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The purpose of out study is to establish the way for making vibration power generation floor. In the consideration of our study is composed of three processes. The first is to establish the design method obtaining the desirable maximum power from cantilever piezoelectric vibration unit. The 2nd is to construct the vibrating floor. The 3rd is to estimate the charging efficiency using the capacitor. After all we examine the average output power by the vibration power generation floor. The applications of the vibration power generation floor are assumed as power source of sensor network nodes and foot light at night and so on. Considering for the use of power supplier for sensor network node, the desirable generated power has been estimated more than 100uW averagely. That is our target. We have performed above three processes and succeeded in making the cantilever typed vibration power generating floor which can generate 120uW averagely.

Although evidence for mitochondrial dysfunction in the pathogenesis of bipolar disorder (BD) has been reported, the precise biological basis remains unknown, hampering the search for novel biomarkers. In this study, we performed metabolomics of cerebrospinal fluid (CSF) from male BD patients ( n =54) and age-matched male healthy controls ( n =40). Subsequently, post-mortem brain analyses, genetic analyses, metabolomics of CSF samples from rats treated with lithium or valproic acid were also performed. After multivariate logistic regression, isocitric acid (isocitrate) levels were significantly higher in the CSF from BD patients than healthy controls. Furthermore, gene expression of two subtypes ( IDH3A and IDH3B ) of isocitrate dehydrogenase (IDH) in the dorsolateral prefrontal cortex from BD patients was significantly lower than that of controls, although the expression of other genes including, aconitase ( ACO1 , ACO2 ), IDH1 , IDH2 and IDH3G , were not altered. Moreover, protein expression of IDH3A in the cerebellum from BD patients was higher than that of controls. Genetic analyses showed that IDH genes ( IDH1 , IDH2 , IDH3A , IDH3B ) and ACO genes ( ACO1 , ACO2 ) were not associated with BD. Chronic (4 weeks) treatment with lithium or valproic acid in rats did not alter CSF levels of isocitrate, and mRNA levels of Idh3a , Idh3b , Aco1 and Aco2 genes in the rat brain. These findings suggest that abnormality in the metabolism of isocitrate by IDH3A in the mitochondria plays a key role in the pathogenesis of BD, supporting the mitochondrial dysfunction hypothesis of BD. Therefore, IDH3 in the citric acid cycle could potentially be a novel therapeutic target for BD.

The elderly population will grow rapidly over the next 25 years. The majority of patients with serious or life-threatening infections will be old. It is imperative that primary care physicians and infectious diseases specialists become aware of and knowledgeable about the special and unique aspects of infections in the geriatric population.

Background:Janus kinase inhibitors (JAKi) represent a novel class of oral targeted disease-modifying drugs, heralding a recent revolution in the therapeutic landscape for rheumatoid arthritis (RA) and other immune-mediated conditions. These inhibitors, which can complement or even replace conventional and biological drugs, operate through a distinctive mechanism involving intracellular disruption of the JAK-STAT pathway—a pivotal player in the immune response. The Hill coefficient (H) serves to describe the sigmoidicity of a drug’s concentration-response curve. When H > 2.0, a “time-dependent” effect is observed, where the critical factor is not the peak drug concentration but the crossing of a threshold beneath which the effect becomes negligible. The prolonged serum concentration above this threshold correlates with a more pronounced effect. Conversely, when H < 2.0, a “concentration-dependent” effect emerges, with the peak concentration holding significance [1]. In the report by Chimalakonda A et al [2], the H for the inhibitory effect of JAK1/3 in tofacitinib, baricitinib, and upadacitinib ranged from 1.0-1.3. For JAK1 inhibition in filgotinib (FIL), the H was nearly 2 [3]. Intriguingly, in a phase II study, FIL at 100 mg BID demonstrated a tendency to be more effective than FIL at 200 mg QD after 12 weeks of treatment [4]. However, the time-dependency of FIL’s effect on rheumatoid arthritis remains unclear.Objectives:The objective of this investigation is to assess whether the impact of FIL on rheumatoid arthritis exhibits time-dependent characteristics.Methods:This constituted a retrospective, observational study involving 25 patients diagnosed with rheumatoid arthritis (RA) who met the 2010 American College of Rheumatology (ACR)/EULAR classification criteria. These patients were prescribed FIL and underwent a minimum 12-week follow-up at our hospital from November 2020 to October 2023. The efficacy of FIL was assessed based on the EULAR response at 12-week treatment, with concurrent measurement of the change in DAS28-CRP. Patients were categorized into three groups based on renal function and FIL dosage: FIL 200 mg group [FIL200], FIL 100 mg with chronic kidney disease (CKD) (eGFR < 60 ml/min/1.73m2) [FIL100CKD], and FIL 100 mg without CKD [FIL100].Results:The median age of the patients was 69.0 years (IQR: 61.0-76.0), and the median disease duration was 156 months (102-180). The median DAS28-CRP was 3.60 (3.16-4.49). Comparing the FIL100CKD group to the FIL200 group, the former exhibited a higher median age (80.0 vs. 73.0 year, P<0.05). However, other patient backgrounds showed no statistically significant differences. No significant variations were observed in the number of concomitant MTX, other csDMARDs, or prednisolone among the three groups. But, there was a tendency towards fewer patients being biologics- and JAKi-naive in the FIL200 group (FIL100 group; 60.0%, FIL100CKD group; 66.7% and FIL200 group; 14.3%, respectively). In terms of treatment outcomes, the EULAR response and ΔDAS28-CRP at 12 weeks tended to be higher in the FIL100, FIL100CKD, and FIL200 groups, in that sequential order (Figure 1).Conclusion:FIL exhibits a Hill coefficient close to 2, implying a time-dependent pharmacodynamic effect rather than concentration dependence. In cases with eGFR <60, the time above IC5 for JAK1 is extended (FIL100; approximately 6 hours, FIL100CKD; approximately 8 hours, FIL200; approximately 9.5 hours) [5,6]. Clinical data derived from the current study imply that the efficacy of FIL is time-dependent. Further studies are needed to confirm this.REFERENCES:[1] Czock D, Keller F. J Pharmacokinet Phar. 2007;34(6):727–51.[2] Chimalakonda A, et al. Dermatology Ther. 2021;11(5):1763–76.[3] Namour F, et al. Clin Pharmacokinet. 2015;54(8):859–74.[4] Westhovens R, et al. Ann Rheum Dis. 2017;76(6):998.[5] Namour F, et al. Brit J Clin Ph REFERENCES armaco. 2018;84(12):2779–89.[6] Veeravalli V, et al. Drug Safety. 2020;1–15.12W EULAR responseAcknowledgements:NIL.Disclosure of Interests:None declared.

Background:Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that eventually leads to the destruction of cartilage and bone[1]. A type I interferon (INF-I) signature (ISG) is detectable in the peripheral blood of RA patients and may be present in the preclinical phase of the disease[2]. INF-Is have been implicated in the pathogenesis of RA. JAK inhibitors (Jakinibs) block the activation of the IFN pathway by inhibiting JAKs, resulting in a very promising therapeutic strategy for adults suffering from autoimmune, inflammatory and haematological diseases such as RA. We have shown that serum Mac-2BPGi (M2BP) levels are significantly elevated in patients with rheumatic diseases associated with type 1 interferonopathies, including rheumatoid arthritis, compared to healthy controls[3]. At present, the significance of M2BP in RA is unclear.Objectives:The aim of this study is to evaluate the utility of serum M2BP levels in patients with RA.Methods:This was a retrospective cross-sectional study. A total of 135 eligible RA patients were included in this study in our department’s database from January to April 2020, excluding patients with neither RA disease activity nor laboratory data including M2BP. Serum levels of M2BP were measured using the HISCLÒ M2BP glycosylation isomer assay kit. Clinical remission was defined as a Simplified Disease Activity Index (SDAI) ≤ 3.3. Serum M2BP levels were categorised into tertiles (LOW, MID and HIGH).Results:The median age of patients was 67.0 (IQR: 57.0-73.0) years, and the median disease duration was 13.0 (9.0-6.5) years. The median SDAI was 2.02 (1.16-5.11) and the median Disease Activity Score 28-C-reactive protein (DAS28-CRP) was 1.61 (1.26-2.12). Of the 135 patients, 85 were in clinical remission (REM). There were no significant differences between the REM and non-REM groups in the proportion of methotrexate (MTX) use, biologics and JAK inhibitors use, but prednisolone (PSL) use and csDMARDs other than MTX were significantly higher in the non-REM group. Median serum M2BP levels were 0.85 cut-off index (C.O.I.) (0.63-1.18). M2BP was significantly correlated with SDAI and DAS28-CRP (r=0.230 and r=0.238, respectively). Serum M2BP tended to be lower in the SDAI remission group compared to the non-remission group (0.79 vs. 0.93); serum M2BP levels were significantly lower in the DAS28-CRP remission group compared to the non-remission group (0.80 vs. 1.07, p<0.02). The proportion of SDAI remission tended to decrease with increasing serum M2BP, whereas the proportion of DAS28-CRP remission significantly decreased with increasing serum M2BP. Multiple regression analysis of serum M2BP identified age and SDAI as independent factors. In this multiple regression analysis, treatment with biologics and JAKinib, excluding abatacept (ABT), tended to reduce M2BP compared to csDMARDs alone. The use of MTX and PSL also tended to reduce it. And treatment with JAKinibs tended to reduce M2BP more than the other treatments.Conclusion:The study showed that serum M2BP levels correlate with disease activity in rheumatoid arthritis as an independent factor. Previous studies have reported that serum M2BP correlates with type 1 interferon signalling in RA, and this study found a trend for JAKinibs treatment to reduce M2BP more than other treatments. Therefore, it has been suggested that serum M2BP may be a marker not only for the assessment of disease activity, but also for treatment selection and response in RA.REFERENCES:[1] Drossaers-Bakker KW, de BM, van ZD, et al. Arthritis Rheum 1999;42:1854–60.[2] Lubbers, J. et al. Ann. Rheum. Dis. 72, 776–780 (2013).[3] Yoshikawa T, Azuma K, Furukawa T, Tamura M, Hashimoto T, Morimoto M, et al. Ann Rheum Dis. 2021;80(Suppl 1):1181.1-1181.Acknowledgements:NIL.Disclosure of Interests:None declared.

Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10-9 ), a region known to contain regulatory genes for plasma lipid levels (FADS1/2/3). A subsequent meta-analysis of Phase I/II and the Psychiatric GWAS Consortium for BD (PGC-BD) identified another novel BD gene, NFIX (Pbest =5.8 × 10-10 ), and supported three regions previously implicated in BD susceptibility: MAD1L1 (Pbest =1.9 × 10-9 ), TRANK1 (Pbest =2.1 × 10-9 ) and ODZ4 (Pbest =3.3 × 10-9 ). Polygenicity of BD within Japanese and trans-European-Japanese populations was assessed with risk profile score analysis. We detected higher scores in BD cases both within (Phase I/II) and across populations (Phase I/II and PGC-BD). These were defined by (1) Phase II as discovery and Phase I as target, or vice versa (for 'within Japanese comparisons', Pbest ~10-29 , R2 ~2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for 'trans-European-Japanese comparison,' Pbest ~10-13 , R2 ~0.27%). This 'trans population' effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates~0.7). These results indicate that (1) two novel and three previously implicated loci are significantly associated with BD and that (2) BD 'risk' effect are shared between Japanese and European populations.

Residents of long-term care facilities (LTCFs) are at great risk for infection. Most residents are older and have multiple comorbidities that complicate recognition of infection; for example, typically defined fever is absent in more than one-half of LTCF residents with serious infection. Furthermore, LTCFs often do not have the on-site equipment or personnel to evaluate suspected infection in the fashion typically performed in acute care hospitals. In recognition of the differences between LTCFs and hospitals with regard to hosts and resources present, the Infectious Diseases Society of America first provided guidelines for evaluation of fever and infection in LTCF residents in 2000. The guideline presented here represents the second edition, updated by data generated over the intervening 8 years. It focuses on the typical elderly person institutionalized with multiple chronic comorbidities and functional disabilities (e.g., a nursing home resident). Specific topic reviews and recommendations are provided with regard to what resources are typically available to evaluate suspected infection, what symptoms and signs suggest infection in a resident of an LTCF, who should initially evaluate the resident with suspected infection, what clinical evaluation should be performed, how LTCF staff can effectively communicate about possible infection with clinicians, and what laboratory tests should be ordered. Finally, a general outline of how a suspected outbreak of a specific infectious disease should be investigated in an LTCF is provided.

The risk of schizophrenia is increased in offspring whose mothers experience malnutrition during pregnancy. Polyunsaturated fatty acids (PUFAs) are dietary components that are crucial for the structural and functional integrity of neural cells, and PUFA deficiency has been shown to be a risk factor for schizophrenia. Here, we show that gestational and early postnatal dietary deprivation of two PUFAs—arachidonic acid (AA) and docosahexaenoic acid (DHA)—elicited schizophrenia-like phenotypes in mouse offspring at adulthood. In the PUFA-deprived mouse group, we observed lower motivation and higher sensitivity to a hallucinogenic drug resembling the prodromal symptoms in schizophrenia. Furthermore, a working-memory task-evoked hyper-neuronal activity in the medial prefrontal cortex was also observed, along with the downregulation of genes in the prefrontal cortex involved in oligodendrocyte integrity and the gamma-aminobutyric acid (GABA)-ergic system. Regulation of these genes was mediated by the nuclear receptor genes Rxr and Ppar , whose promoters were hyper-methylated by the deprivation of dietary AA and DHA. In addition, the RXR agonist bexarotene upregulated oligodendrocyte- and GABA-related gene expression and suppressed the sensitivity of mice to the hallucinogenic drug. Notably, the expression of these nuclear receptor genes were also downregulated in hair-follicle cells from schizophrenia patients. These results suggest that PUFA deficiency during the early neurodevelopmental period in mice could model the prodromal state of schizophrenia through changes in the epigenetic regulation of nuclear receptor genes.

Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P =9.3 × 10 −9 , 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e.g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P =0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.

Given the complexity and heterogeneity of the genomic architecture underlying schizophrenia, molecular analyses of these patients with defined and large effect-size genomic defects could provide valuable clues. We established human-induced pluripotent stem cells from two schizophrenia patients with the 22q11.2 deletion (two cell lines from each subject, total of four cell lines) and three controls (total of four cell lines). Neurosphere size, neural differentiation efficiency, neurite outgrowth, cellular migration and the neurogenic-to-gliogenic competence ratio were significantly reduced in patient-derived cells. As an underlying mechanism, we focused on the role of DGCR8 , a key gene for microRNA (miRNA) processing and mapped in the deleted region. In mice, Dgcr8 hetero-knockout is known to show a similar phenotype of reduced neurosphere size (Ouchi et al. , 2013). The miRNA profiling detected reduced expression levels of miRNAs belonging to miR-17/92 cluster and miR-106a/b in the patient-derived neurospheres. Those miRNAs are reported to target p38α, and conformingly the levels of p38α were upregulated in the patient-derived cells. p38α is known to drive gliogenic differentiation. The inhibition of p38 activity by SB203580 in patient-derived neurospheres partially restored neurogenic competence. Furthermore, we detected elevated expression of GFAP , a gliogenic (astrocyte) marker, in postmortem brains from schizophrenia patients without the 22q11.2 deletion, whereas inflammation markers ( IL1B and IL6 ) remained unchanged. In contrast, a neuronal marker, MAP2 expressions were decreased in schizophrenia brains. These results suggest that a dysregulated balance of neurogenic-to-gliogenic competence may underlie neurodevelopmental disorders such as schizophrenia.