevitable. The current study examined the representativeness of COVIREGI-JP data in comparison to open-source national data. The number of infections and deaths among hospitalized COVID-19 patients in COVIREGI-JP were compared to those in national data recorded during the six waves of the COVID-19 epidemic until March 6, 2022. During the period studied, patients in COVIREGI-JP represented 1% of the total COVID-19 cases according to national data; the proportion was high during the first wave (32.7%) and tended to decrease, especially after the fourth wave. The overall proportion of patients from each region varied from 0.8% to 2.5%, but case fatality rates in COVIREGI-JP tended to be higher than those in the national data, with the exception of a few waves, in several regions. The difference was smallest during the first wave. Although COVIREGI-JP consistently registered cases from all regions of the country, the proportion tended to decline after the beginning of the epidemic. Given the epidemiological persistence and the ever-changing epidemiology of COVID-19, continued case registration and data utilization in COVIREGI-JP is desirable, although selection bias in COVIREGI-JP registration of cases should be carefully interpreted.

Effectiveness of remdesivir in hospitalized nonsevere patients with COVID-19 in Japan: A large observational study using the COVID-19 Registry Japan.

OBJECTIVES: To evaluate the effectiveness of remdesivir in the early stage of nonsevere COVID-19. Although several randomized controlled trials have compared the effectiveness of remdesivir with that of a placebo, there is limited evidence regarding its effect in the early stage of nonsevere COVID-19 cases. METHODS: We evaluated the effectiveness of remdesivir in the early stage of nonsevere COVID-19 using the COVID-19 Registry Japan, a nationwide registry of hospitalized patients with COVID-19 in Japan. Two regimens ("start remdesivir" therapy within 4 days from admission versus no remdesivir during hospitalization) among patients without the need for supplementary oxygen therapy were compared by a 3-step processing (cloning, censoring, and weighting) method. The primary outcome was a supplementary oxygen requirement during hospitalization. Secondary outcomes were 30-day in-hospital mortality and the risk of invasive mechanical ventilation or extracorporeal membrane oxygenation (IMV/ECMO). The data of 12,487 cases met our inclusion criteria. The "start remdesivir" regimen showed a lower risk of supplementary oxygen requirement (hazard ratio [HR]: 0.850, 95% confidence interval [CI]: 0.798-0.906, p value < 0.001). Both 30-day in-hospital mortality and risk of IMV/ECMO introduction were not significantly different between the 2 regimens (HRs: 1.04 and 0.983, 95% CI: 0.980-1.09 and 0.906-1.07, p values: 0.210 and 0.678, respectively). CONCLUSIONS: Remdesivir might reduce the risk of oxygen requirement during hospitalization in the early stage of COVID-19; however, it had no positive effect on the clinical outcome and reduction in IMV/ECMO requirement.

Clinical characteristics of the first three waves of hospitalised patients with COVID-19 in Japan prior to the widespread use of vaccination: a nationwide observational study.

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].

Evaluation of the efficacy of anticoagulation therapy in reducing mortality in a nationwide cohort of hospitalized patients with coronavirus disease in Japan.

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.

ProTherm and ProNIT: thermodynamic databases for proteins and protein-nucleic acid interactions.

ProTherm and ProNIT are two thermodynamic databases that contain experimentally determined thermodynamic parameters of protein stability and protein-nucleic acid interactions, respectively. The current versions of both the databases have considerably increased the total number of entries and enhanced search interface with added new fields, improved search, display and sorting options. As on September 2005, ProTherm release 5.0 contains 17,113 entries from 771 proteins, retrieved from 1497 scientific articles (approximately 20% increase in data from the previous version). ProNIT release 2.0 contains 4900 entries from 273 research articles, representing 158 proteins. Both databases can be queried using WWW interfaces. Both quick search and advanced search are provided on this web page to facilitate easy retrieval and display of the data from these databases. ProTherm is freely available online at http://gibk26.bse.kyutech.ac.jp/jouhou/Protherm/protherm.html and ProNIT at http://gibk26.bse.kyutech.ac.jp/jouhou/pronit/pronit.html.

The Diamond STING server.

Diamond STING is a new version of the STING suite of programs for a comprehensive analysis of a relationship between protein sequence, structure, function and stability. We have added a number of new functionalities by both providing more structure parameters to the STING Database and by improving/expanding the interface for enhanced data handling. The integration among the STING components has also been improved. A new key feature is the ability of the STING server to handle local files containing protein structures (either modeled or not yet deposited to the Protein Data Bank) so that they can be used by the principal STING components: (Java)Protein Dossier ((J)PD) and STING Report. The current capabilities of the new STING version and a couple of biologically relevant applications are described here. We have provided an example where Diamond STING identifies the active site amino acids and folding essential amino acids (both previously determined by experiments) by filtering out all but those residues by selecting the numerical values/ranges for a set of corresponding parameters. This is the fundamental step toward a more interesting endeavor-the prediction of such residues. Diamond STING is freely accessible at http://sms.cbi.cnptia.embrapa.br and http://trantor.bioc.columbia.edu/SMS.

ProTherm, version 4.0: thermodynamic database for proteins and mutants.

Release 4.0 of ProTherm, thermodynamic database for proteins and mutants, contains approximately 14,500 numerical data (approximately 450% of the first version) of several thermodynamic parameters along with experimental methods and conditions, and structural, functional and literature information. The sequence and structural information of proteins is connected with thermodynamic data through links between entries in Protein Data Bank, Protein Information Resource and SWISS-PROT and the data in ProTherm. We have separated the Gibbs free energy change obtained at extrapolated temperature from the data on denaturation temperature measured by the thermal denaturation method. We have added the statistics of amino acid replacements and links to homologous structures to each protein. Further, we have improved the search and display options to enhance search capability through the web interface. ProTherm is freely available at http://gibk26. bse.kyutech.ac.jp/jouhou/Protherm/protherm.html.

Light-harvesting heptadecameric porphyrin assemblies.

New porphyrin assemblies containing 17 porphyrin molecules are constructed by using free base TPP-type porphyrins having eight pyrazine moieties 1. Spectroscopic titration of dimeric [meso-tetrakis(2-carboxy-4-nonylphenyl)porphyrinato]zinc(II) 2 with these porphyrins shows that the processes of the formation of the heptadecameric porphyrin assemblies may be analyzed as eight independent equilibrium processes with an identical binding constant. All binding constants are larger than 5 x 107 M-1 which is the determinable upper limit of the present titration method. In all cases, the fluorescence spectrum of the 1:8 mixture of 1 and 2 consists of the major fluorescence of 1 and the minor one of 2.pyrazine complex even in the presence of the large excess of the antenna pigments. The observed spectra are well reconstructed by the form of faF1 + fbF2, where F1 and F2 are the fluorescence of 1 and the 2.pyrazine complex measured separately at the corresponding concentrations. Interestingly, the general trend that values of fa are nearly equal to those of r564 x (1 - fb) in all cases is found, where r564 is the absorption ratios of the 2.pyrazine moiety and the central free base porphyrin in the assemblies at 564 nm. The observation indicates the excitation of the central porphyrin is directly enhanced by the absorption of the antenna pigments even in such large scale assemblies. Thus, the antenna effect for 1 having largest r564 results in 77 times fluorescence enhancement of the central free base porphyrin. The systems also show interesting dependency of energy-transfer efficiencies on the topological arrangement of the antenna elements.