Aims: Past observational studies have reported on the association between antipsychotic drugs and venous thromboembolism (VTE); however, the conclusions remain controversial, and its mechanisms are yet to be fully understood. Thus, in this study, we aim to determine the associations of antipsychotic drugs with VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE), and their potential mechanisms.

Methods: We first mined the adverse event signals of VTE, DVT, and PE caused by antipsychotic drugs in Food and Drug Administration Adverse Event Reporting System (FAERS). Next, we used two-sample Mendelian randomization (MR) method to investigate the association of antipsychotic drug target gene expression with VTE, DVT, and PE, using single-nucleotide polymorphisms as genetic instruments. We not only used the expression of all antipsychotic drug target genes as exposure to perform MR analyses but also analyzed the effect of single target gene expression on the outcomes.

Results: In the FAERS, 1694 cases of VTE events were reported by 16 drugs. However, using the MR approach, no significant association was determined between the expression of all antipsychotic target genes and VTE, DVT, or PE, either in blood or brain tissue. Although the analysis of single gene expression data showed that the expression of nine genes was associated with VTE events, these targets lacked significant pharmacological action.

Conclusions: Adverse event mining results have supported the claim that antipsychotic drugs can increase the risk of VTE. However, we failed to find any genetic evidence for this causal association and potential mechanisms. Thus, vigilance is still needed for antipsychotic drug-related VTE despite the limited supporting evidence.

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Background: N-3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory properties and are expected to prevent the onset of allergies. However, epidemiological studies investigating the relationship between child allergies and maternal intake of n-3 PUFAs or fish have yielded inconsistent results.

Methods: Following exclusions from a dataset comprising 103,057 records from the Japan Environment and Children's Study, 72,105 participants were divided into five groups according to mothers' intake of n-3 PUFAs or fish during pregnancy to assess the risk of their children being diagnosed with allergy by 3 years old. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) for child allergies were calculated using multivariable logistic regression analyses with reference to the lowest intake group.

Results: Levels of maternal intake of n-3 PUFAs or fish showed inverted associations (i.e., reduced risk) with the incidence of physician-diagnosed allergic rhinoconjunctivitis or parent-reported symptoms of current rhinitis with eye symptoms at different time points and the cumulative incidence from birth to 3 years of age. Inverted associations were also found for current wheeze at 1-<2 years of age and current eczema at 1-<2 and 0-<3 years of age. However, for food allergies, no significant associations were observed in the incidence in each group compared with the lowest intake group at any age.

Conclusions: The findings suggest that n-3 PUFA intake during pregnancy may reduce the risk of developing allergic diseases and symptoms in children. In addition, consumption of n-3 PUFAs or fish is very unlikely to increase the risk of allergy given that the results are from a country with high fish consumption. Trial registration: UMIN000030786 https://rctportal.niph.go.jp/detail/um?trial_id=UMIN000030786.

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Aims: Evidence regarding the modification effects of age, sex, ethnicity, socioeconomic status, or weight status on the associations of sedentary behavior (SB) with cardiovascular diseases (CVDs) is limited. Moreover, the mechanisms for the associations also remain unclear. We aimed to investigate the possible influence of these factors on the associations of SB with CVD events and whether the associations are mediated by metabolic phenotypes.

Methods: This study included 42,619 participants aged 20-74 years, recruited from the Shanghai Suburban Adult Cohort and Biobank study. SB was assessed at baseline and integrated with health information systems to predict future CVD events. Cox proportional hazards models, interaction analyses, restricted cubic splines and causal mediation analyses were used for assessments.

Results: Compared to those with ＜3 h/d sedentary time, participants having SB ≥ 5 h/d had significantly higher risks of CVD (HR[95%CI]: 1.27[1.12-1.44]), coronary heart disease (CHD, 1.35[1.14-1.60]), and ischemic stroke (IS, 1.30[1.06-1.60]). The association of CHD was more pronounced in the retired individuals than their counterparts (1.45[1.20-1.76] versus 1.06[0.74-1.52], p_interaction=0.046). When SB was expressed as a continuous variable, a 1 h/d increment in SB was positively associated with risks of CVD (1.03[1.01-1.05]), CHD (1.04[1.01-1.07]), and IS (1.05[1.01-1.08]). High-density lipoprotein cholesterol (HDL-C, proportion mediated: 12.54%, 12.23%, and 11.36%, all p＜0.001), followed by triglyceride (TG, 5.28%, 4.77%, and 4.86%, all p＜0.01) and serum uric acid (SUA, 3.64%, 4.24%, and 2.29%, all p＜0.05) were major mediators through metabolic phenotypes.

Conclusions: Higher SB was associated with elevated risks of CVD events. The detrimental effect of SB on CHD risk was more pronounced among retired individuals. Moreover, HDL-C, TG and SUA partially mediated the relationships between SB and CVD events. Our findings may have implications for preventing and controlling CVD associated with SB.

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Aims: Obicetrapib is a highly selective cholesteryl ester transfer protein (CETP) inhibitor shown to reduce low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB), when taken as monotherapy and in combination with ezetimibe on a background of statins, in clinical trials predominantly conducted in Northern European/Caucasian participants. We characterized the efficacy, safety, and tolerability of obicetrapib within an Asian-Pacific region population.

Methods: This double-blind, randomized, phase 2 trial examined obicetrapib 2.5, 5, and 10 mg/d, compared with placebo, for 8 weeks as an adjunct to stable statin therapy (atorvastatin 10 or 20 mg/d or rosuvastatin 5 or 10 mg/d) in Japanese men and women who had not achieved 2022 Japan Atherosclerosis Society Guidelines and had LDL-C ＞70 mg/dL or non-high-density lipoprotein cholesterol (non-HDL-C) ＞100 mg/dL and triglycerides (TG) ＜400 mg/dL. Endpoints included LDL-C, non-HDL-C, HDL-C, very low-density lipoprotein cholesterol, apolipoproteins, TG, steady state pharmacokinetics (PK) in obicetrapib arms, safety, and tolerability.

Results: In the 102 randomized subjects (mean age 64.8 y, 71.6% male), obicetrapib significantly lowered median LDL-C, apoB, and non-HDL-C, and raised HDL-C at all doses; responses in the obicetrapib 10 mg group were -45.8%, -29.7%, -37.0%, and +159%, respectively (all p＜0.0001 vs. placebo). The PK profile demonstrated near complete elimination of drug by 4 weeks. Obicetrapib was well tolerated and there were no adverse safety signals.

Conclusions: All doses of obicetrapib taken as an adjunct to stable statin therapy significantly lowered atherogenic lipoprotein lipid parameters, showed near complete elimination of drug by 4 weeks, and were safe and well tolerated in a Japanese population, similar to previous studies of obicetrapib conducted in predominantly Caucasian participants.

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Aim: There is little information on the relationships of serum small dense low-density lipoprotein cholesterol (sdLDL-C) levels and serum triglyceride (TG) levels with cardiovascular events in patients with coronary artery disease (CAD) and type 2 diabetes mellitus (DM) who are receiving statins. The aim of this study was to evaluate the relationships of serum TG levels and sdLDL-C levels as residual risks for cardiovascular events in patients with CAD and type 2 DM who were being treated with statins.

Methods: The subjects were divided into four groups based on TG levels and sdLDL-C levels: sdLDL-C of ＜40.0 mg/dL and TG of ＜150 mg/dL, sdLDL-C of ≥ 40.0 mg/dL and TG of ＜150 mg/dL, sdLDL-C of ＜40.0 mg/dL and TG of ≥ 150 mg/dL, and sdLDL-C of ≥ 40.0 mg/dL and TG of ≥ 150 mg/dL. During a median follow-up period of 1419 days, cardiovascular events occurred in 34 patients.

Results: The incidences of cardiovascular events were significantly higher in patients with sdLDL-C of ≥ 40.0 mg/dL and TG of ＜150 mg/dL and in patients with sdLDL-C of ≥ 40.0 mg/dL and TG of ≥ 150 mg/dL, but not in patients with sdLDL-C of ＜40.0 mg/dL and TG of ≥ 150 mg/dL, than in patients with sdLDL-C of ＜40.0 mg/dL and TG of ＜150 mg/dL.

Conclusions: Under the condition of treatment with statins, patients with CAD and type 2 DM who had sdLDL-C levels of ≥ 40.0 mg/dL had a high risk for cardiovascular events even though serum TG levels were controlled at ＜150 mg/dL.

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Aim: No data are currently available regarding the association between Lp(a) and the cardiovascular outcomes in patients with coronary artery disease (CAD) according to their family history (FHx) of CAD. This study aimed to evaluate the significance of Lp(a) in predicting major adverse cardiovascular events (MACEs) in patients with chronic coronary syndrome (CCS) with or without FHx.

Methods: A total of 6056 patients with CCS were enrolled. Information on FHx was collected, and the plasma Lp(a) levels were measured. All patients were followed up regularly. The independent and joint associations of Lp(a) and FHx with the risk of MACEs, including cardiovascular death, nonfatal myocardial infarction, and stroke, were analyzed.

Results: With over an average of 50.35±18.58 months follow-up, 378 MACEs were recorded. A Cox regression analysis showed an elevated Lp(a) level to be an independent predictor for MACEs in patients with [hazard ratio (HR): 2.77, 95% confidence interval (CI): 1.38-5.54] or without FHx (HR: 1.35, 95% CI: 1.02-1.77). In comparison to subjects with non-elevated Lp(a) and negative FHx, patients with elevated Lp(a) alone were at a nominally higher risk of MACEs (HR: 1.26, 95% CI: 0.96-1.67), while those with both had the highest risk (HR: 1.93, 95% CI: 1.14-3.28). Moreover, adding Lp(a) to the original model increased the C-statistic by 0.048 in subjects with FHx (p=0.004) and by 0.004 in those without FHx (p=0.391).

Conclusions: The present study is the first to suggest that Lp(a) could be used to predict MACEs in CCS patients with or without FHx; however, its prognostic significance was more noteworthy in patients with FHx.

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Background: Atopic dermatitis and autoimmune diseases are highly heritable conditions that may co-occur from an early age.

Methods: The primary study is a national administrative cohort study involving 499,428 children born in 2002, tracked until 2017. Atopic dermatitis was defined as five or more principal diagnoses of atopic dermatitis and two or more topical steroid prescriptions. We estimated the risks for the occurrence of 41 autoimmune diseases, controlling for risk factors. In addition, we sourced a gene library from the National Library of Medicine to conduct a comprehensive gene ontology. We used Gene Weaver to identify gene set similarity and clustering, and used GeneMania to generate a network for shared genes.

Results: Exposed and unexposed groups included 39,832 and 159,328 children, respectively. During a mean follow-up of 12 years, the exposed group had an increased risk of autoimmune disease (hazard ratio, 1.27 [95 % confidence interval, 1.23-1.32]) compared to the unexposed group. The hazard ratios of autoimmune illnesses consistently increased with two- and five years lag times and alternative atopic dermatitis definitions. Shared genes between atopic dermatitis and autoimmune diseases were associated with comorbidities such as asthma, bronchiolitis, and specific infections. Genetic interactions of these shared genes revealed clustering in Th1, Th2, Th17, and non-classifiable pathways.

Conclusions: Atopic dermatitis was significantly associated with an increased risk of subsequent autoimmune disease. we identified the genetically associated disease in atopic dermatitis patients comorbid with autoimmune disease and demonstrated a genetic network between atopic dermatitis and autoimmune diseases.

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More than 5 years have passed since the Diffusion Tensor Image Analysis ALong the Perivascular Space (DTI-ALPS) method was proposed with the intention of evaluating the glymphatic system. This method is handy due to its noninvasiveness, provision of a simple index in a straightforward formula, and the possibility of retrospective analysis. Therefore, the ALPS method was adopted to evaluate the glymphatic system for many disorders in many studies. The purpose of this review is to look back and discuss the ALPS method at this moment.

The ALPS-index was found to be an indicator of a number of conditions related to the glymphatic system. Thus, although this was expected in the original report, the results of the ALPS method are often interpreted as uniquely corresponding to the function of the glymphatic system. However, a number of subsequent studies have pointed out the problems on the data interpretation. As they rightly point out, a higher ALPS-index indicates predominant Brownian motion of water molecules in the radial direction at the lateral ventricular body level, no more and no less. Fortunately, the term “ALPS-index” has become common and is now known as a common term by many researchers. Therefore, the ALPS-index should simply be expressed as high or low, and whether it reflects a glymphatic system is better to be discussed carefully. In other words, when a decreased ALPS-index is observed, it should be expressed as “decreased ALPS-index” and not directly as “glymphatic dysfunction”. Recently, various methods have been proposed to evaluate the glymphatic system. It has become clear that these methods also do not seem to reflect the entirety of the extremely complex glymphatic system. This means that it would be desirable to use various methods in combination to evaluate the glymphatic system in a comprehensive manner.

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Objective: With the accelerated population aging, multimorbidity has become an important healthcare issue. However, few studies have examined multimorbidity and its impact on the use of medical and long-term care services in Japan. Therefore, this study aimed to examine the association between multimorbidity and the use of medical and long-term care services among older adults living in the depopulated mountainous areas of Japan.

Patients and Methods: A cross-sectional study was conducted using insurance claims data from late-stage medical insurance and long-term care insurance (April 2017 to March 2018) for older adults ≥75 years residing in a mountainous area in the Tottori prefecture. In addition to the descriptive analysis, multiple generalized linear regressions with family gamma and log-link functions were used to examine the association between the number of morbidities and total annual medical and long-term care expenditures.

Results: A total of 970 participants ≥75 years were included in the analysis. Participants who had two or more morbidities constituted 86.5% of the total sample. Furthermore, participants with mental disorders were found to have more comorbidities. The number of comorbidities is associated with higher medical and long-term care expenditures.

Conclusion: Multimorbidity was dominant among late-stage older adults living in depopulated mountainous areas of Japan, and the number of morbidities was associated with higher economic costs of medical and long-term care services. Mitigating the impact of multimorbidity among older adults in depopulated regions of Japan is an urgent challenge. Future research should investigate the degree and effectiveness of social protections for vulnerable older adults living in remote areas.

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Postoperative epidural fibrosis (EF) is still a major limitation to the success of spine surgery. Fibrotic adhesions in the epidural space, initiated via local trauma and inflammation, can induce difficult-to-treat pain and constitute the main cause of failed back surgery syndrome, which not uncommonly requires operative revision.

Manifold agents and methods have been tested for EF relief in order to mitigate this longstanding health burden and its socioeconomic consequences. Although several promising strategies could be identified, few have thus far overcome the high translational hurdle, and there has been little change in standard clinical practice. Nonetheless, notable research progress in the field has put new exciting avenues on the horizon.

In this review, we outline the etiology and pathogenesis of EF, portray its clinical and surgical presentation, and critically appraise current efforts and novel approaches toward enhanced prevention and treatment.

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Aim: The carotid sinuses and aortic arch are baroreceptor-resident arteries (BRAs) and atherosclerosis-susceptible sites of brain-supplying arteries, which would impair baroreflex-mediated blood pressure (BP) regulation and prompt coronary atherosclerosis. We sought to determine the relationship between total atherosclerosis burden (TAB) of BRAs and coronary atherosclerosis burden (AB) in patients with ischemic cerebrovascular disease (ICVD) and explore the potential contribution of BP profiles to this relationship.

Methods: In this cross-sectional analysis of patients with ICVD who simultaneously undertook computed tomography angiography and 24-hour ambulatory BP monitoring, TAB of BRAs was scored based on the atherosclerotic vessel circumference ratio of the carotid sinuses and aortic arch, while the ABs of the intracranial, cervical, aortic, and coronary arteries were scored based on stenosis severity and plaque complexity as routine.

Results: Among the 230 patients analyzed, coronary AB was significantly correlated with TAB of BRAs, independently of, and more tightly than the ABs of the intracranial, cervical, and aortic arteries, and the stenosis- and complexity-based AB of BRA-located arteries (bilateral common and extracranial internal carotid arteries and aortic arch). Both coronary AB and TAB of BRAs were negatively associated with the night-to-day BP dipping ratios, which was quite different from the relationship between intracranial AB and 24-hour BP characteristics. These findings were also true for patients with ICVD without a history of coronary artery disease.

Conclusion: Evaluating TAB of BRAs might provide a new link between atherosclerosis of brain- and heart-supplying arteries, connected partially by BP circadian rhythm. It might facilitate identifying patients with ICVD with heavy coronary AB and comprehensively managing vascular risk.

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This study explores factors involved in the performance of shadowing vs. repeating trainings. Two groups of 24 Japanese university students participated in two sessions of shadowing and repeating trainings, six times each. Their reproduction rates (the ratio of successfully repeated syllables) show that, in the first session, with audio materials shorter than 2 seconds, the learners demonstrate significantly better performance in repeating than in shadowing. With speech ranging from 2 to 2.5 seconds, the two methods show no significant difference. With input over 2.5 seconds, shadowing exhibits significantly higher reproduction rates. These results suggest that the approximately 2-second phonological loop is more deeply involved in repeating. In the second session, however, the participants tend to have greater reproduction rates for repeating even with materials over 2.5 seconds, suggesting the effect of repeated trials. Still, even after five trials, there were six sequences of successive function words and/or alternating content and function words that yielded reproduction rates below 70%, suggesting learner difficulty in perceiving and/or reproducing large stress-related durational variation in spoken English.

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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.

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The 22nd archaeological excavation in the Matsue Campus of Shimane University, Matsue, Japan, was conducted in preparation for the construction of the Next Generation Tatara Co-Creation Centre. Analyses of grain size, total organic carbon (TOC), total nitrogen (TN), and total sulfur (TS) contents, and microfossils were made in this study. The results are described as follows. The study sequence was divided into seven sedimentary layers: 4c, 4b, 4a, 3b, 3a, 2, and 1, in ascending order. The Kikai-Akahoya (K-Ah) tephra was intercalated into a horizon at an altitude of -2.5 m in the southern subarea and -2.6 m in the northern subarea. A Si layer composed of pale greenish gray very fine-grained silt was interpreted as a flood event layer aged at approximately 7000–6800 cal. yr BP and traceable in other locations of the campus. The paleoenvironment of the 4c layer was a mud bottom of slightly oxidative innermost part of a paleo-bay of Lake Shinji, dated at approximately 7900 cal. yr BP. The local environment then changed into a closed bay at approximately 7500 cal. yr BP. Salinity decreased at the horizon of the boundary between the 4c and 4b layer (ca. 6400–6200 cal. yr BP) and the paleoenvironment evolved into the easternmost part of closed brackish paleo-Shinji Lake. The paleoenvironmental setting of the 4a (intertidal sand bar), 3 (supratidal sand bar with reeds), 2 (freshwater marsh), and 1 (rice field) layers observed here confirm the sequence reported by the previous studies.

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We aimed to determine whether adhesive components could increase the release time of effective fluoride concentration from an experimental fluoride varnish applied to bovine teeth. An experimental fluoride varnish containing 5% sodium fluoride (EX1) was prepared and combined with 35% hydroxyethyl methacrylate (HEMA) (EX2), 5% glutaraldehyde (EX3), or 35% HEMA/5% glutaraldehyde mixture (EX4). Two commercially available fluoride varnishes were used for comparison. Each group was applied to bovine incisors, and the fluoride release and pH were monitored for 30 days. Cell viability analysis, scanning electron microscopy, and energy-dispersive spectroscopy were performed. EX4 released the highest and most effective concentration of fluoride for the longest period and reached neutral pH at the earliest; the release was maintained for up to 30 days without cytotoxicity. In conclusion, EX4 is considered to be the most effective varnish to prevent dental caries.

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Vitamin E (VE) is a lipophilic vitamin, and Evans and Bishop demonstrated the existence of a hitherto unrecognized dietary factor essential for normal reproduction in rat. During 100 years after the discovery, α-tocopherol (α-Toc) has been the representative species in VE homologues, and both naturally occurring and synthetically prepared α-Toc have been widely used and studied. Although it is indicated by a single-word VE, research on VE involves various chemical species. It is important to understand the fine structure and accurate characteristics of individual VE species when using VE. Each VE sample has compositional and/or isomer issues, and furthermore, the usability greatly varies depending on the modified species of esterification. The VE industry involves many interdisciplinary fields. Improvements in formulation technology and confirmation of the novel biological activity of VE greatly owns its utility and opens up new applications. As the interim period between the start and end of the agenda for Sustainable Development Goals (SDGs), in this minireview, the recent trends and future guidelines of VE, especially α- Toc, in relation to the SDGs have been demonstrated.

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Purpose: To review dental sleep medicine in older adults based on the literature.

Study selection: This narrative review focuses on sleep physiology, common sleep disorders, and obstructive sleep apnea (OSA) in older adults and their management.

Results: Sleep physiology differs between older and younger adults, with sleep disturbances occurring more frequently in older adults. The prevalence of insomnia increases in older adults due to age-related changes in sleep physiology. Insomnia, sleep-disordered breathing, periodic limb movement disorder, restless legs syndrome, and rapid eye movement (REM) sleep behavior disorder are common sleep disorders in older adults. OSA is more prevalent in older adults, and its effects on them are considered more substantial than those on younger adults. The treatment of older patients with mandibular advancement devices may be less effective and more complex owing to potential impairments in oral and dental health. Furthermore, the prevalence of edentulism in older adults is decreasing while life expectancy is increasing.

Conclusions: As older adults have comorbidities that affect sleep quality, dentists should consider the effects of sleep physiology and sleep disorders in these patients. OSA may decrease the quality of life and increase the risk of developing other diseases. Therefore, dentists proposing treatment with mandibular advancement devices need to inform patients of their potential lack of efficacy and the requirement for careful follow-up owing to known and unknown side effects.

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Background: Reduced exercise capacity is a prognostic indicator of adverse outcomes in patients with acute myocardial infarction (AMI). However, few studies have evaluated the effectiveness of comprehensive cardiac rehabilitation (CR) in this population. This study aimed to clarify the efficacy of comprehensive CR in patients with AMI and reduced exercise capacity.

Methods and Results: This cohort study included 610 patients with AMI who underwent percutaneous coronary intervention. Major adverse cardiovascular events (MACE) were compared between patients who participated in comprehensive outpatient CR for 150 days (CR group; n=430) and those who did not (non-CR group; n=180). During the mean (±SD) follow-up period of 6.1±4.0 years, the CR group exhibited a lower incidence of MACE (log-rank P=0.002). Multivariable analysis revealed that Killip classification, diuretics at discharge, and participation in comprehensive CR were independently associated with MACE. The CR group was further divided into 2 groups, namely reduced exercise capacity (% predicted peak V̇O₂<80%; n=241) and preserved exercise capacity (≥80%; n=147), based on the initial cardiopulmonary exercise test. Despite distinct exercise capacities, the incidence of MACE was comparable and physical parameters improved similarly after comprehensive CR in both groups.

Conclusions: Comprehensive CR in patients with AMI effectively reduced the incidence of MACE regardless of initial exercise capacity. Cardiologists should actively encourage patients with low exercise capacity to participate in comprehensive CR.

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