Wakaba Fukushima

Messenger RNA (mRNA) vaccines effectively induce protective immunity, but antigen-specific CD8+ T cell responses exhibit limited persistence. In this study, we aimed to assess CD8+ T cell responses following a third dose of the Pfizer BNT162b2 COVID-19 vaccine and identify factors contributing to their longevity. Using HLA tetramers, we analyzed antigen-specific CD8+ T cells in 141 vaccinated individuals (86.5% female) and identified 2 groups: those with strong responses (strong group) and those with weak responses (weak group) 6 mo after the third mRNA vaccination. Transcriptomic analysis revealed that Notch signaling was upregulated in the strong group, and in vitro, the inhibition of Notch signaling significantly reduced CD8+ T cell expansion. These findings suggest that Notch signaling may contribute to maintain long-term antigen-specific CD8+ T cell responses following mRNA vaccination. Targeting this pathway could offer novel strategies for enhancing vaccine-induced cellular immunity and long-lasting protection.

Purpose The cumulative probability of a first-time dislocation (CPD) after total hip arthroplasties (THAs) with a 22-mm head was reported in 2004 to rise steadily to 7% at 25 years. Later reports employing larger heads indicated that dislocations were concentrated in shorter periods after THA. Therefore, dislocations may occur differently over time depending on head sizes, which has not been clearly demonstrated. The purpose was to examine this hypothesis. Methods With first-time dislocation as the endpoint, the Cox proportional-hazards regression model and the Kaplan–Meier analyses were applied to 6,339 THAs performed for nontraumatic osteonecrosis of the femoral head, considering all possible influencing variables. Follow-up was 6.5 years on average (range, 0 to 27). Results First-time dislocations occurred in 289 THAs (4.6%) at a mean of 2.9 years (range, 0 to 19) following THA, with head sizes of 22, 26, 28, 32, and ≧ 36 mm in 33, 76, 86, 58, and 36 THAs, respectively (dislocation rate: 13.5, 8.2, 5.7, 2.5, and 2.7%, respectively; p < 0.001 in χ2 test). CPD increased linearly after THA in the 22-mm group, while larger-head groups showed a steep early rise followed by a decline. Conclusion First-time dislocations occurred differently over time with different head sizes.

Objectives: Alcohol consumption is a recognized risk factor for osteonecrosis of the femoral head (ONFH), as well as hypertension, and malignant tumors. Aldehyde dehydrogenase 2 (ALDH2) activity influences alcohol-associated risks by modulating acetaldehyde metabolism; however, its role in ONFH remains unclear. This study aimed to investigate whether the alcohol flushing response, a proxy for ALDH2, modifies the relationship between alcohol consumption and ONFH. Methods: A hospital-based case–control study was conducted on newly diagnosed patients with ONFH and controls recruited. Information on alcohol flushing responses was collected using a self-administered questionnaire and categorized into current/former flushers (inactive ALDH2) and never flushers (active ALDH2). Odds ratios (OR) and their 95% confidence intervals (CI) of various levels of alcohol consumption (habitual drinking, heavy drinking, and drinking of ≥320 g/week) were assessed for ONFH using a logistic regression model. Stratified analysis and multiplicative interaction were used to investigate the effect modification by the alcohol flushing response on the association between alcohol consumption and ONFH. Results: A total of 118 cases with ONFH and 213 controls were included (mean age, 45 years; 197 men and 134 women). The adjusted ORs of alcohol consumption for the development of ONFH were 1.5 (95% CI: 0.4–6.0) and 3.7 (0.3–41.3) for habitual drinking, 1.6 (0.4–5.6) and 2.0 (0.1–24.2) for heavy drinking, and 3.8 (0.8–17.6) and 4.5 (0.4–49.2) for drinking of ≥320 g/week among current/former and never flushers, respectively. No significant multiplicative interactions were observed. Conclusions: Alcohol flushing response may not modify the relationship between alcohol consumption and the risk of ONFH.

A clear consensus on the factors contributing to adverse reactions following the mRNA COVID-19 vaccine has yet to be reached. Therefore, the present study investigated adverse reactions following the first three doses of the BNT162b2 mRNA COVID-19 vaccine and examined associated factors, including previous experience of adverse reactions. Two prospective cohort studies were integrated for this study, and 218 participants (79% female; median age 46.5 years) who had completed all three doses of BNT162b2 were included in the final analyses. Data were collected through self-administered electronic questionnaires. Local and systemic adverse reactions following vaccinations were classified with severity grading. Modified Poisson regression models were used to examine the association of adverse reactions. Local reactions were reported by 91-96% of participants, with moderate or severe local reactions in 27-43%. Systemic reactions were reported by 56-88% of participants, with moderate or severe systemic reactions in 19-56%. Participants with a history of moderate or severe local reactions were more likely to subsequently have moderate or severe local reactions (relative risk: 2.32 [95% confidence interval: 1.52-3.55] for the second dose, 1.89 [1.33-2.69] for the third dose), but not systemic reactions. Participants with a history of moderate or severe systemic reactions were more likely to subsequently have moderate or severe systemic reactions (1.31 [0.99-1.72] for the second dose, 2.18 [1.56-3.06] for the third dose), but not local reactions. These results may contribute to a more detailed understanding of mRNA COVID-19 vaccines and provide information for future vaccine development.

A nationwide multicenter follow-up cohort study of hip-replacement arthroplasties performed for nontraumatic osteonecrosis of the femoral head (ONFH) was conducted to clarify factors associated with need for reoperation. We analyzed 7393 arthroplasties including 6284 total hip arthroplasties (THAs), 886 bipolar hemiarthroplasties (BPs), 188 total resurfacing arthroplasties, and 35 hemi-resurfacing arthroplasties (hRSs). The identified risk factors were combined systemic steroid use and excessive alcohol consumption (both ONFH-associated factors), a lateral approach, alumina BPs (aBPs), and hRSs, which were reported previously. The present study performed further analyses separately for THAs and BPs to clarify risk factors in each surgical group. A Cox proportional-hazard model identified the following risk factors: the acetabular-articulating materials of conventional polyethylene (cPE) and metal in the THAs and both ONFH-associated factors, minimum-incision surgery (MIS), and aBPs in the BPs. The risk factors were specific to each surgical group. In the ONFH patients, when performing THA, cPE and metal are not recommended as the acetabular-articulating material. When performing BP, patients with both ONFH-associated factors should be treated carefully, and the employment of MIS and use of aBP are not good strategies.

Background: The decline in measles vaccination coverage is a global concern. In Japan, coverage of the first-dose of measles vaccine, which had exceeded the target of 95.0% since fiscal year (FY) 2010, fell to 93.5% in FY 2021. Vaccination coverage increased to 95.4% in FY 2022 but varied by municipality. Few studies have focused on regional disparities in measles vaccination coverage. This study aimed to clarify the regional disparities in measles vaccination coverage by municipality in Japan and their associated factors.Methods: In this ecological study, the measles vaccination coverage in FY 2022; population density; area deprivation index (ADI, an indicator of socioeconomic status); proportion of foreign nationals, single-father households, single-mother households, and mothers aged ≥30 years; and number of medical facilities, pediatricians, and non-pediatric medical doctors in 1,698 municipalities were extracted from Japanese government statistics. Negative binomial regression was performed with the number of children vaccinated against measles as the dependent variable, number of children eligible for measles vaccination as the offset term, and other factors as independent variables.Results: Vaccination coverage was less than 95.0% in 54.3% of municipalities. Vaccination coverage was significantly positively associated with population density and negatively associated with the proportion of single-father households, mothers aged ≥30 years, and the ADI (incidence rate ratio [IRR]: 1.004, 0.976, 0.999, 0.970, respectively).Conclusion: This study showed regional disparities in measles vaccination coverage in Japan. Single-father households, age of mothers, and socioeconomic status may be key factors when municipalities consider strategies to improve vaccination coverage.

Background: Current influenza A vaccines primarily induce neutralizing antibodies targeting the variable hemagglutinin (HA) head domain, limiting their effectiveness against diverse or emerging influenza A virus (IAV) subtypes. The conserved HA stem domain, particularly the long α-helix (LAH) epitope, is a focus of universal vaccine research due to its cross-protective potential. Additionally, Fc-mediated functions such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) are recognized as important protective immune mechanisms. This study evaluated IgG responses to the HA head, stem, and LAH regions and assessed cross-reactive potential through neutralization, ADCC, and ADCP assays. Methods: IgG responses to the HA head, stem, and LAH regions were measured in vaccinated individuals. Functional assays were conducted for neutralization, ADCC, and ADCP to evaluate the association between antibody levels and immune function. Results: The results showed that HA head-specific IgG increased significantly after vaccination in 50 individuals, whereas stem-specific IgG increased by 72% and LAH-specific IgG by 12–14%. Among the induced antibody subclasses, IgG1 was predominantly increased. Neutralization titers were detected in viruses of the same strain as the vaccine strain, but not in classical or pandemic strains (H5N1, H7N9). HA stem-specific IgG1 antibody titers showed a significant correlation with ADCC/ADCP activity breadth, but no correlation was observed with neutralization breadth. Conclusions: These findings suggest that although current influenza vaccines can induce HA stem-targeted cross-reactive antibodies, their quantity may be insufficient for broad cross-protection, underscoring the need for improved vaccine strategies.

Vaccine hesitancy primarily consists of confidence, complacency, and convenience, including geographical accessibility. However, few studies in developed countries have focused on the association between geographical accessibility to vaccination services and vaccination status and previous studies have shown conflicting results. This cross-sectional study aimed to clarify the association between the number of medical facilities within a 15-minute driving distance from the place of residence and influenza vaccination status, using a large nationwide internet survey in Japan (n = 27,440). Postal codes were used to determine participants' place of residence and the number of medical facilities within a 15-minute drive was calculated using geographic information system data. Participants were classified into quartiles based on the number of medical facilities nearby. They reported their influenza vaccination status over the past year. Modified Poisson regression analysis was conducted with influenza vaccination status as the dependent variable and the number of medical facilities nearby as the independent variable, adjusted for covariates stratified by age (under 65 years: or 65 years and older). Among participants aged 65 years and older, those with fewer medical facilities within a 15-minute drive of their place of residence were significantly less likely to have received an influenza vaccination than those with more medical facilities nearby (prevalence ratio in Q1 relative to Q4: 0.93, 95% confidence interval 0.87-0.99). In contrast, no association was observed among participants aged under 65 years. Geographical accessibility to vaccination services may influence vaccine hesitancy among older adults in Japan, a developed country.