Association of homocysteine with white matter dysconnectivity in schizophrenia.

Several studies have shown white matter (WM) dysconnectivity in people with schizophrenia (SZ). However, the underlying mechanism remains unclear. We investigated the relationship between plasma homocysteine (Hcy) levels and WM microstructure in people with SZ using diffusion tensor imaging (DTI). Fifty-three people with SZ and 83 healthy controls (HC) were included in this retrospective observational study. Tract-Based Spatial Statistics (TBSS) were used to evaluate group differences in WM microstructure. A significant negative correlation between plasma Hcy levels and WM microstructural disruption was noted in the SZ group (Spearman's ρ = -.330, P = 0.016) but not in the HC group (Spearman's ρ = .041, P = 0.712). These results suggest that increased Hcy may be associated with WM dysconnectivity in SZ, and the interaction between Hcy and WM dysconnectivity could be a potential mechanism of the pathophysiology of SZ. Further, longitudinal studies are required to investigate whether high Hcy levels subsequently cause WM microstructural disruption in people with SZ.

Upper Respiratory Symptoms as Long COVID: Insight from a Multicenter Cohort Study.

Objective: This study aimed to investigate the clinical features of long COVID cases presenting with upper respiratory symptoms, a topic not yet fully elucidated. Study Design: Prospective cohort study. Setting: A multicenter study involving 26 medical facilities in Japan. Methods: Inclusion criteria were patients aged ≥18 years old with a confirmed COVID-19 diagnosis via severe acute respiratory syndrome coronavirus 2 polymerase chain reaction or antigen testing, who were hospitalized at the participating medical facilities. Analyzing clinical information and patient-reported outcomes from 1009 patients were analyzed. The outcome measured the degree of initial symptoms for taste or olfactory disorders and assessed the likelihood of these symptoms persisting as long COVID, as well as the impact on quality of life if the upper respiratory symptoms persisted as long COVID. Results: Patients with high albumin, low C-reactive protein, and low lactate dehydrogenase in laboratory tests tended to experience taste or olfactory disorders as part of long COVID. Those with severe initial symptoms had a higher risk of experiencing residual symptoms at 3 months, with an odds ratio of 2.933 (95% confidence interval [CI], 1.282-6.526) for taste disorders and 3.534 (95% CI, 1.382-9.009) for olfactory disorders. Presence of upper respiratory symptoms consistently resulted in lower quality of life scores. Conclusion: The findings from this cohort study suggest that severe taste or olfactory disorders as early COVID-19 symptoms correlate with an increased likelihood of persistent symptoms in those disorders as long COVID.

Efficacy of Pharmacotherapy for Seasonal Influenza in Young and Middle-aged Adults: A Systematic Review and Network Meta-analysis.

Background Seasonal influenza affects healthcare demand. However, the efficacy of anti-influenza drugs, particularly among young patients at a low risk of complications, has rarely been evaluated. Therefore, we evaluated the efficacy of anti-influenza drugs against seasonal influenza in healthy young and middle-aged adults. Methods A systematic review and network meta-analysis were conducted. The Cochrane Central Register of Controlled Trials and Medical Literature Analysis and Retrieval System Online were searched for original articles reporting double-blind, randomized controlled trials published up to the end of July 2023. Clinical trials that tested the efficacy of anti-influenza drugs in young and middle-aged patients with seasonal influenza were also included. The primary outcome was time to fever alleviation. The efficacy and adverse effects of these treatments were estimated using a Bayesian hierarchical random-effects model and a Markov chain Monte Carlo simulation. Results In total, 24 articles with 34 treatments and 8,949 individuals were included. Oseltamivir (300 mg/day for 5 days) showed the largest reduction in time to fever alleviation by -19.1 (95% confidence interval [CI]: -29.4, -10.7) h compared with a placebo. Baloxavir marboxil (40 mg/day) reduced the time to symptom alleviation by -28.2 (95% CI: -42.7, -13.7) h, and peramivir (300 mg/day) administered by intravenous infusion for 1 day reduced the time to resumption of usual activities by -43.5 (95% CI: -72.8, -14.2) h. Conclusion Several pharmaceutical treatments were able to reduce the recovery time for fever and symptom alleviation and resumption of usual activities in young and middle-aged adults with seasonal influenza without increasing the risk of complications.

Cluster analysis of long COVID in Japan and association of its trajectory of symptoms and quality of life.

BACKGROUND: Multiple prolonged symptoms observed in patients who recovered from COVID-19 are defined as long COVID. Although diverse phenotypic combinations are possible, they remain unclear. This study aimed to perform a cluster analysis of long COVID in Japan and clarify the association between its characteristics and background factors and quality of life (QOL). METHODS: This multicentre prospective cohort study collected various symptoms and QOL after COVID-19 from January 2020 to February 2021. This study included 935 patients aged ≥18 years with COVID-19 at 26 participating medical facilities. Hierarchical cluster analysis was performed using 24 long COVID symptom at 3 months after diagnosis. RESULTS: Participants were divided into the following five clusters: numerous symptoms across multiple organs (cluster 1, n=54); no or minor symptoms (cluster 2, n=546); taste and olfactory disorders (cluster 3, n=76); fatigue, psychoneurotic symptoms and dyspnoea (low prevalence of cough and sputum) (cluster 4, n=207) and fatigue and dyspnoea (high prevalence of cough and sputum) (cluster 5, n=52). Cluster 1 included elderly patients with severe symptoms, while cluster 3 included young female with mild symptoms. No significant differences were observed in the comorbidities. Cluster 1 showed the most impaired QOL, followed by clusters 4 and 5; these changes as well as the composition of symptoms were observed over 1 year. CONCLUSIONS: We identified patients with long COVID with diverse characteristics into five clusters. Future analysis of these different pathologies could result in individualised treatment of long COVID. TRIAL REGISTRATION NUMBER: The study protocol is registered at UMIN clinical trials registry (UMIN000042299).

Sleep duration, its change, and risk of dementia among Japanese: The Japan Public Health Center-based Prospective Study.

OBJECTIVE: Previous findings on the association between sleep duration, changes in sleep duration, and long-term dementia risk were mixed. Thus, we aimed to investigate the association between midlife sleep duration, its change, and dementia. METHODS: We recruited 41,731 Japanese (40-71 years) and documented their habitual sleep duration at baseline (1990-1994) and a 5-year follow-up survey. Changes in sleep duration were calculated as differences between baseline and 5-year measurements. We identified dementia using the Long-Term Care Insurance system (2007-2016). Hazard ratios (HRs) and 95% confidence intervals (CIs) of dementia were calculated using the area-stratified Cox model. RESULTS: During 360,389 person-years, 4621 participants exhibited dementia. The multivariable HRs of dementia compared with 7 h of sleep were 1.13 (95% CI: 0.98-1.30) for 3-5 h, 0.93 (0.85-1.02) for 6 h, 1.06 (0.99-1.14) for 8 h, 1.13 (1.01-1.27) for 9 h, and 1.40 (1.21-1.63) for 10-12 h with a J-shaped fashion (p for linear < 0.001 and quadratic < 0.001). For its change, the HRs compared with no change were 1.02 (0.90-1.16) for decreased ≥2 h, 0.95 (0.88-1.03) for decreased 1 h, 1.00 (0.91-1.09) for increased 1 h, and 1.37 (1.20-1.58) for increased ≥2 h. The positive association for decreased sleep duration was observed in individuals with an initial sleep duration of ≤7 h, but not in those with ≥8 h (p for interaction = 0.007). CONCLUSIONS: Long and increased sleep duration was associated with a higher risk of dementia.

Associations of conservatism and jumping to conclusions biases with aberrant salience and default mode network.

AIM: While conservatism bias refers to the human need for more evidence for decision-making than rational thinking expects, the jumping to conclusions (JTC) bias refers to the need for less evidence among individuals with schizophrenia/delusion compared to healthy people. Although the hippocampus-midbrain-striatal aberrant salience system and the salience, default mode (DMN), and frontoparietal networks ("triple networks") are implicated in delusion/schizophrenia pathophysiology, the associations between conservatism/JTC and these systems/networks are unclear. METHODS: Thirty-seven patients with schizophrenia and 33 healthy controls performed the beads task, with large and small numbers of bead draws to decision (DTD) indicating conservatism and JTC, respectively. We performed independent component analysis (ICA) of resting functional magnetic resonance imaging (fMRI) data. For systems/networks above, we investigated interactions between diagnosis and DTD, and main effects of DTD. We similarly applied ICA to structural and diffusion MRI to explore the associations between DTD and gray/white matter. RESULTS: We identified a significant main effect of DTD with functional connectivity between the striatum and DMN, which was negatively correlated with delusion severity in patients, indicating that the greater the anti-correlation between these networks, the stronger the JTC and delusion. We further observed the main effects of DTD on a gray matter network resembling the DMN, and a white matter network connecting the functional and gray matter networks (all P < 0.05, family-wise error [FWE] correction). Function and gray/white matter showed no significant interactions. CONCLUSION: Our results support the novel association of conservatism and JTC biases with aberrant salience and default brain mode.

Cough and sputum in long COVID are associated with severe acute COVID-19: a Japanese cohort study.

BACKGROUND: Multiple prolonged symptoms are observed in patients who recover from acute coronavirus disease 2019 (COVID-19), defined as long COVID. Cough and sputum are presented by patients with long COVID during the acute and post-acute phases. This study aimed to identify specific risk factors for cough and sputum in patients with long COVID. METHODS: Hospitalized patients with COVID-19 aged 18 years were enrolled in a multicenter cohort study at 26 medical institutions. Clinical data during hospitalization and patient-reported outcomes after discharge were collected from medical records, paper-based questionnaires, and smartphone apps. RESULTS: At the 3-, 6-, and 12-month follow-ups, there were no differences in the incidence rates of wet and dry coughs. In contrast, the proportion of patients presenting sputum without coughing increased over time compared to those with sputum and coughing. Univariate analyses of cough and sputum at all follow-up visits identified intermittent mandatory ventilation (IMV), smoking, and older age as risk factors for prolonged symptoms. At the 12-month follow-up, persistent cough and sputum were associated with the characteristics of severe COVID-19 based on imaging findings, renal and liver dysfunction, pulmonary thromboembolism, and higher serum levels of LDH, KL-6, and HbA1C. The Kaplan-Meier curves showed that the severity of acute COVID-19 infection was correlated with prolonged cough and sputum production. Multivariable logistic regression analysis showed that IMV ventilator management were independent risk factors for prolonged cough and sputum at 12 months. CONCLUSIONS: In a Japanese population with long COVID, prolonged cough and sputum production were closely associated with severe COVID-19. These findings emphasize that a preventive approach including appropriate vaccination and contact precaution and further development of therapeutic drugs for COVID-19 are highly recommended for patients with risk factors for severe infection to avoid persistent respiratory symptoms.

Asthma is a risk factor for general fatigue of long COVID in Japanese nation-wide cohort study.

BACKGROUND: Multiple prolonged symptoms are observed in patients who recover from an acute COVID-19 infection, which is defined as long COVID. General fatigue is frequently observed in patients with long COVID during acute and post-acute phases. This study aimed to identify the specific risk factors for general fatigue in long COVID. METHODS: Hospitalized patients with COVID-19 aged over 18 years were enrolled in a multicenter cohort study at 26 medical institutions. Clinical data during hospitalization and patient-reported outcomes after discharge were collected from medical records, paper-based questionnaires, and smartphone apps. RESULTS: Among prolonged symptoms through 1-year follow-ups, general fatigue was the most interfering symptom in daily life. Patients with protracted fatigue at all follow-up periods had lower quality of life scores at the 12-month follow-up. Univariate logistic regression analysis of the presence or absence of general fatigue at the 3-month, 6-month, and 12-month follow-ups identified asthma, younger age, and female sex as risk factors for prolonged fatigue. Multivariable logistic regression analysis revealed that asthma was an independent risk factor for persistent fatigue during the 12-month follow-up period. Longitudinal changes in the symptoms of patients with or without asthma demonstrated that general fatigue, not cough and dyspnea, was significantly prolonged in patients with asthma. CONCLUSIONS: In a Japanese population with long COVID, prolonged general fatigue was closely linked to asthma. A preventive approach against COVID-19 is necessary to avoid sustained fatigue and minimize social and economic losses in patients with asthma.

Calcium channel blockers may reduce the development of long COVID in females.

With the rising numbers of patients infected with severe acute respiratory syndrome coronavirus 2, long coronavirus disease 2019 (COVID-19)-a sequelae of COVID-19-has become a major problem. Different sexes and age groups develop different long COVID symptoms, and the risk factors for long COVID remain unclear. Therefore, we performed subgroup analyses of patients with COVID-19, classifying them into different groups. In this multicenter cohort study, using an original questionnaire, we examined patients (≥18 years old) diagnosed with COVID-19 from November 2020 to March 2022 and hospitalized at participating medical facilities. In total, 1066 patients were registered (361 female, 620 male). Hypertension was the most common comorbidity (n = 344; 32.5%). Females with hypertension were significantly less likely to develop long COVID symptoms than those without hypertension (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.27-0.98; p = 0.043). In females, Ca channel blocker administration, rather than having hypertension, was significantly associated with reductions in the frequency of alopecia (OR 0.14, 95% CI 0.03-0.67, p = 0.015), memory impairment (OR 0.14, 95% CI 0.02-0.82, p = 0.029), sleeping disorders (OR 0.17, 95% CI 0.04-0.67, p = 0.012), tinnitus (OR 0.23, 95% CI 0.05-0.98, p = 0.047), sputum (OR 0.31, 95% CI 0.10-0.92, p = 0.035), and fever (OR 0.33, 95% CI 0.12-0.93, p = 0.036). Several long COVID symptoms, including alopecia, were significantly negatively associated with Ca channel-blocker administration in female patients with long COVID. Calcium channel blockers may reduce the development of long COVID in females.

Comprehensive analysis of long COVID in a Japanese nationwide prospective cohort study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly since 2019, and the number of reports regarding long COVID has increased. Although the distribution of long COVID depends on patient characteristics, epidemiological data on Japanese patients are limited. Hence, this study aimed to investigate the distribution of long COVID in Japanese patients. This study is the first nationwide Japanese prospective cohort study on long COVID. METHODS: This multicenter, prospective cohort study enrolled hospitalized COVID-19 patients aged ≥18 years at 26 Japanese medical institutions. In total, 1200 patients were enrolled. Clinical information and patient-reported outcomes were collected from medical records, paper questionnaires, and smartphone applications. RESULTS: We collected data from 1066 cases with both medical records and patient-reported outcomes. The proportion of patients with at least one symptom decreased chronologically from 93.9% (947/1009) during hospitalization to 46.3% (433/935), 40.5% (350/865), and 33.0% (239/724) at 3, 6, and 12 months, respectively. Patients with at least one long COVID symptom showed lower quality of life and scored higher on assessments for depression, anxiety, and fear of COVID-19. Female sex, middle age (41-64 years), oxygen requirement, and critical condition during hospitalization were risk factors for long COVID. CONCLUSIONS: This study elucidated the symptom distribution and risks of long COVID in the Japanese population. This study provides reference data for future studies of long COVID in Japan.

Longitudinal long COVID symptoms in Japanese patients after COVID-19 vaccinations.

We conducted a subgroup analysis of a study on the long-term effects of COVID-19 (long COVID) in Japan to assess the effect of vaccination on long COVID symptoms. We assessed the clinical course of 111 patients with long COVID at the time of vaccination. The follow-up period was one year from the onset of COVID-19 or until the administration of the third vaccine dose. Of the 111 patients, 15 (13.5%) reported improvement, four (3.6%) reported deterioration, and 92 (82.9%) reported no change in their long COVID symptoms after vaccination. The most common long COVID symptoms before vaccination were alopecia, dyspnea, muscle weakness, fatigue, and headache among participants whose symptoms improved. Reduced dyspnea and alopecia were the most frequently reported improvements in symptoms after vaccination. Some symptoms persisted, including sleep disturbance, myalgia, and hypersensitivity. Vaccination did not appear to have a clinically important effect on patients with long COVID symptoms.

Cerebral cortical structural alteration patterns across four major psychiatric disorders in 5549 individuals.

According to the operational diagnostic criteria, psychiatric disorders such as schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and autism spectrum disorder (ASD) are classified based on symptoms. While its cluster of symptoms defines each of these psychiatric disorders, there is also an overlap in symptoms between the disorders. We hypothesized that there are also similarities and differences in cortical structural neuroimaging features among these psychiatric disorders. T1-weighted magnetic resonance imaging scans were performed for 5,549 subjects recruited from 14 sites. Effect sizes were determined using a linear regression model within each protocol, and these effect sizes were meta-analyzed. The similarity of the differences in cortical thickness and surface area of each disorder group was calculated using cosine similarity, which was calculated from the effect sizes of each cortical regions. The thinnest cortex was found in SZ, followed by BD and MDD. The cosine similarity values between disorders were 0.943 for SZ and BD, 0.959 for SZ and MDD, and 0.943 for BD and MDD, which indicated that a common pattern of cortical thickness alterations was found among SZ, BD, and MDD. Additionally, a generally smaller cortical surface area was found in SZ and MDD than in BD, and the effect was larger in SZ. The cosine similarity values between disorders were 0.945 for SZ and MDD, 0.867 for SZ and ASD, and 0.811 for MDD and ASD, which indicated a common pattern of cortical surface area alterations among SZ, MDD, and ASD. Patterns of alterations in cortical thickness and surface area were revealed in the four major psychiatric disorders. To our knowledge, this is the first report of a cross-disorder analysis conducted on four major psychiatric disorders. Cross-disorder brain imaging research can help to advance our understanding of the pathogenesis of psychiatric disorders and common symptoms.

Allergic fungal rhinosinusitis: What we can learn from allergic bronchopulmonary mycosis.

Allergic fungal rhinosinusitis (AFRS) and allergic bronchopulmonary mycosis (ABPM) are inflammatory disorders of the respiratory tract resulting from type 1 and 3 hypersensitivity reactions against fungi. The hallmark features of both diseases are eosinophil infiltration into the airway mucosa caused by localized type 2 inflammation and concomitant viscid secretions in the airways. Eosinophilic mucin-induced compression of adjacent anatomic structures leads to bone erosion and central bronchiectasis in the upper and lower respiratory tracts, respectively. Although these diseases share common features in their pathogenesis, they also exhibit notable differences. Epidemiologic findings are diverse, with AFRS typically presenting at a younger age, exhibiting less complicated bronchial asthma, and displaying lower total immunoglobulin E levels in laboratory findings compared with ABPM. Furthermore, despite their similar pathogenesis, the rarity of sinio-bronchial allergic mycosis in both AFRS and ABPM underscores the distinctions between these two diseases. This review aims to clarify the similarities and differences in the pathogenesis of AFRS and ABPM to determine what can be learned about AFRS from ABPM, where more is known.

Profile of Nagasaki Islands Study (NaIS): A Population-Based Prospective Cohort Study on Multi-disease.

In an aging society, it is important to visualize the conditions of people living with diseases or disabilities, such as frailty and sarcopenia, and determine the environmental and genetic factors underlying such conditions. Atherosclerosis and arterial stiffness are key conditions between these factors and noncommunicable diseases. In 2014, we launched a population-based prospective open-cohort study, the Nagasaki Islands Study (NaIS), which was conducted in Goto City, located in the remote islands of Nagasaki Prefecture, Japan, mostly involving middle-aged and older residents. We conducted our own health checkups along with the annual standardized checkups organized by the municipality; recruited study participants; and started to follow-up with them for vital status (death), migration, and occurrence of diseases such as myocardial infarction, stroke, fracture, and human T-cell leukemia virus type 1 (HTLV-1) -associated uveitis. Our checkups were conducted as baseline surveys in different areas of Goto City during the fiscal years 2014-2016, secondary surveys during 2017-2019, and tertiary surveys since 2021, consisting of medical interviews, physical examinations, blood and urine tests, body composition measurements, osteoporosis screening, arterial stiffness measurements, carotid ultrasonography, and dental examination. A total of 4,957 residents participated in either the baseline or secondary surveys and were followed-up; and 3,594 and 3,364 residents (aged 27-96 and 28-98 years) participated in the baseline and secondary surveys, respectively. In conclusion, the NaIS has been undertaken to reveal the influence of aging and risk factors of noncommunicable diseases and disabilities, with an aim to contribute towards better healthcare in the future.

Association between enhanced carbonyl stress and decreased apparent axonal density in schizophrenia by multimodal white matter imaging.

Carbonyl stress is a condition featuring increased rich reactive carbonyl compounds, which facilitate the formation of advanced glycation end products including pentosidine. We previously reported the relationship between enhanced carbonyl stress and disrupted white matter integrity in schizophrenia, although which microstructural component is disrupted remained unclear. In this study, 32 patients with schizophrenia (SCZ) and 45 age- and gender-matched healthy volunteers (HC) were recruited. We obtained blood samples for carbonyl stress markers (plasma pentosidine and serum pyridoxal) and multi-modal magnetic resonance imaging measures of white matter microstructures including apparent axonal density (intra-cellular volume fraction (ICVF)) and orientation (orientation dispersion index (ODI)), and inflammation (free water (FW)). In SCZ, the plasma pentosidine level was significantly increased. Group comparison revealed that mean white matter values were decreased for ICVF, and increased for FW. We found a significant negative correlation between the plasma pentosidine level and mean ICVF values in SCZ, and a significant negative correlation between the serum pyridoxal level and mean ODI value in HC, regardless of age. Our results suggest an association between enhanced carbonyl stress and axonal abnormality in SCZ.

Annexin A1 is a cell-intrinsic metalloregulator of zinc in human ILC2s.

Group 2 innate lymphoid cells (ILC2s) produce large amounts of type 2 cytokines including interleukin-5 (IL-5) and IL-13 in response to various stimuli, causing allergic and eosinophilic diseases. However, the cell-intrinsic regulatory mechanisms of human ILC2s remain unclear. Here, we analyze human ILC2s derived from different tissues and pathological conditions and identify ANXA1, encoding annexin A1, as a commonly highly expressed gene in non-activated ILC2s. The expression of ANXA1 decreases when ILC2s activate, but it increases autonomously as the activation subsides. Lentiviral vector-based gene transfer experiments show that ANXA1 suppresses the activation of human ILC2s. Mechanistically, ANXA1 regulates the expression of the metallothionein family genes, including MT2A, which modulate intracellular zinc homeostasis. Furthermore, increased intracellular zinc levels play an essential role in the activation of human ILC2s by promoting the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways and GATA3 expression. Thus, the ANXA1/MT2A/zinc pathway is identified as a cell-intrinsic metalloregulatory mechanism for human ILC2s.

Commonalities and differences in ECT-induced gray matter volume change between depression and schizophrenia.

BACKGROUND: Electroconvulsive therapy (ECT) is one of the most effective treatments for depression and schizophrenia, particularly in urgent or treatment-resistant cases. After ECT, regional gray matter volume (GMV) increases have been repeatedly reported both in depression and schizophrenia. However, the interpretation of these findings remains entangled because GMV changes do not necessarily correlate with treatment effects and may be influenced by the intervention itself. We hypothesized that the comparison of longitudinal magnetic resonance imaging data between the two diagnostic groups will provide clues to distinguish diagnosis-specific and transdiagnostic changes. METHOD: Twenty-nine Japanese participants, including 18 inpatients with major depressive disorder and 11 with schizophrenia, underwent longitudinal voxel-based morphometry before and after ECT. We investigated GMV changes common to both diagnostic groups and those specific to each group. Moreover, we also evaluated potential associations between GMV changes and clinical improvement for each group. RESULTS: In both diagnostic groups, GMV increased in widespread areas after ECT, sharing common regions including: anterior temporal cortex; medial frontal and anterior cingulate cortex; insula; and caudate nucleus. In addition, we found a schizophrenia-specific GMV increase in a region including the left pregenual anterior cingulate cortex, with volume increase significantly correlating with clinical improvement. CONCLUSIONS: Transdiagnostic volume changes may represent the effects of the intervention itself and pathophysiological changes common to both groups. Conversely, diagnosis-specific volume changes are associated with treatment effects and may represent pathophysiology-specific impacts of ECT.

Systolic Blood Pressure and Objective Hearing Thresholds Among Japanese Middle-Aged Adults: A Facility-Based Retrospective Cohort Study.

INTRODUCTION: Very few studies have compared the magnitude of the changes in the hearing thresholds at 1 and 4 kHz according to the systolic blood pressure (SBP). We investigated the effects of SBP on repeated measures of hearing threshold using pure-tone audiometry. METHODS: This retrospective cohort study included 5,479 (for the analysis at 1 kHz) and 2,045 (for 4 kHz) individuals aged 50 to 59 years who underwent facility-based health checkups. A multivariable generalized linear mixed model was constructed for the analysis at 1 and 4 kHz. RESULTS: The mean follow-up durations were 30,262 and 7,454 person-years, respectively. The interaction of SBP and year was significantly associated with the change in hearing threshold in both analyses at 1 kHz (with estimated slope, 0.00080; 95% confidence interval, 0.00049-0.00110) and 4 kHz (with estimated slope, 0.0042; 95% confidence interval, 0.0028-0.0057). The 10-year changes in hearing threshold with baseline SBP of 110 and 140 mm Hg were 0.4 and 0.6 dB at 1 kHz and 1.0 and 2.3 dB at 4 kHz, respectively. CONCLUSIONS: Higher SBP was associated with an increased hearing threshold at both 1 and 4 kHz among middle-aged individuals.