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We recently reported a method for recovering and quantifying residual proteins bound to surfaces of various medical instruments via thermal coagulation under neutral pH and room temperature. The method effectively recovered and solubilised coagulated proteins at high temperatures in dry and humid conditions, with a protein recovery rate of > 90%. This study validated the previous method by comparing residual protein recovery from test samples using a conventional extraction solution (1% SDS, [pH 11.0]) and proposed solution (1% SDS, 10 mM TCEP, and 10 mM HEPES [pH 7.0]). To mimic soiled medical equipment, pseudo-blood-contaminated stainless steel plates were prepared. Residual protein was recovered using conventional and proposed solutions under varying temperature and humidity conditions. Quantitative protein recovery limits were determined at nine facilities. Compared with the conventional solution, the proposed solution recovered proteins more effectively from samples processed at temperatures > 60 °C. However, low recovery rates were observed for samples processed at 95 °C, possibly owing to differences in protein adhesion due to sample and plate-surface properties. Our findings present a method for quantifying residual proteins on medical instruments exposed to high temperatures during use or disinfection. Further studies should standardise test soiling conditions, materials, and solutions to evaluate cleaning methods., (© 2024. The Author(s).)

Diagnosis improvement requires physician-nurse collaboration. This study explored nurses' concerns regarding physicians' diagnoses and how they were communicated to physicians. This cross-sectional study, employing a web-based questionnaire, included nurses registered on Japan's largest online media site from June 26, 2023, to July 31, 2023. The survey inquired whether participants felt concerned about a physician's diagnosis within a month, if they communicated their concerns once they arose, and, if not, their reasons. The reasons for not being investigated were also examined. The nurses' frequency of feeling concerned about a physician's diagnosis and the barriers to communicating these concerns to the physician were evaluated. Overall, 430 nurses answered the survey (female, 349 [81.2%]; median age, 45 [35-51] years; median years of experience, 19 [12-25]). Of the nurses, 61.2% experienced concerns about a physician's diagnosis within the past month; 52.5% felt concerned but did not communicate this to the physician. The most common reasons for not communicating included concern about the physician's pride, being ignored when communicating, and the nurse not believing that a diagnosis should be made. Our results highlight the need to foster psychologically safe workplaces for nurses and create educational programs encouraging nurse involvement in diagnosis., (© 2024. The Author(s).)

A lack of adherence to long-term antiretroviral therapy may impact viral suppression. The current study examined the relationship between medication adherence and clinical outcomes in people with human immunodeficiency virus infection (PWH) receiving bictegravir, emtricitabine, and tenofovir alafenamide fumarate (B/F/TAF). A retrospective cohort study using two Japanese claims databases was conducted. Adherence was measured by the proportion of days covered (PDC). Patients were grouped into 3 PDC category and persistence was estimated by Kaplan-Meier method. Cox regression analysis was performed to investigate whether the PDC was associated with treatment discontinuation. Among 952 patients, 820 (86.1%), 95 (10.0%), and 37 (3.9%) patients were grouped into the PDC ≥ 90%, 80- < 90%, and < 80% groups, respectively. Across all PDC groups, more than 90% of patients who received B/F/TAF were receiving treatment at 1 year. There was no significant difference in the risk of discontinuation between the lower PDC groups (80- < 90% and < 80%) and the PDC ≥ 90% group (0.400 [0.096, 1.661]; 2.244 [0.663, 7.594], hazard ratio [95% confidence interval], respectively). A drug resistance test was implemented for 15 patients, none of whom discontinued B/F/TAF after the test. The results suggest that events that could cause discontinuation, such as virologic failure, were not associated with PDC., (© 2024. The Author(s).)

Identifying the types of exercise that enhance cerebral blood flow is crucial for developing exercise programs that enhance cognitive function. Nevertheless, few studies have explored the amount of light-intensity, short-duration exercises that individuals can easily perform on cerebral blood flow, particularly in children. We examined the effects of these exercises on the hemodynamics of the prefrontal cortex (PFC) using functional near-infrared spectroscopy. Participants comprised 41 children (aged 12.1 ± 1.5 years, 37% female) who engaged in seven light-intensity exercises, with each movement performed in two patterns lasting 10 or 20 s. Changes in oxygenated hemoglobin (oxy-Hb) levels at rest and during exercise were compared using analysis of covariance, with sex and age as covariates. Significant increases in oxy-Hb were observed in multiple regions of the PFC during all forms of exercise (including dynamic and twist stretching [66.6%, 8/12 regions, η 2  = 0.07-0.27], hand and finger movements [75.0%, 9/12 regions, η 2  = 0.07-0.16], and balance exercises (100.0%, 6/6 regions, η 2  = 0.13-0.25]), except for static stretching with monotonic movements. This study implies that short-duration, light-intensity exercises, provided that they entail a certain degree of cognitive and/or physical demands, can activate the PFC and increase blood flow., (© 2024. The Author(s).)

Mycobacteroides (Mycobacterium) abscessus, which causes a variety of infectious diseases in humans, is becoming detected more frequently in clinical specimens as cases are spreading worldwide. Taxonomically, M. abscessus is composed of three subspecies of M. abscessus subsp. abscessus, M. abscessus subsp. bolletii, and M. abscessus subsp. massiliense, with different susceptibilities to macrolides. In order to identify rapidly these three subspecies, we determined useful biomarker proteins, including ribosomal protein L29, L30, and hemophore-related protein, for distinguishing the subspecies of M. abscessus using the matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) profiles. Thirty-three clinical strains of M. abscessus were correctly identified at the subspecies-level by the three biomarker protein peaks. This study ultimately demonstrates the potential of routine MALDI-MS-based laboratory methods for early identification and treatment for M. abscessus infections., (© 2024. The Author(s).)

The efficacy of second-line chemotherapy in patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) is unclear. This study aimed to evaluate the efficacy of second-line chemotherapy in patients with pulmonary LCNEC. We retrospectively reviewed patients with pulmonary LCNEC or possible LCNEC (pLCNEC) who received platinum-based chemotherapy as the first-line treatment. Among these patients, we evaluated the efficacy of second-line treatment by comparing patients with small cell lung cancer (SCLC group). Of the 61 patients with LCNEC or pLCNEC (LCNEC group) who received first-line chemotherapy, 39 patients were treated with second-line chemotherapy. Among the 39 patients, 61.5% received amrubicin monotherapy. The median progression-free survival (PFS) and overall survival (OS) in the LCNEC groups were 3.3 and 8.3 months, respectively. No significant differences in the PFS (hazard ratio [HR]: 0.924, 95% confidence interval [CI] 0.647-1.320; P = 0.664) and OS (HR: 0.926; 95% CI 0.648-1.321; P = 0.670) were observed between the LCNEC and SCLC groups. In patients treated with amrubicin, the PFS (P = 0.964) and OS (P = 0.544) were not different between both the groups. Second-line chemotherapy, including amrubicin, may be considered as a treatment option for patients with pulmonary LCNEC., (© 2024. The Author(s).)

To investigate the association between lactate metabolism and glaucoma, we conducted a multi-institutional cross-sectional clinical study and a retinal metabolomic analysis of mice with elevated intraocular pressure (IOP) induced by intracameral microbead injection. We compared lactate concentrations in serum and aqueous humor in age-matched 64 patients each with primary open-angle glaucoma (POAG) and cataract. Neither serum nor aqueous humor lactate concentrations differed between the two groups. Multiple regression analysis revealed that only body mass index showed a significant positive correlation with serum and aqueous humor lactate concentration in POAG patients (r s  = 0.376, P = 0.002, and r s  = 0.333, P = 0.007, respectively), but not in cataract patients. L-Lactic acid was one of the most abundantly detected metabolites in mouse retinas with gas chromatography and mass spectrometry, but there were no significant differences among control, 2-week, and 4-week IOP elevation groups. After 4 weeks of elevated IOP, D-glucose and L-glutamic acid ranked as the top two for a change in raised concentration, roughly sevenfold and threefold, respectively (ANOVA, P = 0.004; Tukey-Kramer, P < 0.05). Glaucoma may disrupt the systemic and intraocular lactate metabolic homeostasis, with a compensatory rise in glucose and glutamate in the retina., (© 2024. The Author(s).)

Antibody tests are used as surveillance tools for informing health policy making. However, results may vary by type of antibody assay and timing of sample collection following infection. Long-term longitudinal cohort studies on antibody assay seropositivity have remained limited, especially among Asian populations. Using blood samples obtained at health physicals (2020-2022) of healthcare workers (mass vaccinated with mRNA COVID-19 vaccines) at a Japanese medical center, we measured N-specific antibodies using two commercially available systems. Roche Elecsys Anti-SARS-CoV-2 measures total antibodies and Abbott Alinity SARS-CoV-2 IgG measures only IgG. Among 2538 participants, seroprevalence was found to be 16.6% via total antibody assay versus 12.9% by IgG-only (including grayzone) by mid-June 2022. For 219 cases with a previous PCR-confirmed infection, positivity was 97.3% using total antibody assay versus 76.3% using IgG-only assay at the 2022 health physical. Using PCR positive test date as day 0, while the positivity of the total antibody assay was retained for the entire study period (until more than 24-months post-infection), the IgG-only assay's positivity declined after month 4. The Mantel-Haenszel test found a significant difference in the two assays' seropositivity, between stratified groups of "within 3 months" and "4 months or more" from infection (P < 0.001). Our study found significant differences in seropositivity over time of total antibody versus IgG-only assays, suggesting an optimal assay for retaining sensitivity over the entire infection period when designing seroprevalence studies., (© 2024. The Author(s).)

Zinc deficiency, affecting more than 2 billion people globally, poses a significant public health burden due to its numerous unfavorable effects, such as impaired immune function, taste and smell disorders, pneumonia, growth retardation, visual impairment, and skin disorders. Despite its critical role, extensive large-scale studies investigating the correlation between patient characteristics and zinc deficiency still need to be completed. We conducted a retrospective, cross-sectional observational study using a nationwide Japanese claims database from January 2019 to December 2021. The study population included 13,100 patients with available serum zinc concentration data, excluding individuals under 20 and those assessed for zinc concentrations after being prescribed zinc-containing medication. Significant associations with zinc deficiency were noted among older adults, males, and inpatients. Multivariate analysis, adjusting for age and sex, indicated significant associations with comorbidities, including pneumonitis due to solids and liquids with an adjusted Odds Ratio (aOR) of 2.959; decubitus ulcer and pressure area (aOR 2.403), sarcopenia (aOR 2.217), COVID-19 (aOR 1.889), and chronic kidney disease (aOR 1.835). Significant association with medications, including spironolactone (aOR 2.523), systemic antibacterials (aOR 2.419), furosemide (aOR 2.138), antianemic preparations (aOR 2.027), and thyroid hormones (aOR 1.864) were also found. These results may aid clinicians in identifying patients at risk of zinc deficiency, potentially improving care outcomes., (© 2024. The Author(s).)

Despite Japan's high vaccination coverage, daily numbers of new COVID-19 cases have been high. However, studies on the seroprevalence among Japanese people and the causative factors for rapid spread have remained limited. In this study, we aimed to examine the seroprevalence and associated factors in healthcare workers (HCWs) of a medical center in Tokyo using blood samples drawn at annual check-ups from 2020 to 2022. We found that of the 3,788 HCWs in 2022 (by mid-June), 669 were seropositive for N-specific antibodies (tested by Roche Elecsys Anti-SARS-CoV-2 assay); the seroprevalence surged from 0.3% in 2020 and 1.6% in 2021 to 17.7% in 2022. Notably, our study found 325 (48.6%; 325/669) cases were infected without awareness. Among those with a previously PCR-confirmed SARS-CoV-2 infection during the past three years, 79.0% (282/357) were found after January 2022, after the Omicron variant was first detected in Tokyo at the end of 2021. This study indicates the fast spread of the SARS-CoV-2 among HCWs during the Omicron surge in Japan. The high percentage of infection without awareness may be a key driving factor causing rapid person-to-person transmission, as shown in this medical center with high vaccination coverage and strict infection control measures., (© 2023. The Author(s).)

Mycobacterium abscessus species (MABS) is the most commonly isolated rapidly growing mycobacteria (RGM) and is one of the most antibiotic-resistant RGM with rapid progression, therefore, treatment of MABS is still challenging. We here presented a new combination treatment with sitafloxacin that targeted rough morphotypes of MABS, causing aggressive infections. Thirty-four clinical strains of MABS were isolated from various clinical samples at the Juntendo university hospital from 2011 to 2020. The susceptibility to a combination of sitafloxacin and antimicrobial agents was compared to that of the antimicrobial agents alone. Out of 34 MABS, 8 strains treated with sitafloxacin-amikacin combination, 9 of sitafloxacin-imipenem combination, 19 of sitafloxacin-arbekacin combination, and 9 of sitafloxacin-clarithromycin combination showed synergistic effects, respectively. Sitafloxacin-arbekacin combination also exhibited the synergistic effects against 10 of 22 Mycobacterium abscessus subspecies massiliense (Mma) strains and 8 of 11 Mycobacterium abscessus subspecies abscessus (Mab) strains, a highly resistant subspecies of MABS. The sitafloxacin-arbekacin combination revealed more synergistic effects in rough morphotypes of MABS (p = 0.008). We demonstrated the synergistic effect of the sitafloxacin-arbekacin combination against MABS. Further, this combination regimen might be more effective against Mab or rough morphotypes of MABS., (© 2023. The Author(s).)

COVID-19 antibody testing has been developed to investigate humoral immune response in SARS-CoV-2 infection. To assess the serological dynamics and neutralizing potency following SARS-CoV-2 infection, we investigated the neutralizing (NT) antibody, anti-spike, and anti-nucleocapsid antibodies responses using a total of 168 samples obtained from 68 SARS-CoV-2 infected patients. Antibodies were measured using an authentic virus neutralization assay, the high-throughput laboratory measurements of the Abbott Alinity quantitative anti-spike receptor-binding domain IgG (S-IgG), semiquantitative anti-spike IgM (S-IgM), and anti-nucleocapsid IgG (N-IgG) assays. The quantitative measurement of S-IgG antibodies was well correlated with the neutralizing activity detected by the neutralization assay (r = 0.8943, p &lt; 0.0001). However, the kinetics of the SARS-CoV-2 NT antibody in severe cases were slower than that of anti-S and anti-N specific antibodies. These findings indicate a limitation of using the S-IgG antibody titer, detected by the chemiluminescent immunoassay, as a direct quantitative marker of neutralizing activity capacity. Antibody testing should be carefully interpreted when utilized as a marker for serological responses to facilitate diagnostic, therapeutic, and prophylactic interventions., (© 2022. The Author(s).)

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge 1-5 . Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target., (© 2022. The Author(s).)

In 2020, we reported a low seroprevalence of N-specific antibodies in 4147 health care workers (HCWs) at a frontline hospital in Tokyo, Japan. In Japan, a vaccine campaign was launched in early 2021. We re-evaluated seroprevalences of N- and S-specific antibodies in 2202 HCWs who took two doses of the BNT162b2 vaccine. In 2021, N-specific seroprevalence remains as low as 1.59%. The seroprevalences were comparable among all HCWs regardless of exposure levels. Almost all of the HCWs elicited S-specific antibodies after vaccination. However, the HCWs who had COVID-19 elicited higher S-specific antibody titers than those who did not have COVID-19. In the HCWs without a history of COVID-19, 1.1% (23 out of 2185) were seropositive with N-specific antibodies, indicating the existence of asymptomatic infections. Also, S-specific antibody titers were higher in females and younger HCWs, and in those who had severe side effects. However, S-specific antibody titers were lower depending on the number of days after the second dose of vaccination specifically in elderly individuals. In conclusion, this study indicates N-specific seroprevalence remains low in HCWs at a frontline hospital in Tokyo. The mRNA vaccine elicited S-specific antibody in HCWs, however, the titers decreased as the days proceeded., (© 2022. The Author(s).)

To report the status of switch rates and time-to-switch of antiretroviral therapy (ART) regimens by evaluating anchor drug classes and common switching patterns in Japanese people living with human immunodeficiency virus (HIV, PLWH). This cross-sectional cohort study extracted data of 28,089 PLWH from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), which contains data representing the entire population of Japan. PLWH with first prescription records of ART administered between January 2011 and March 2019 were identified (n = 16,069). The median time-to-switch and switch rates of anchor drug classes were estimated by Kaplan-Meier analysis. Brookmeyer-Crowley and Greenwood methods were used to estimate 95% confidence intervals for switch rates and median days, respectively. Switch rates were compared between anchor drug classes by year using log-rank tests. A total of 3108 (19.3%) PLWH switched anchor drug classes from first to second regimens. Switch rates increased continuously over 8 years for non-nucleoside reverse transcriptase inhibitors (NNRTIs) (14.9-65.5%) and protease inhibitors (PIs) (13.2-67.7%), with median time-to-switch of 1826 and 1583 days, respectively. Integrase strand transfer inhibitors (INSTIs) maintained a low switch rate (3.0-7.6%), precluding median-days calculation. Overall, the majority of patients treated initially with NNRTIs and PIs switched to INSTIs regardless of switching times (< 1 year: 67.3% and 85.9%, respectively; ≥ 1 year: 95.5% and 93.6%, respectively). The foremost switching strategies for first-to-second ART regimens are from NNRTIs or PIs to INSTIs regimens that maintain low switch rates long term. There was no observable difference in trend between sex, age and status of AIDS disease at first ART regimen. INSTIs HIV agents may be the most durable anchor drug class for PLWH receiving ART., (© 2022. The Author(s).)

Here, we aimed to evaluate the clinical performance of a novel automated immunoassay HISCL SARS-CoV-2 Antigen assay kit designed to detect the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This kit comprises automated chemiluminescence detection systems. Western blot analysis confirmed that anti-SARS-CoV antibodies detected SARS-CoV-2N proteins. The best cut-off index was determined, and clinical performance was tested using 115 serum samples obtained from 46 patients with coronavirus disease 2019 (COVID-19) and 69 individuals who tested negative for COVID-19 through reverse transcription quantitative polymerase chain reaction (RT-qPCR). The HISCL Antigen assay kit showed a sensitivity of 95.4% and 16.6% in samples with copy numbers > 100 and < 99, respectively. The kit did not cross-react with human coronaviruses causing seasonal common cold and influenza, and none of the 69 individuals without COVID-19 were diagnosed with positive results. Importantly, 81.8% of the samples with low virus load (< 50 copy numbers) were diagnosed as negative. Thus, using HISCL antigen assay kits may reduce overdiagnosis compared with RT-qPCR tests. The rapid and high-throughput HISCL SARS-CoV-2 Antigen assay kit developed here proved suitable for screening infectious COVID-19 and may help control the pandemic., (© 2021. The Author(s).)

Post-trauma patients are at great risk of pulmonary embolism (PE), however, data assessing specific risk factors for post-traumatic PE are scarce. This was a nested case-control study using the Japan Trauma Data Bank between 2004 and 2017. We enrolled patients aged ≥ 16 years, Injury Severity Score ≥ 9, and length of hospital stay ≥ 2 days, with PE and without PE, using propensity score matching. We conducted logistic regression analyses to examine risk factors for PE. We included 719 patients with PE and 3595 patients without PE. Of these patients, 1864 [43.2%] were male, and their median Interquartile Range (IQR) age was 73 [55-84] years. The major mechanism of injury was blunt (4282 [99.3%]). Median [IQR] Injury Severity Score (ISS) was 10 [9-18]. In the multivariate analysis, the variables spinal injury [odds ratio (OR), 1.40 (1.03-1.89)]; long bone open fracture in upper extremity and lower extremity [OR, 1.51 (1.06-2.15) and OR, 3.69 (2.89-4.71), respectively]; central vein catheter [OR, 2.17 (1.44-3.27)]; and any surgery [OR, 4.48 (3.46-5.81)] were independently associated with PE. Spinal injury, long bone open fracture in extremities, central vein catheter placement, and any surgery were risk factors for post-traumatic PE. Prompt initiation of prophylaxis is needed for patients with such trauma., (© 2021. The Author(s).)

ETS variant transcription factor 4 (ETV4) is a recently identified transcription factor that regulates gene expression-based biomarkers of asthma and IL6 production in an airway epithelial cell line. Given that ETV4 has not yet been implicated in asthma genetics, we performed genetic association studies of adult asthma in the ETV4 region using two independent Japanese cohorts (a total of 1532 controls and 783 cases). SNPs located between ETV4 and mesenchyme homeobox 1 (MEOX1) were significantly associated with adult asthma, including rs4792901 and rs2880540 (P = 5.63E-5 and 2.77E-5, respectively). The CC haplotype of these two SNPs was also significantly associated with adult asthma (P = 8.43E-7). Even when both SNPs were included in a logistic regression model, the association of either rs4792901 or rs2880540 remained significant (P = 0.013 or 0.007, respectively), suggesting that the two SNPs may have independent effects on the development of asthma. Both SNPs were expression quantitative trait loci, and the asthma risk alleles at both SNPs were correlated with increased levels of ETV4 mRNA expression. In addition, the asthma risk allele at rs4792901 was associated with increased serum IL6 levels (P = 0.041) in 651 healthy adults. Our findings imply that ETV4 is involved in the pathogenesis of asthma, possibly through the heightened production of IL6., (© 2021. The Author(s).)

Immune response involving various immunoglobulin (Ig) isotypes and subtypes to microbiome is involved in the pathogenesis and disease activity of inflammatory bowel diseases (IBDs). To clarify the presence of Ig-coated bacteria in the intestine and its association with disease activity in ulcerative colitis (UC) and Crohn's disease (CD), we extracted and classified Ig-coated bacteria from fecal samples of 42 patients with IBD and 12 healthy controls (HCs) using flow cytometry and 16S ribosomal RNA sequence analysis. The percentage of bacteria coated with IgA and IgM was higher in patients with IBD than in HCs, and IgG-coated bacteria were found only in patients with IBD. Moreover, the percentages of bacteria coated with IgG1, IgG2, IgG3, and IgM in UC samples and IgG3, IgG4, and IgM in CD samples were correlated with disease activities. The proportions of Bacteroides ovatus and Streptococcus increased during the active phase of CD. Hence, the detailed analysis of Ig-coated bacteria and Ig subtypes using flow cytometry could aid in developing useful indicators of disease activity and identifying more disease-related bacteria, which could become novel treatment targets for IBDs., (© 2021. The Author(s).)

The impact of infection on the prognosis of trauma patients according to severity remains unclear. We assessed the impact of infection complications on in-hospital mortality among patients with trauma according to severity. This retrospective cohort study used a nationwide registry of trauma patients. Patients aged ≥ 18 years with blunt or penetrating trauma who were admitted to intensive care units or general wards between 2004 and 2017 were included. We compared the baseline characteristics and outcomes between patients with and without infection and conducted a multivariable logistic regression analysis to investigate the impact of infection on in-hospital mortality according to trauma severity, which was classified as mild [Injury Severity Score (ISS) < 15], moderate (ISS 15-29), or severe (ISS ≥ 30). Among the 150,948 patients in this study, 10,338 (6.8%) developed infections. Patients with infection had greater in-hospital mortality than patients without infection [1085 (10.5%) vs. 2898 (2.1%), p < 0.01]. After adjusting for clinical characteristics, in-hospital mortality differed between trauma patients with and without infection according to trauma severity [17.1% (95% CI 15.2-18.9%) vs. 2.9% (95% CI 2.7-3.1%), p < 0.01, in patients with mild trauma; 14.8% (95% CI 13.3-16.3%) vs. 8.4% (95% CI 7.9-8.8%), p < 0.01, in patients with moderate trauma; and 13.5% (95% CI 11.2-15.7%) vs. 13.7% (95% CI 12.4-14.9%), p = 0.86, in patients with severe trauma]. In conclusion, the effect of infection complications in patients with trauma on in-hospital mortality differs by trauma severity.

Healthcare workers (HCWs) are highly exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The actual coronavirus disease (COVID-19) situation, especially in regions that are less affected, has not yet been determined. This study aimed to assess the seroprevalence of SARS-CoV-2 in HCWs working in a frontline hospital in Tokyo, Japan. In this cross-sectional observational study, screening was performed on consented HCWs, including medical, nursing, and other workers, as part of a mandatory health checkup. The screening test results and clinical characteristics of the participants were recorded. The antibody seroprevalence rate among the 4147 participants screened between July 6 and August 21, 2020, was 0.34% (14/4147). There was no significant difference in the seroprevalence rate between frontline HCWs with a high exposure risk and HCWs working in other settings with a low exposure risk. Of those seropositive for SARS-CoV-2, 64% (9/14) were not aware of any symptoms and had not previously been diagnosed with COVID-19. In conclusion, this study provides insights into the extent of infection and immune status in HCWs in Japan, which has a relatively low prevalence of COVID-19. Our findings aid in formulating public health policies to control virus spread in regions with low-intensity COVID-19.

We report on a potential method to separate sugars by using the specific interaction between fullerenes and saccharides in liquid chromatography (LC). Aromatic rings with high electron density are believed to interact strongly with saccharides due to CH-π and/or OH-π interactions. In this study, the fullerene-bonded columns were used to separate saccharides by LC under aqueous conditions. As a result, 2-aminobenzamide-labeled glucose homopolymer (Glcs) was effectively separated by both C60 and C70 columns in the range of Glc-1 to Glc-20 and high blood glucose level being retained in greater quantity. Furthermore, similar separations were identified by LC-mass spectrometry with non-labeled glucose homopolymers. Theoretical study based on molecular dynamics and DFT calculation demonstrated that a supramolecular complex of saccharide-fullerene was formed through CH-π and/or OH-π interactions, and that the interactions between saccharide and fullerene increase with the increase units of the saccharide. Additionally, the C60 column retained disaccharides containing maltose, trehalose, and sucrose. In this case, it was assumed that the retention rates were determined by the difference of the dipole moment in each saccharide. These results suggest that the dipole-induced dipole interaction was dominant, and that maltose-with the higher dipole moment-was more strongly retained compared to other disaccharides having lower dipole moment.

Expression quantitative trait locus (eQTL) analyses have enabled us to predict the function of disease susceptibility SNPs. However, eQTL for the effector memory T cells (TEM) located in the lamina propria mononuclear cells (LPMCs), which play an important role in Crohn's disease (CD), are not yet available. Thus, we conducted RNA sequencing and eQTL analyses of TEM cells located in the LPMCs from IBD patients (n = 20). Genome-wide association study (GWAS) was performed using genotyping data of 713 Japanese CD patients and 2,063 controls. We compared the results of GWAS and eQTL of TEM, and also performed a transcriptome-wide association study using eQTL from Genotype Tissue Expression project. By eQTL analyses of TEM, correlations of possible candidates were confirmed in 22,632 pairs and 2,463 genes. Among these candidates, 19 SNPs which showed significant correlation with tenascin-XA (TNXA) expression were significantly associated with CD in GWAS. By TWAS, TNFSF15 (FDR = 1.35e-13) in whole blood, ERV3-1 (FDR = 2.18e-2) in lymphocytes, and ZNF713 (FDR = 3.04e-2) in the sigmoid colon was significantly associated with CD. By conducting integration analyses using GWAS and eQTL data, we confirmed multiple gene transcripts are involved in the development of CD.

Understanding the structure-property relationship of glass material is still challenging due to a lack of periodicity in disordered materials. Here, we report the properties and atomic structure of vanadium phosphate glasses characterized by reverse Monte Carlo modelling based on neutron/synchrotron X-ray diffraction and EXAFS data, supplemented by Raman and NMR spectroscopy. In vanadium-rich glass, the water durability, thermal stability and hardness improve as the amount of P 2 O 5 increases, and the network former of the glass changes from VO x polyhedra to the interplay between VO x polyhedra and PO 4 tetrahedra. We find for the first time that the coordination number of oxygen atoms around a V 4+ is four, which is an unusually small coordination number, and plays an important role for water durability, thermal stability and hardness. Furthermore, we show that the similarity between glass and crystal beyond the nearest neighbour distance is important for glass properties. These results demonstrate that controlling the oxygen coordination and valence of the network-forming cation is necessary for designing the properties of glass.

The clinical implications of bacteremia among septic patients remain unclear, although a vast amount of data have been accumulated on sepsis. We aimed to compare the clinical characteristics and outcomes of severe sepsis patients with and without bacteremia. This secondary analysis of a multicenter, prospective cohort study included 59 intensive care units (ICUs) in Japan between January 2016 and March 2017. The study cohort comprised 1,184 adults (aged ≥ 16 years) who were admitted to an ICU with severe sepsis and diagnosed according to the Sepsis-2 criteria. Of 1,167 patients included in the analysis, 636 (54.5%) had bacteremia. Those with bacteremia had significantly higher rates of septic shock (66.4% vs. 58.9%, p = 0.01) and higher sepsis severity scores, including the Acute Physiology and Chronic Health Evaluation (APACHE) II and the Sequential Organ Failure Assessment (SOFA). No significant difference in in-hospital mortality was seen between patients with and without bacteremia (25.6% vs. 21.0%, p = 0.08). In conclusion, half of severe sepsis patients in ICUs have bacteremia. Although patients with bacteremia had more severe state, between-group differences in patient-centered outcomes, such as in-hospital mortality, have not been fully elucidated.

The detailed comorbidity status of hospitalized elderly patients throughout Japan has remained largely unknown; therefore, our goal was to rigorously explore this situation and its implications as of the 2015 fiscal year (from April 2015 to March 2016). This study was based on a health insurance claims database, covering all insured policy holders in Japan aged ≥60 years (male: n = 2,135,049, female: 1,969,019) as of the 2015 fiscal year. Comorbidity status was identified by applying principal factor analysis to the database. The factors identified in male patients were [1] myocardial infarction, hypertension, dyslipidemia, and diabetes mellitus; [2] congestive heart failure (CHF), cardiac arrhythmia, and renal failure; [3] Parkinson's disease, dementia, cerebrovascular disease, and pneumonia; [4] cancer and digestive disorders; and [5] rheumatoid arthritis and hip fracture. However, in female patients, the results obtained for the quaternary and quinary factors were the opposite of those obtained in male patients. In superelderly patients, dementia, cerebrovascular disease, and pneumonia appeared as the tertiary factor, and hip fracture and osteoporosis appeared as the quaternary factor. The comorbidities in the elderly patients suggest the importance of coronary heart disease and its related metabolic disorders; in superelderly patients, fracture and osteoporosis appeared as factors, in addition to dementia and pneumonia.

Detection of dysmorphic cells in peripheral blood (PB) smears is essential in diagnostic screening of hematological diseases. Myelodysplastic syndromes (MDS) are hematopoietic neoplasms characterized by dysplastic and ineffective hematopoiesis, which diagnosis is mainly based on morphological findings of PB and bone marrow. We developed an automated diagnostic support system of MDS by combining an automated blood cell image-recognition system using a deep learning system (DLS) powered by convolutional neural networks (CNNs) with a decision-making system using extreme gradient boosting (XGBoost). The DLS of blood cell image-recognition has been trained using datasets consisting of 695,030 blood cell images taken from 3,261 PB smears including hematopoietic malignancies. The DLS simultaneously classified 17 blood cell types and 97 morphological features of such cells with >93.5% sensitivity and >96.0% specificity. The automated MDS diagnostic system successfully differentiated MDS from aplastic anemia (AA) with high accuracy; 96.2% of sensitivity and 100% of specificity (AUC 0.990). This is the first CNN-based automated initial diagnostic system for MDS using PB smears, which is applicable to develop new automated diagnostic systems for various hematological disorders.

A comprehensive screening method using machine learning and many factors (biological characteristics, Helicobacter pylori infection status, endoscopic findings and blood test results), accumulated daily as data in hospitals, could improve the accuracy of screening to classify patients at high or low risk of developing gastric cancer. We used XGBoost, a classification method known for achieving numerous winning solutions in data analysis competitions, to capture nonlinear relations among many input variables and outcomes using the boosting approach to machine learning. Longitudinal and comprehensive medical check-up data were collected from 25,942 participants who underwent multiple endoscopies from 2006 to 2017 at a single facility in Japan. The participants were classified into a case group (y = 1) or a control group (y = 0) if gastric cancer was or was not detected, respectively, during a 122-month period. Among 1,431 total participants (89 cases and 1,342 controls), 1,144 (80%) were randomly selected for use in training 10 classification models; the remaining 287 (20%) were used to evaluate the models. The results showed that XGBoost outperformed logistic regression and showed the highest area under the curve value (0.899). Accumulating more data in the facility and performing further analyses including other input variables may help expand the clinical utility.

Voriconazole (VRCZ) induces the development of UV-associated skin cancers. The mechanism underlying the VRCZ-induced carcinogenesis has been largely unknown. Here, we showed that VRCZ metabolites plus UVA generated reactive oxygen species and resultant DNA damage of the epidermis, but did not induce substantial apoptosis in human keratinocytes (KCs). Furthermore, VRCZ per se stimulates aryl hydrocarbon receptor (AhR) and upregulates COX-2, which is a pivotal enzyme for the promotion of UV-associated tumors, in an AhR-ARNT dependent manner of the classical (genomic) pathway. Our findings suggest that the phototoxic moieties of VRCZ metabolites may participate in the initiation phase of VRCZ skin cancer, while VRCZ per se promotes the tumor development. Therefore, during VRCZ therapy, sun exposure protection is essential to prevent photocarcinogenesis caused by VRCZ metabolites plus UV. Chemoprevention with selective COX-2 inhibitors may be helpful to repress the development of skin cancers derived from DNA-damaged KCs.

Spin liquid (SL) systems have been the subject of much attention recently, as they have been theoretically predicted to not freeze, even at 0 K. Despite extensive searches being made for such a system, only a few candidates have been found. All of these candidates share geometrical frustrations that are based on triangular lattices. We applied vibrational spectroscopy to one of the candidates of a molecule-based SL system, and we compared its results against three antiferromagnetic compounds and four charge-ordered compounds. All of their structural motifs belong to triangular lattices. The C=C stretching modes in the SL state indicated that there were charge and lattice fluctuations. These fluctuations were suppressed but non-negligible in the AF compounds. This finding is potentially significant, as it indicates that a hidden lattice and charge fluctuation are the driving force of a geometrical frustration, which eventually leads to a SL state.

Influenza A virus (IAV) membrane proteins hemagglutinin (HA) and neuraminidase (NA) are determinants of virus infectivity, transmissibility, pathogenicity, host specificity, and major antigenicity. HA binds to a virus receptor, a sialoglycoprotein or sialoglycolipid, on the host cell and mediates virus attachment to the cell surface. The hydrolytic enzyme NA cleaves sialic acid from viral receptors and accelerates the release of progeny virus from host cells. In this study, we identified a novel function of HA and NA as machinery for viral motility. HAs exchanged binding partner receptors iteratively, generating virus movement on a receptor-coated glass surface instead of a cell surface. The virus movement was also dependent on NA. Virus movement mediated by HA and NA resulted in a three to four-fold increase in virus internalisation by cultured cells. We concluded that cooperation of HA and NA moves IAV particles on a cell surface and enhances virus infection of host cells.

We developed a spongy-like porous polymer (spongy monolith) consisting of poly(ethylene-co-glycidyl methacrylate) with continuous macropores that allowed efficient in situ reaction between the epoxy groups and proteins of interest. Immobilization of protein A on the spongy monolith enabled high-yield collection of immunoglobulin G (IgG) from cell culture supernatant even at a high flow rate. In addition, immobilization of pepsin on the spongy monolith enabled efficient online digestion at a high flow rate.

Immunoglobulin A (IgA) is the main antibody isotype secreted into the intestinal lumen. IgA plays a critical role in the defence against pathogens and in the maintenance of intestinal homeostasis. However, how secreted IgA regulates gut microbiota is not completely understood. In this study, we isolated monoclonal IgA antibodies from the small intestine of healthy mouse. As a candidate for an efficient gut microbiota modulator, we selected a W27 IgA, which binds to multiple bacteria, but not beneficial ones such as Lactobacillus casei. W27 could suppress the cell growth of Escherichia coli but not L. casei in vitro, indicating an ability to improve the intestinal environment. Indeed W27 oral treatment could modulate gut microbiota composition and have a therapeutic effect on both lymphoproliferative disease and colitis models in mice. Thus, W27 IgA oral treatment is a potential remedy for inflammatory bowel disease, acting through restoration of host-microbial symbiosis.

Data Sources: Data was sought using Medline and the Cochrane Library, and relevant chapters from three major endodontic texts were consulted: Principles and Practice of Endodontics (4th Edn; editors; Torabinejad and Walton; 2008); Pathways of the Pulp (9th edition; editors, Cohen and Hargreaves; 2006), and Endodontics (6th edition; editors, Ingle, Bakland and Baumgartner; 2008). Every issue was also searched of the most recent 2 years of the following major endodontic journals: International Endodontic Journal; Journal of Endodontics; and Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology along with the reference lists of identified articles., Study Selection: Articles were included from peer-reviewed journals if they were published in English, and reported clinical and/or radiographic outcome data for nonsurgical endodontic retreatment or for endodontic surgery, with followup data for a minimum of 25 teeth and a minimum 2-year mean followup period. Studies reporting outcomes based on individual roots as opposed to whole teeth, or that did not report clinical or radiographic outcomes, which were animal studies, or studies that reported histological data only, were excluded., Data Extraction and Synthesis: When necessary, the reviewers recalculated success and failure rates when they were not directly provided in papers' tables or in the text, or when only particular data subsets met the inclusion criteria. To facilitate meta-analysis, the data were standardised according to a commonly applied classification system used to assess outcomes for nonsurgical retreatment and surgical endodontics: (1) Complete healing; (2) Incomplete healing; (3) Uncertain healing; and (4) Unsatisfactory healing (failures). When uncertainty existed regarding which of the above four categories correlated with those reported in a given article, the data were assigned to the lower healing category. For this review, success was defined as teeth categorised as showing complete healing or incomplete healing. Weighted success rates, pooled success rates, and 95% confidence interval (CI) estimates of outcomes were generated in the metaanalysis from compiled data from the included studies by using the DerSimonian-Laird random effects pooling method., Results: Twenty-six endodontic surgery and eight nonsurgical retreatment articles were included. There were only four randomised controlled trials (one in the nonsurgical retreatment, and three in the endodontic surgery group). A significantly higher success rate was found for endodontic surgery at 2-4 years (77.8%) than for nonsurgical retreatment for the same followup period (70.9%; P <0.05). At 4-6 years, however, this relationship was reversed, with nonsurgical retreatment showing a higher success rate of 83.0%, compared with 71.8% for endodontic surgery (P <0.05). Insufficient numbers of articles were available to make comparisons after 6 years of followup. Endodontic surgery studies showed a statistically significant decrease in success with each increasing followup interval (P <0.05). The weighted success for 2-4 years was 77.8%, which declined at 4-6 years to 71.8% and further declined at >6 years to 62.9% (P <0.05). Conversely, the nonsurgical retreatment success rates demonstrated a statistically significant increase in weighted success at 2-4 years (70.9%) versus 4-6 years (83.0%; P <0.05)., Conclusions: On the basis of these results it appears that endodontic surgery offers more favourable initial success, but nonsurgical retreatment offers a more favourable long-term outcome.

Adiponectin is an adipocyte hormone that ameliorates insulin resistance and prevents diabetes. Patients with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) are at a high risk of developing diabetes and cardiovascular diseases. Since treatment with angiotensin II receptor blockers retards the development of diabetes, the effects of losartan on serum adiponectin levels were examined with regard to insulin sensitivity in pre-diabetic patients. Sixty-five patients with IFG/IGT (42 males, 23 females, 63+/-13 years old) were randomized to receive 25-100 mg of losartan (n=33) or a calcium channel blocker (CCB, n=32) for 3 months. Before and after the treatment, changes in blood pressure, insulin sensitivity (HOMA-R) and serum concentrations of high molecular weight (HMW)-adiponectin and free fatty acid (FFA) were assessed. At baseline, the HMW-adiponectin concentration negatively correlated with the patient's body mass index, HOMA-R and triglyceride levels, and positively correlated with high-density lipoprotein (HDL)-cholesterol levels. However, the HMW-adiponectin concentration showed no correlation with blood pressure. HMW-adiponectin concentrations were similar between the losartan group and the CCB group. Both the losartan and CCB treatments similarly and significantly reduced the mean blood pressure (107+/-7 mmHg to 95+/-7 mmHg, p<0.0001, and 104+/-6 mmHg to 93+/-9 mmHg, p<0.0001, respectively). Losartan treatment resulted in a significant increase in HMW-adiponectin concentrations (45.9%) and a significant decrease in HOMA-R (23.9%) and FFA concentrations (26.5%); the percent changes were greater than those induced by CCB treatment (p<0.001, p<0.05 and p<0.01, respectively). We conclude that losartan increases the serum HMW-adiponectin concentration and concurrently improves insulin sensitivity in subjects with IFG/IGT. These results suggest that losartan may prevent diabetes by increasing serum adiponectin levels.

Data Sources: Searches for relevant studies were made using the Cochrane Oral Health Group's Trials Register, CENTRAL, Medline and Embase. The major oral medicine journals were also searched by hand and reference lists of included studies and reviews were checked. Endodontics experts were contacted by e-mail. No language limitations were imposed., Study Selection: Randomised controlled trials (RCT) and quasi-RCT of root canal treatment were included. Surgical endodontic treatment was excluded. The outcomes considered were the number of teeth extracted for endodontic problems; radiological success (absence of any periapical radiolucency) after at least 1 year; postoperative pain; painkiller use; swelling; or sinus track formation., Data Extraction and Synthesis: Data were collected using a specific extraction form. The validity of the studies included was assessed on the basis of allocation concealment, blindness of the study, and loss of participants. Data were analysed by calculating risk ratios. When valid and relevant data were collected, a meta-analysis of the data was undertaken., Results: Twelve RCT were included in the review. Four studies had a low risk of bias, four a moderate risk, and another four had a high risk of bias. The frequency of radiological success and immediate postoperative pain were not significantly different between single- and multiple-visit root canal treatments. People who had single-visit treatment reported a higher frequency of painkiller use and swelling, but the results for swelling were not significantly different between the two groups. We found no study that included tooth loss and sinus track formation among its primary outcomes., Conclusions: No difference exists in the effectiveness of root canal treatment, in terms of radiological success, between single- and multiple-visit treatments. Most short- and long-term complications are also similar in terms of frequency, although patients undergoing a single visit may experience a slightly higher frequency of swelling and are significantly more likely to take painkillers.

Design: This was a randomised controlled trial (RCT)., Intervention: Root-end resection and preparation with a round dental bur was compared with the use of ultrasonic diamond coated retro-tips., Outcome Measure: Treatment was considered a success when the radiological and clinical criteria listed (Table 1) were met., Results: Out of a total group of 399 patients who were included in the study, adequate followup could be obtained in 290 patients. The overall success rate in the ultrasonic group was 80.5% and in the group treated with a bur was 70.9% (P 0.056). In molars, the difference in success rate was significant (P 0.02)., Conclusions: The use of an ultrasonic device in apical surgery showed a clear benefit over the traditional treatment. Especially in molars, the results were significant.

Data Sources: Medline and reference lists of identified articles in English only., Study Selection: Initial screening identified studies on humans with radiographic information on the terminal point of obturation. Subsequently studies with (a) a minimum follow-up of at least 2 years; (b) data on termination of obturation/instrumentation; (c) failures of treatment defined adequately (with a minimum radiographic evaluation for failure outlined and defined); (d) data available on success/failure of root canal therapy in relationship to the obturation/instrumentation length; and (e) presence or absence of rarefaction included., Data Extraction and Synthesis: This meta-analysis considered three categories of obturation length from the radiographic apex: (a) 0-1 mm (group A), (b) >1 mm but <3 mm (group B), (c) obturated past the radiographic apex, including sealer (group C). The studies were independently assessed for quality with readers blinded to the names of the authors and their institutions, names of the journals, sources of funding, and acknowledgements. Statistical analyses were done using the DerSimonian and Laird estimates., Results: Four studies met the inclusion criteria. In terms of percentage rates of success, the meta-analysis showed that obturation 0-1 mm short of the apex (group A) was better than obturation 1-3 mm short of the apex (group B); both were superior to obturation beyond the apex (group C). The success rate in group A was 28.9% better than group C and 5.9% better than group B (95% CI=-3.8%, 61.5%), P=0.08 and (95% CI=-1.3%, 13.1%), P=0.11, respectively. After adjustment for quality, the results remained unchanged., Conclusions: The results demonstrate that obturating materials extruding beyond the radiographic apex correlated with a poorer prognosis. In addition, we realised that standardised protocols are necessary in endodontic procedures and in dental research. If studies are to be compared and the information used clinically, the design of the studies must be similar and repeatable. The results of prospective studies will then be comparable and the data can be combined statistically, thereby creating a more powerful, clinically useful meta-analysis.

Data Sources: Sources were Medline and the Cochrane Library., Study Selection: Studies included were in vivo with human subjects, had experimental and control groups, and gave quantitative results in English, German or French., Data Extraction and Synthesis: Success and failure rates were derived from randomised controlled trials (RCT), clinical controlled trials (CCT), cohort studies (CS) and case-controlled studies (CCS). Qualitative synthesis of results was performed., Results: Two RCT, six CCT and 14 CCS were identified. The two RCT suggest that glass ionomer may be more effective than amalgam, conversely one CCT showed amalgam to be more effective. CCTs also suggest that EBA (reinforced zinc oxide eugenol) cement, composite with GLUMA (Bayer AG., Leverkusen, Germany) and gold leaf retrograde filling may be more effective than amalgam. A further CCT suggested that gutta-percha used as a retrograde filing is less effective than when used following an orthograde approach., Conclusions: Based on the outcome of two RCT, glass ionomer appears as effective as amalgam. EBA cement, composite with GLUMA and gold leaf and orthograde gutta-percha may also be as effective as amalgam. Evidence is limited, however, and further research is needed.

Protons with energies up to approximately 10(15) eV are the main component of cosmic rays, but evidence for the specific locations where they could have been accelerated to these energies has been lacking. Electrons are known to be accelerated to cosmic-ray energies in supernova remnants, and the shock waves associated with such remnants, when they hit the surrounding interstellar medium, could also provide the energy to accelerate protons. The signature of such a process would be the decay of pions (pi(0)), which are generated when the protons collide with atoms and molecules in an interstellar cloud: pion decay results in gamma-rays with a particular spectral-energy distribution. Here we report the observation of cascade showers of optical photons resulting from gamma-rays at energies of approximately 10(12) eV hitting Earth's upper atmosphere, in the direction of the supernova remnant RX J1713.7-3946. The spectrum is a good match to that predicted by pion decay, and cannot be explained by other mechanisms.

The synthesis and biological properties of 1-N-[4-(substituted)amidino and guanidino-2-hydroxybutyryl]kanamycins A and B are described. Reaction of 3,3",6'-tri-N-tert-butoxycarbonyl-amikacin with an appropriate amidinating or guanidinating reagent and subsequent deblocking gave a series of amikacin derivatives having an amidino or guanidino group on the 4"'-position. The corresponding kanamycin B analogs were also prepared by a similar procedure. Among these derivatives, 1-N-(4-formamidino- and guanidino-2-hydroxybutyryl)kanamycins A (7a and 7k) and B (11 and 14) exhibited antibacterial activity similar to the corresponding 4-amino analogs. The nephrotoxic potential of selected compounds is also briefly discussed.