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Introduction: Evidence is scarce on cumulative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections among healthcare workers during the pandemic. This study aimed to describe cumulative infections, including undiagnosed cases, and identify factors associated with infection in healthcare workers in Japan.Methods: Using serosurveys conducted across six national centers in Japan, we tracked coronavirus disease 2019 (COVID-19) cumulative infections. Seropositivity was defined as a positive result for SARS-CoV-2 nucleocapsid protein using the Roche assay, and cumulative infection was defined as the proportion of participants who tested positive for anti-nucleocapsid antibodies and/or self-reported a history of laboratory-confirmed or clinically diagnosed COVID-19 since the start of the pandemic. A robust Poisson regression model was used to investigate factors associated with infection risk as of September 2023.Results: Cumulative infection, which was less than 5% until the end of 2021, increased after the emergence of the Omicron variant. Specifically, cumulative infection reached 14.6% in July 2022 (BA.1/2), 37.4% in December 2022 (BA.5), 53.3% in September 2023 (XBB subvariants), and 71.5% in December 2023 (JN.1 subvariant). The proportion of undiagnosed cases detected by antibody testing alone, without a prior diagnosis, decreased from 60.9% in December 2020 to 24.7% in December 2023. Individuals aged 50 to 59 years (prevalence ratio [PR] 0.73; 95% confidence interval [CI], 0.67–0.79) and 60 years or older (PR 0.67; 95% CI, 0.59–0.77) had lower cumulative infections than those aged under 30 years old. Physicians and nurses had significantly higher cumulative infections than administrative staff, with fully adjusted PR of 1.09 (95% CI, 1.01–1.18) and 1.18 (95% CI, 1.08–1.30), respectively.Conclusion: Among healthcare workers in Japan, cumulative SARS-CoV-2 infection markedly increased after the emergence of the Omicron variant, whereas the proportion of undiagnosed cases has decreased throughout the pandemic. Younger people (<50 years), as well as physicians and nurses, have faced a higher risk of infection.

Incretins, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), secreted from enteroendocrine cells after food ingestion, are currently recognized to regulate glucose metabolism through insulin secretion. We previously demonstrated that platelet-derived growth factor-BB (PDGF-BB) induces the migration of osteoblast-like MC3T3-E1 cells through mitogen-activated protein (MAP) kinases, including p38 MAP kinase. In the present study, we investigated whether or not incretins affect the osteoblast migration. The PDGF-BB-induced cell migration was significantly reinforced by GLP-1, GIP or cAMP analogues in MC3T3-E1 cells and normal human osteoblasts. The upregulated migration by GLP-1 or cAMP analogues was suppressed by H89, an inhibitor of protein kinase A. The amplification by GLP-1 of migration induced by PDGF-BB was almost completely reduced by SB203580, a p38 MAP kinase inhibitor in MC3T3-E1 cells and normal human osteoblasts. In addition, GIP markedly strengthened the PDGF-BB-induced phosphorylation of p38 MAP kinase. Exendin-4, a GLP-1 analogue, induced Rho A expression and its translocation from cytoplasm to plasma membranes in osteoblasts at the epiphyseal lines of developing mouse femurs in vivo . These results strongly suggest that incretins accelerates the PDGF-BB-induced migration of osteoblasts via protein kinase A, and the up-regulation of p38 MAP kinase is involved in this acceleration. Our findings may highlight the novel potential of incretins to bone physiology and therapeutic strategy against bone repair.

Key summary points Aim To evaluate the association between diabetes-related foot disease and diabetes-related complications in older patients with diabetes mellitus. Finding We found that hypertension, diabetes-related peripheral neuropathy, and grip strength were significantly associated with diabetes-related foot disease in older patients with diabetes mellitus. Additionally, the combination of diabetes-related peripheral neuropathy and hypertension further increased the risk of diabetes-related foot disease in comparison with either of the two independently. Messages Patients presenting with a history of the aforementioned complications should have their feet examined at an early stage and engage in preventative measures against severe diabetes-related foot disease. Purpose To examine the relationship of diabetes-related foot disease (DFD) with diabetes and age-related complications in older patients with diabetes mellitus (DM). Methods We examined 562 outpatients with diabetes, aged ≥ 65 years, for DFD. The variables collected in this study were demographics, DM-related complications, treatment method, and age-related complications. Differences in the complications were compared between patients with and without DFD. Logistic regression analysis was used to determine the associations of DFD with DM and age-related complications. Results A total of 246 patients (43.8%) had DFD. Logistic regression analysis identified low grip strength [Odds ratio (OR): 1.83, 95% confidence interval (CI) 1.21–2.76), hypertension (OR: 1.81, 95% CI 1.09–3.00), and diabetes-related peripheral neuropathy (DPN) (OR: 1.92, 95% CI 1.24–2.98) to be significantly associated with DFD. Patients with DPN and hypertension had a higher risk of DFD than patients with DPN or hypertension alone. Individuals with DPN and low grip strength (OR: 1.74, 95% CI 1.09–2.81) were at a lower risk than those with low grip strength alone. Conclusion Hypertension, DPN, and low grip strength were significantly associated with DFD in older patients with DM, with the risk of DFD being higher in patients with both DPN and hypertension. When considering DFD in older patients with DM, low grip strength should be considered equally important as a DM-related complication.

Aim In acute medicine, we occasionally treat life‐threatening conditions such as sepsis and trauma, which cause severe thrombocytopenia. Serum thrombopoietin levels have been reported to increase under the condition of thrombocytopenia related to severity. Collagen is a crucial activator of platelets, and Rho family members, such as Rho/Rho‐kinase and Rac, play roles as active molecules involved in the intracellular signaling pathways in platelet activation. The present study aimed to elucidate the effects of thrombopoietin (TPO) on subthreshold low‐dose collagen‐stimulated human platelets in terms of Rho/Rho‐kinase and Rac. Methods Platelet‐rich plasma donated from healthy volunteers was stimulated by the subthreshold low‐dose of collagen after pretreatment with TPO and/or NSC23766, an inhibitor of the Rac‐guanine nucleotide exchange factor interaction, or Y27632, an inhibitor of Rho‐kinase. Platelet aggregation was measured using an aggregometer based on laser‐scattering methods. Proteins involved in intracellular signaling were analyzed using western blotting, and the secretion of platelet‐derived growth factor‐AB from activated platelets was determined using an enzyme‐linked immunosorbent assay. Results Under the existence of TPO, the low dose of collagen remarkably elicited the aggregation and platelet‐derived growth factor‐AB secretion of platelets, which were suppressed by NSC23766 and Y27632. The combination of TPO and collagen considerably induced a transient increase of guanosine triphosphate (GTP)‐binding Rac and GTP‐binding Rho followed by an increase of phosphorylated cofilin, a Rho‐kinase substrate. Conclusion These results strongly suggest that TPO and collagen in low doses cooperatively potentiate human platelet activation through both Rac and Rho/Rho‐kinase mediated pathways. Thrombopoietin and collagen in low doses cooperatively potentiate human platelet activation via both Rac and Rho/Rho‐kinase mediated pathways. The effect of TPO on platelet activation under the stimulation of collagen, even though of which the levels are insufficient to trigger by itself, might indicate a compensatory mechanism to enhance platelet activation in thrombocytopenia.

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.

Patients with underlying medical conditions are at high risk of developing serious symptoms of the coronavirus disease 2019 than healthy individuals; therefore, it is necessary to evaluate the immune response to vaccination among them to formulate precision and personalized vaccination strategies. However, inconsistent evidence exists regarding whether patients with underlying medical conditions have lower anti-SARS-CoV-2 spike IgG antibody titers. We performed a cross-sectional study enrolling 2762 healthcare workers who received second doses of BNT162b2 vaccination from three medical and research institutes between June and July, 2021. Medical conditions were surveyed by a questionnaire, and spike IgG antibody titers were measured with chemiluminescent enzyme immunoassay using serum collected on the median of 62 days after the second vaccination. Multilevel linear regression model was used to estimate geometric mean and ratio of mean (95% confidence interval, CI) for the presence and absence of medical conditions and treatments. Among all participants (median age, 40 years [interquartile range, 30–50]; male proportion, 29.4%), the prevalence of hypertension, diabetes, chronic lung disease, cardiovascular disease, and cancer was 7.5%, 2.3%, 3.8%, 1.8%, and 1.3%, respectively. Patients with treated hypertension had lower antibody titers than those without hypertension; the multivariable-adjusted ratio of mean (95% CI) was 0.86 (0.76–0.98). Patients with untreated and treated diabetes had lower antibody titers than those without diabetes; the multivariable-adjusted ratio of mean (95% CI) was 0.63 (0.42–0.95) and 0.77 (0.63–0.95), respectively. No substantial difference was observed between the presence or absence of chronic lung disease, cardiovascular disease, or cancer. Patients with untreated hypertension and patients with untreated and treated diabetes had lower spike IgG antibody titers than participants without those medical conditions, suggesting that continuous monitoring of antibody titers and further booster shots could be necessary to maintain adaptive immunity in patients with hypertension or diabetes.

Tramadol is a useful analgesic which acts as a serotonin and noradrenaline reuptake inhibitor in addition to μ-opioid receptor agonist. Cytoplasmic serotonin modulates the small GTPase activity through serotonylation, which is closely related to the human platelet activation. We recently reported that the combination of subthreshold collagen and CXCL12 synergistically activates human platelets. We herein investigated the effect and the mechanism of tramadol on the synergistic effect. Tramadol attenuated the synergistically stimulated platelet aggregation (300 μM of tramadol, 64.3% decrease, p<0.05). Not morphine or reboxetine, but duloxetine, fluvoxamine and sertraline attenuated the synergistic effect of the combination on the platelet aggregation (30 μM of fluvoxamine, 67.3% decrease, p<0.05; 30 μM of sertraline, 67.8% decrease, p<0.05). The geranylgeranyltransferase inhibitor GGTI-286 attenuated the aggregation of synergistically stimulated platelet (50 μM of GGTI-286, 80.8% decrease, p<0.05), in which GTP-binding Rac was increased. The Rac1-GEF interaction inhibitor NSC23766 suppressed the platelet activation and the phosphorylation of p38 MAPK and HSP27 induced by the combination of collagen and CXCL12. Tramadol and fluvoxamine almost completely attenuated the levels of GTP-binding Rac and the phosphorylation of both p38 MAPK and HSP27 stimulated by the combination. Suppression of the platelet aggregation after the duloxetine administration was observed in 2 of 5 patients in pain clinic. These results suggest that tramadol negatively regulates the combination of subthreshold collagen and CXCL12-induced platelet activation via Rac upstream of p38 MAPK.

Interleukin-6 (IL-6) is a pro-inflammatory and bone-resorptive cytokine that also regulates bone formation. We previously showed that prostaglandin E 1 (PGE 1 ) induces the synthesis of IL-6 by activating p44/p42 mitogen-activated protein kinase (MAPK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 MAPK in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether heat shock protein 70 (HSP70), a molecular chaperone that coordinates protein folding and homeostasis, affects PGE 1 -stimulated IL-6 synthesis in MC3T3-E1 cells through the MAPK activation. The osteoblast-like MC3T3-E1 cells were treated with HSP70 inhibitors—VER-155008 and YM-08—, PD98059, SB203580 or SP600125 and then stimulated with PGE 1 . IL-6 synthesis was evaluated using an IL-6 enzyme-linked immunosorbent assay kit. IL-6 mRNA expression was measured by real-time RT-PCR. The phosphorylation of p38 MAPK was evaluated by Western blotting. We found that VER-155008, an HSP70 inhibitor, enhanced the PGE 1 -stimulated IL-6 release and IL-6 mRNA expression. YM-08, another HSP70 inhibitor, also enhanced PGE 1 -stimulated IL-6 release. PD98059, a p44/p42 MAPK inhibitor, and SP600125, a SAPK/JNK inhibitor, upregulated PGE 1 -stimulated IL-6 release. On the other hand, SB203580, a p38 MAPK inhibitor, suppressed PGE 1 -stimulated IL-6 release. YM-08 stimulated the PGE 1 -induced phosphorylation of p38 MAPK. SB203580 suppressed the amplification by YM-08 of the PGE 1 -stimulated IL-6 release. Our results suggest that HSP70 inhibitors upregulate the PGE 1 -stimulated IL-6 synthesis through p38 MAPK in osteoblasts and therefore affect bone remodeling.

Patients with underlying medical conditions are at high risk of developing serious symptoms of the coronavirus disease 2019 than healthy individuals; therefore, it is necessary to evaluate the immune response to vaccination among them to formulate precision and personalized vaccination strategies. However, inconsistent evidence exists regarding whether patients with underlying medical conditions have lower anti-SARS-CoV-2 spike IgG antibody titers. We performed a cross-sectional study enrolling 2762 healthcare workers who received second doses of BNT162b2 vaccination from three medical and research institutes between June and July, 2021. Medical conditions were surveyed by a questionnaire, and spike IgG antibody titers were measured with chemiluminescent enzyme immunoassay using serum collected on the median of 62 days after the second vaccination. Multilevel linear regression model was used to estimate geometric mean and ratio of mean (95% confidence interval, CI) for the presence and absence of medical conditions and treatments. Among all participants (median age, 40 years [interquartile range, 30-50]; male proportion, 29.4%), the prevalence of hypertension, diabetes, chronic lung disease, cardiovascular disease, and cancer was 7.5%, 2.3%, 3.8%, 1.8%, and 1.3%, respectively. Patients with treated hypertension had lower antibody titers than those without hypertension; the multivariable-adjusted ratio of mean (95% CI) was 0.86 (0.76-0.98). Patients with untreated and treated diabetes had lower antibody titers than those without diabetes; the multivariable-adjusted ratio of mean (95% CI) was 0.63 (0.42-0.95) and 0.77 (0.63-0.95), respectively. No substantial difference was observed between the presence or absence of chronic lung disease, cardiovascular disease, or cancer. Patients with untreated hypertension and patients with untreated and treated diabetes had lower spike IgG antibody titers than participants without those medical conditions, suggesting that continuous monitoring of antibody titers and further booster shots could be necessary to maintain adaptive immunity in patients with hypertension or diabetes.