Actin network architecture can ensure robust centering or sensitive decentering of the centrosome.

The orientation of cell polarity depends on the position of the centrosome, the main microtubule-organizing center (MTOC). Microtubules (MTs) transmit pushing forces to the MTOC as they grow against the cell periphery. How the actin network regulates these forces remains unclear. Here, in a cell-free assay, we used purified proteins to reconstitute the interaction of a microtubule aster with actin networks of various architectures in cell-sized microwells. In the absence of actin filaments, MTOC positioning was highly sensitive to variations in microtubule length. The presence of a bulk actin network limited microtubule displacement, and MTOCs were held in place. In contrast, the assembly of a branched actin network along the well edges centered the MTOCs by maintaining an isotropic balance of pushing forces. An anisotropic peripheral actin network caused the MTOC to decenter by focusing the pushing forces. Overall, our results show that actin networks can limit the sensitivity of MTOC positioning to microtubule length and enforce robust MTOC centering or decentering depending on the isotropy of its architecture.

NuMA assemblies organize microtubule asters to establish spindle bipolarity in acentrosomal human cells.

In most animal cells, mitotic spindle formation is mediated by coordination of centrosomal and acentrosomal pathways. At the onset of mitosis, centrosomes promote spindle bipolarization. However, the mechanism through which the acentrosomal pathways facilitate the establishment of spindle bipolarity in early mitosis is not completely understood. In this study, we show the critical roles of nuclear mitotic apparatus protein (NuMA) in the generation of spindle bipolarity in acentrosomal human cells. In acentrosomal human cells, we found that small microtubule asters containing NuMA formed at the time of nuclear envelope breakdown. In addition, these asters were assembled by dynein and the clustering activity of NuMA. Subsequently, NuMA organized the radial array of microtubules, which incorporates Eg5, and thus facilitated spindle bipolarization. Importantly, in cells with centrosomes, we also found that NuMA promoted the initial step of spindle bipolarization in early mitosis. Overall, these data suggest that canonical centrosomal and NuMA-mediated acentrosomal pathways redundantly promote spindle bipolarity in human cells.

Prevalence of osteosarcopenia and its association with mortality and fractures among patients undergoing hemodialysis.

INTRODUCTION: Osteosarcopenia is an age-related syndrome characterized by the coexistence of osteoporosis and sarcopenia. Little is known about the clinical implications of osteosarcopenia among patients undergoing hemodialysis. This study investigated the prevalence of osteosarcopenia and its association with all-cause mortality and fractures in this population. MATERIALS AND METHODS: This retrospective cohort study included outpatients undergoing hemodialysis in Japan. Sarcopenia was defined according to the recommendations of the Asian Working Group for Sarcopenia 2019. Osteoporosis was defined as a T-score of the calcaneus bone < - 2.5. We divided patients into three groups: robust (no osteoporosis or sarcopenia), osteoporosis or sarcopenia alone (osteoporosis without sarcopenia or sarcopenia without osteoporosis), and osteosarcopenia (osteoporosis and sarcopenia). Cox proportional-hazard and negative binomial regression models were used to estimate the associations between osteosarcopenia and all-cause mortality and fractures. RESULTS: Among the 328 patients (mean age, 65.5 ± 11.3 years; men, 59.1%), the prevalence of osteosarcopenia was 22.9%. During the follow-up period (1972 person-years), 131 deaths and 113 fractures occurred. Patients with osteoporosis or sarcopenia alone (hazard ratio 1.36; 95% confidence interval 0.85-2.18) and osteosarcopenia (hazard ratio 2.13; 95% confidence interval, 1.23-3.68) showed a higher risk of all-cause mortality than the robust group. Similar results were observed for the risk of fractures in patients with osteosarcopenia. CONCLUSIONS: Patients undergoing hemodialysis showed a high prevalence of osteosarcopenia, and osteosarcopenia was associated with a poor prognosis in this patient population. Assessing osteosarcopenia may be useful for accurate prognostic stratification of patients undergoing hemodialysis.

Coffee and green tea consumption with the risk of COVID-19 among the vaccine recipients in Japan: a prospective study.

BACKGROUND: While coffee and green tea have been suggested to have immunoprotective effects, it remains elusive whether they can decrease the risk of COVID-19. OBJECTIVE: We prospectively examined the association between coffee and green tea consumption and the risk of COVID-19 among mRNA vaccine recipients during the epidemic of the Omicron variant. METHOD: Participants were 2,110 staff (aged 18 to 76 years) of a large medical facility in Tokyo, who attended a serosurvey in June 2022, predominatly received ≥3 doses of vaccine, and were followed for COVID-19 until December 2022. Coffee and green tea consumption was ascertained via a questionnaire. COVID-19 was identified through the in-house registry. Cox proportional hazards model was used to estimate the hazard ratios (HRs) of COVID-19 across the categories of beverage consumption. RESULT: During 6 months of follow-up, 225 (10.6%) cases of COVID-19 were identified. Contrary to the expectation, higher consumption of coffee was associated with a significant increase in the risk of COVID-19; multivariable-adjusted HRs (95% CI) was 1.00, 0.92 (0.62-1.35), 1.48 (0.99-2.22), and 1.82 (1.20-2.76) for <1 cup/day, 1 cup/day, 2 cups/day, and ≥3 cups/day, respectively (p trend=0.003). Green tea consumption was not significantly associated with the risk of COVID-19. The association with coffee was attenuated if serologically detected infection was added to the cases. CONCLUSION: In a cohort of Japanese hospital staff who received COVID-19 vaccine, higher consumption of coffee was associated with an increased risk of COVID-19 during the epidemic of the Omicron variant. There was no evidence of a significant association between green tea consumption and COVID-19 risk.

Comparison of waist circumference and waist-to-height ratio as predictors of clustering of cardiovascular risk factors among middle-aged people in rural Khanh Hoa, Vietnam.

OBJECTIVE: Given the population-level variation in stature, a universal cut-off for waist circumference (WC) may not be appropriate for some populations. We compared the performance of WC and waist-to-height ratio (WHtR) to detect the clustering of cardiovascular disease (CVD) risk factors in rural Vietnam. METHODS: We obtained data from a baseline survey of the Khanh Hoa Cardiovascular Study comprising 2942 middle-aged residents (40-60 years). We used areas under the receiver operating characteristics curve (AUROC), net reclassification index (NRI), and integrated discrimination improvement (IDI) to compare the performance of WC and WHtR in predicting CVD risk clustering (≥2 of the following risk factors: hypertension, diabetes, dyslipidemia, and elevated C-reactive protein). RESULTS: The optimal cut-off values for WC were 81.8 and 80.7 cm for men and women, respectively. Regarding the clustering of CVD risk factors, the AUROC (95% CI) of WC and WHtR were 0.707 (0.676 to 0.739) and 0.719 (0.689 to 0.749) in men, and 0.682 (0.654 to 0.709) and 0.690 (0.663 to 0.717) in women, respectively. Compared with WC, WHtR had a better NRI (0.229; 0.102-0.344) and IDI (0.012; 0.004-0.020) in men and a better NRI (0.154; 0.050-0.257) in women. CONCLUSIONS: The optimal WC cut-off for Vietnamese men was approximately 10 cm below the recommended Asian cut-off. WHtR might perform slightly better in predicting the clustering of CVD risk factors among the rural population in Vietnam.

Preinfection Neutralizing Antibodies, Omicron BA.5 Breakthrough Infection, and Long COVID: A Propensity Score-Matched Analysis.

BACKGROUND: Data are limited on the role of preinfection humoral immunity protection against Omicron BA.5 infection and long coronavirus disease (COVID) development. METHODS: We conducted nested case-control analysis among tertiary hospital staff in Tokyo who donated blood samples in June 2022 (1 month before Omicron BA.5 wave), approximately 6 months after receiving a third dose of COVID-19 mRNA vaccine. We measured live virus-neutralizing antibody titers against wild type and Omicron BA.5, and anti-receptor-binding domain (RBD) antibody titers at preinfection, and compared them between cases and propensity-matched controls. Among the breakthrough cases, we examined association between preinfection antibody titers and incidence of long COVID. RESULTS: Preinfection anti-RBD and neutralizing antibody titers were lower in cases than controls. Neutralizing titers against wild type and Omicron BA.5 were 64% (95% confidence interval [CI], 42%-77%) and 72% (95% CI, 53%-83%) lower, respectively, in cases than controls. Individuals with previous Omicron BA.1/BA.2 infections were more frequent among controls than cases (10.3% vs 0.8%), and their Omicron BA.5 neutralizing titers were 12.8-fold higher than infection-naive individuals. Among cases, preinfection antibody titers were not associated with incidence of long COVID. CONCLUSIONS: Preinfection immunogenicity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may play a role in protecting against the Omicron BA.5 infection but not preventing long COVID.

Dyslipidemia and SARS-CoV-2 spike antibody titres after the second and third doses of the BNT162b2 vaccine among healthcare workers in Japan.

OBJECTIVE: This study aimed to examine the sex-associated differences in the relationship between dyslipidemia and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike immunoglobulin (Ig)G antibodies among BNT162b2 vaccine recipients. METHODS: Participants were staff members (aged 21-75 years) of a medical and research institution who underwent an anti-SARS-CoV-2 spike IgG antibody test after the second (n = 1872) and third doses (n = 1075) of the BNT162b2 vaccine. Dyslipidemia was defined as triglyceride level ≥150 mg/dl, high-density lipoprotein-cholesterol level <40 mg/dl, low-density lipoprotein-cholesterol level ≥140 mg/dl, or lipid-lowering medication use. Multivariable linear regression was used to calculate the ratio of means for SARS-CoV-2 spike IgG titre according to dyslipidemia status. RESULTS: The prevalence of dyslipidemia was 38.0% in men and 19.6% in women. The relationship between dyslipidemia and SARS-CoV-2 spike IgG titres after the second dose differed markedly by sex (P for interaction <0.001). In men, dyslipidemia was associated with significantly lower IgG titres: the ratio of means (95% confidence interval) was 0.82 (0.72-0.93). However, this association disappeared after the third dose (0.96 [0.78-1.18]). Of the dyslipidemia components, hypertriglyceridemia was inversely associated with SARS-CoV-2 spike IgG antibody titre after both the second and third doses (ratio of means: 0.82 [0.70-0.95] and 0.73 [0.56-0.95], respectively). In women, IgG titres did not differ according to dyslipidemia or hypertriglyceridemia status after either dose. CONCLUSIONS: These results suggest a detrimental role of hypertriglyceridemia in the humoral immune response to the BNT162b2 vaccine for COVID-19 in men but not in women.

Reserved gait capacity and mortality among patients undergoing hemodialysis.

BACKGROUND: Patients undergoing hemodialysis (HD) have difficulty increasing their gait speed in daily life. The extent of the increase from the usual gait speed (UGS) to the maximum gait speed (MGS) is considered the reserved gait capacity (RGC). Little is known regarding the implications of RGC. This study aimed to investigate the association between RGC and all-cause mortality in patients undergoing HD. METHODS: In this retrospective study, we assessed the usual and maximum 10-m walking speed of outpatients who underwent HD between October 2002 and August 2021. RGC was defined as the ratio of MGS to UGS. Patients were divided into three groups according to the tertiles of RGC (low, moderate and high). A Cox proportional hazards regression model was used to examine the association between RGC and all-cause mortality. RESULTS: Of the 496 (median age 66.0 years; men 59%) participants, 186 patients died during the follow-up (incident ratio of 62.0 per 1000 person-years). The patients with moderate [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.46-0.94] and high (HR 0.44, 95% CI 0.30-0.65) RGC had a lower risk of mortality than the low RGC group. Furthermore, even when restricted to a population with only UGS <1.0 m/s, the group with high RGC still had a lower risk of mortality than those with low RGC (HR 0.55, 95% CI 0.33-0.94). CONCLUSIONS: Lower RGC was independently associated with an increased risk of all-cause mortality among patients on HD; high RGC had a survival advantage even with a slow UGS.

Comparison of the association between six different frailty scales and clinical events in patients on hemodialysis.

BACKGROUND: Frailty is associated with adverse outcomes in patients undergoing hemodialysis (HD). However, no study has used various frailty assessments in patients on HD to examine their association with clinical events. In this study, we investigated the association between clinical events and six frailty scales. METHODS: Outpatients who underwent HD between 2018 and 2020 were retrospectively enrolled. Frailty was defined using the Fried Frailty Phenotype, Study of Osteoporotic Fractures (SOF) Index, Short Physical Performance Battery (SPPB), Frail Screening Index, FRAIL scale and Clinical Frailty Scale. Outcomes were clinical events, including a composite of multiple (i.e. recurrent) all-cause hospitalizations, fractures and/or all-cause mortality. The association of clinical events and the frailty scales were investigated using negative binomial regression analysis. RESULTS: Fried Frailty Phenotype [incident rate ratio (IRR), 1.62; 95% confidence interval (CI), 1.49-1.76], SOF Index (IRR, 1.42; 95% CI, 1.10-1.83), SPPB (IRR, 1.79; 95% CI, 1.11-2.88) and Clinical Frailty Scale (IRR, 1.65; 95% CI, 1.04-2.61) were significantly associated with clinical events. However, Frail Screening Index (IRR, 1.38; 95% CI, 0.60-3.18) and FRAIL scale (IRR, 1.30; 95% CI, 0.88-1.92) showed no significant association with clinical events. CONCLUSIONS: Objective frailty assessments (SPPB) and medical staff impression-based frailty (Clinical Frailty Scale) may be useful prognostic predictors for patients on HD. Questionnaire-based frailty assessment should be carefully considered when used as a measurement of frailty.

Cumulative and undiagnosed SARS-CoV-2 infection among the staff of a medical research centre in Tokyo after the emergence of variants.

To describe the trend of cumulative incidence of coronavirus disease 19 (COVID-19) and undiagnosed cases over the pandemic through the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants among healthcare workers in Tokyo, we analysed data of repeated serological surveys and in-house COVID-19 registry among the staff of National Center for Global Health and Medicine. Participants were asked to donate venous blood and complete a survey questionnaire about COVID-19 diagnosis and vaccine. Positive serology was defined as being positive on Roche or Abbott assay against SARS-CoV-2 nucleocapsid protein, and cumulative infection was defined as either being seropositive or having a history of COVID-19. Cumulative infection has increased from 2.0% in June 2021 (pre-Delta) to 5.3% in December 2021 (post-Delta). After the emergence of the Omicron, it has increased substantially during 2022 (16.9% in June and 39.0% in December). As of December 2022, 30% of those who were infected in the past were not aware of their infection. Results indicate that SARS-CoV-2 infection has rapidly expanded during the Omicron-variant epidemic among healthcare workers in Tokyo and that a sizable number of infections were undiagnosed.

Omicron BA.1 neutralizing antibody response following Delta breakthrough infection compared with booster vaccination of BNT162b2.

BACKGROUND: Longitudinal data are lacking to compare booster effects of Delta breakthrough infection versus third vaccine dose on neutralizing antibodies (NAb) against Omicron. METHODS: Participants were the staff of a national research and medical institution in Tokyo who attended serological surveys on June 2021 (baseline) and December 2021 (follow-up); in between, the Delta-dominant epidemic occurred. Of 844 participants who were infection-naïve and had received two doses of BNT162b2 at baseline, we identified 11 breakthrough infections during follow-up. One control matched to each case was selected from boosted and unboosted individuals. We compared live-virus NAb against Wild-type, Delta, and Omicron BA.1 across groups. RESULTS: Breakthrough infection cases showed marked increases in NAb titers against Wild-type (4.1-fold) and Delta (5.5-fold), and 64% had detectable NAb against Omicron BA.1 at follow-up, although the NAb against Omicron after breakthrough infection was 6.7- and 5.2-fold lower than Wild-type and Delta, respectively. The increase was apparent only in symptomatic cases and as high as in the third vaccine recipients. CONCLUSIONS: Symptomatic Delta breakthrough infection increased NAb against Wild-type, Delta, and Omicron BA.1, similar to the third vaccine. Given the much lower NAb against Omicron BA.1, infection prevention measures must be continued irrespective of vaccine and infection history while the immune evasive variants are circulating.

3',4'-Dihydroxyflavonol Attenuates Lipopolysaccharide-Induced Neuroinflammatory Responses of Microglial Cells by Suppressing AKT-mTOR and NF-κB Pathways.

Microglia-related neuroinflammation contributes to the pathogenesis of a variety of neurodegenerative disorders such as Alzheimer's disease. The synthetic flavonoid, 3',4'-dihydroxyflavonol (3,3',4'-trihydroxyflavone), has been shown to protect brain or myocardial ischemia reperfusion-induced cell death and prevent the aggregation of amyloid-ß protein, a process that causes progressive neurodegeneration in Alzheimer's disease. Here, we explored the anti-neuroinflammatory ability of 3',4'-dihydroxyflavonol in lipopolysaccharide (LPS)-activated MG6 microglial cells. 3',4'-Dihydroxyflavonol attenuated LPS-induced tumor necrosis factor-α and nitric oxide secretion in MG6 cells. LPS-induced phosphorylation of mammalian target of rapamycin (mTOR), nuclear factor-κB (NF-κB), and protein kinase B (AKT) (which are all associated with the neuroinflammatory response in microglia) were attenuated by 3',4'-dihydroxyflavonol treatment. Treatment with the mTOR inhibitor, rapamycin, NF-κB inhibitor, caffeic acid phenethyl ester, or AKT inhibitor, LY294002, also attenuated LPS-induced tumor necrosis factor-α and nitric oxide secretion in MG6 cells. LY294002 treatment attenuated LPS-induced phosphorylation of mTOR and NF-κB in MG6 cells. Hence, our study suggests that 3',4'-dihydroxyflavonol can attenuate the neuroinflammatory response of microglial cells by suppressing the AKT-mTOR and NF-κB pathways.

The association between living alone and depressive symptoms and the role of pet ownership among Japanese workers.

BACKGROUND: Living alone has been positively associated with the prevalence of depressive symptoms. We examined how a combination of living alone and pet ownership relates to depressive symptoms. METHODS: As part of the Japan Epidemiology Collaboration on Occupational Health Study, we conducted a survey on health-related lifestyles, including living arrangements and pet ownership, among 12,763 employees of five companies in 2018-2021. Depressive symptoms were assessed using the 11-item Center for Epidemiological Studies-Depression Scale (cutoff score ≥ 9). A Poisson regression model with a robust variance estimator was used to calculate prevalence ratio and 95% confidence interval (CI) while adjusting for covariates. RESULTS: Among the participants, 30.9% were depressed, 17.7% had pets, and 29.1% lived alone. Compared to individuals living with others but not with a pet, those living alone and not with a pet had a 1.17 times higher prevalence ratio of depressive symptoms (95% CI: 1.08-1.26). The corresponding figures were 1.03 (95% CI: 0.95-1.11) for those living with others and pet(s) and 1.42 (95% CI: 1.18-1.69) for those living alone but with pet(s). CONCLUSION: Living alone was significantly associated with a higher prevalence of depressive symptoms. The association was rather stronger among individuals with vs. without pets. Pet ownership may not be associated with decreased depressive symptoms.

Different associations of occupational and leisure-time physical activity with the prevalence of hypertension among middle-aged community dwellers in rural Khánh Hòa, Vietnam.

BACKGROUND: In contrast to high-income countries where physical activity (PA), particularly leisure-time PA, has been shown to be protective against hypertension, few studies have been conducted in low- and middle-income countries. We examined the cross-sectional association between PA and hypertension prevalence among rural residents in Vietnam. METHODS: We used data collected in the baseline survey of a prospective cohort study, among 3000 people aged 40-60 years old residing in rural Khánh Hòa, Vietnam. Hypertension was defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or the use of antihypertensive medication. We assessed occupational PA and leisure-time PA using the Global Physical Activity Questionnaire. A robust Poisson regression model was used to investigate the associations, with adjustment for covariates. RESULTS: The prevalence of hypertension was 39.6%. After adjusting for socio-demographic and lifestyle-related variables, leisure-time PA was positively associated with hypertension prevalence (prevalence ratio [PR]: 1.03 per 10 MET-hour/week, 95% confidence interval [CI] 1.01-1.06). Occupational PA was inversely associated with hypertension prevalence (PR: 0.98 per 50 MET-hour/week, 95% CI = 0.96-0.996). After adjusting for BMI and other health-related variables, the association related to occupational PA became statistically non-significant, while the association related to leisure-time PA remained statistically significant. CONCLUSION: In contrast to previous studies in high-income countries, we found that leisure-time PA was positively associated with hypertension prevalence and occupational PA was associated with a lower hypertension prevalence. This suggests that the association between PA and hypertension might differ depending on the context.

The association between experience of COVID-19-related discrimination and psychological distress among healthcare workers for six national medical research centers in Japan.

BACKGROUND: Discrimination is an important determinant of negative mental health outcomes. This study determined the association between the experience of COVID-19-related discrimination and psychological distress among healthcare workers (HCWs) in Japan. METHODS: This cross-sectional study conducted a health survey among 5703 HCWs of six national medical and research centers in Japan from October 2020 to March 2021. COVID-19-related discrimination was defined either when participants or their family members were badmouthed or when they felt discriminated against in some way. We used the Kessler Psychological Distress Scale (K6) to assess the presence of severe psychological distress (≥ 13 points). We used logistic regression models to examine the association between discrimination and psychological distress. We also identified factors associated with discrimination. RESULTS: Of the participants, 484 (8.4%) reported COVID-19-related discrimination and 486 (8.5%) had severe psychological distress. HCWs who were female vs. male (adjusted odds ratio [AOR] = 1.41, 95% confidence interval [CI] = 1.28-1.55), had high vs. low viral exposure (AOR = 2.31, 95% CI = 1.81-2.93), and worked for 11 or more hours/day vs. 8 or less hours/day (AOR = 1.42, 95% CI = 1.35-1.49) were more likely to have experienced COVID-19-related discrimination. The AOR (95% CI) of severe psychological distress was 1.83 (1.29-2.59) among those who experienced discrimination. In the stratified analysis by sociodemographic and job-related factors, all the interactions did not reach statistical significance (p for interaction > 0.20). CONCLUSION: Experience of COVID-19-related discrimination was associated with severe psychological distress among HCWs. During the pandemic, effective measures should be taken to prevent the development of negative mental health outcomes in HCWs who experience discrimination.

Trajectory of Serum Albumin Prior to Death in Patients Receiving Hemodialysis.

OBJECTIVE: Although some clinical expert guidelines recommend regular monitoring of serum albumin levels in patients undergoing maintenance hemodialysis, little is known about the serum albumin trajectory patterns over time, and it is unclear how the trajectory change before death. METHODS: We performed this retrospective study using data from 421 patients receiving hemodialysis in a dialysis facility. We divided patients into died and survived groups according to whether they died during the observation period. To compare the albumin trajectories during the observation period between the died and survived groups, linear mixed-effect models and a backward timescale from the year of death or study end were used. RESULTS: During the observation period (median, 5.1 years; maximum, 8.4 years), 115 patients receiving dialysis died. The serum albumin level showed steeper decline 3 years before death in the died group than in the survived group. The difference in albumin between the died and survived groups became apparent 3 years before death (difference, 0.08 g/dL; 95% confidence interval, 0.00-0.15 g/dL; P = .04), and the difference widened over time (difference at 1 year before death, 0.24 g/dL; 95% confidence interval, 0.14-0.33 g/dL; P < .001). Furthermore, in an analysis of albumin trajectories according to cause of death, the albumin level showed a downward trend regardless of the cause of death. CONCLUSION: The serum albumin trajectory differed between patients undergoing hemodialysis who died and who survived, supporting the importance of monitoring the albumin trajectory in clinical practice.

Coronavirus Disease 2019 (COVID-19) Breakthrough Infection and Post-Vaccination Neutralizing Antibodies Among Healthcare Workers in a Referral Hospital in Tokyo: A Case-Control Matching Study.

BACKGROUND: While increasing coverage of effective vaccines against coronavirus disease 2019 (COVID-19), emergent variants raise concerns about breakthrough infection. Data are limited, however, whether breakthrough infection during the epidemic of the variant is ascribed to insufficient vaccine-induced immunogenicity. METHODS: We describe incident COVID-19 in relation to the vaccination program among workers of a referral hospital in Tokyo. During the predominantly Delta epidemic, we followed 2415 fully vaccinated staff (BNT162b2) for breakthrough infection and selected 3 matched controls. We measured post-vaccination neutralizing antibodies against the wild-type, Alpha (B.1.1.7), and Delta (B.1.617.2) strains using live viruses and anti-spike antibodies using quantitative assays, and compared them using the generalized estimating equation model between the 2 groups. RESULTS: No COVID-19 cases occurred 1-2 months after the vaccination program during the fourth epidemic wave in Japan, dominated by the Alpha variant, while 22 cases emerged 2-4 months after the vaccination program during the fifth wave, dominated by the Delta variant. In the vaccinated cohort, all 17 cases of breakthrough infection were mild or asymptomatic and participants had returned to work early. There was no measurable difference between cases and controls in post-vaccination neutralizing antibody titers against the wild-type, Alpha, Delta, and anti-spike antibody titers, while neutralizing titers against the variants were considerably lower than those against the wild-type. CONCLUSIONS: Post-vaccination neutralizing antibody titers were not decreased among patients with breakthrough infection relative to their controls under the Delta variant outbreak. The result points to the importance of infection-control measures in the post-vaccination era, irrespective of immunogenicity profile.

Association of Changes of lifestyle behaviors before and during the COVID-19 pandemic with mental health: a longitudinal study in children and adolescents.

BACKGROUND: We examined the prospective associations of changes in lifestyle behaviors before/during the COVID-19 pandemic, namely physical activity and screen time, with mental health. Furthermore, the impacts of physical activity and screen time on mental health during the pandemic were examined cross-sectionally. METHODS: A two-wave longitudinal study was conducted among 2423 children and adolescents in Shanghai, China. Lifestyle behavior variables (physical activity and screen time) and psychological variables (depressive symptoms, anxiety, and stress) were measured using a self-reported questionnaire in January and March 2020. A series of multivariable logistic regressions were performed to examine the associations between changes in lifestyle behaviors in two waves and psychological problems. The combined associations of physical activity and screen time with psychological problems were also explored using the second wave data. RESULTS: Compared to students with persistently short screen time before and during the COVID-19 pandemic, those with prolonged screen time (OR = 1·36 for depression, OR = 1·48 for anxiety) and those with persistently long screen time (OR = 1·70 for depression, OR = 2·13 for anxiety) reported a higher risk of psychological symptoms. The association between changes in physical activity and psychological symptoms was not statistically significant after adjustment for demographic factors, socioeconomic status, and screen time. During the COVID-19 pandemic, engaging in longer screen time (OR = 1·44 for depression, OR = 1·55 for anxiety) was associated with worsened psychological conditions, while engaging in increased physical activity (OR = 0·58 for depression, OR = 0·66 for anxiety) was associated with better psychological conditions. CONCLUSIONS: Our study suggests that promoting physical activity and limiting leisure screen time during the COVID-19 pandemic are important to prevent and mitigate psychological problems in children and adolescents. Therefore, effective interventions targeting lifestyle behaviors are needed to protect children and adolescents' physical and mental health.

Use of heated tobacco products, moderate alcohol drinking, and anti-SARS-CoV-2 IgG antibody titers after BNT162b2 vaccination among Japanese healthcare workers.

The effect of heated tobacco products (HTPs) use and moderate alcohol drinking on immunogenicity to coronavirus disease (COVID-19) vaccines remain elusive. This study aimed to examine the association of tobacco product use and alcohol consumption with anti-SARS-CoV-2 spike IgG antibody titers after the BNT162b2 vaccine. Participants were 3433 healthcare workers receiving two vaccine doses in the 4 national centers for advanced medical and research in Japan. Smoking status and alcohol consumption were assessed via a questionnaire, and anti-SARS-CoV-2 spike IgG titers were measured with chemiluminescent enzyme immunoassay using serum collected on the median of 64 days after the second vaccination. Multilevel linear regression models were used to estimate the geometric mean titers (GMT) and the ratios of means (RoM) between groups with adjustment for covariates. Compared with never-smokers (GMT = 118), IgG antibody titers were significantly lower among HTPs users (including those who also smoked cigarettes) (GMT = 105; RoM = 0.89 [95%CI: 0.78-0.99]) and exclusive cigarettes smokers (GMT = 98; RoM = 0.81 [95%CI: 0.71-0.92]). Compared with non-drinkers of alcohol (GMT = 123), alcohol drinkers consuming <1 go/day (GMT = 113; RoM = 0.93 [95%CI: 0.88-0.98]), 1-1.9 go/day (GMT = 104; RoM = 0.85 [95%CI: 0.78-0.93]), and ≥ 2 go/day (GMT = 103; RoM = 0.84 [95%CI: 0.74-0.96]) had significantly lower antibody titers (P for trend<0.01). Spline analysis showed a large reduction of antibody until around 1 go/day of alcohol consumption, and then they gradually decreased. Results suggest that in addition to conventional cigarette smoking and heavy alcohol drinking, HTPs use and moderate alcohol drinking may be predictors of lower immunological response to COVID-19 vaccine.

Postchemotherapy immune status in infants with acute lymphoblastic leukemia: A report from the JPLSG MLL-10 trial.

The MLL-10 trial (UMIN000004801) modified a Children's Oncology Group (COG) AALL0631 therapy for infants with KMT2A-rearranged acute lymphoblastic leukemia (ALL). In 2016, one registered case developed secondary immunodeficiency during maintenance therapy and eventually died due to cytomegalovirus infection. Around the same time, fatal secondary immunodeficiencies were reported in five infants with ALL in North America who had received COG-based chemotherapy between 1996 and 2015. Given these cases, we decided to conduct a retrospective study on the postchemotherapy immune status of infants with ALL. A questionnaire collected data on posttreatment immune function, frequency of infections, and supportive care for the 34 infants in the MLL-10 trial. Patients receiving allogeneic hematopoietic stem cell transplantation in first remission were excluded. Responses to the survey were obtained in 28 cases (85%). Most patients were immunocompetent after the completion of chemotherapy (median follow-up duration from the day of chemotherapy completion was 431 days), except for the aforementioned case. There were seven patients with nonsevere viral infection, all of whom recovered. In conclusion, severe chemotherapy-induced immunodeficiency in infants with ALL appears to be rare, but prospective data collection of immune function is necessary to clarify this finding.