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BackgroundOne rationale for including patient global assessment (PtGA) in Boolean remission is that PtGA ≤1 reduces the probability of joint findings outside the 28 joints and complements the limitations of 28-joint count assessment [1]. Meanwhile, the criterion of PtGA ≤1 has been questioned, leading to establishment of Boolean2.0 or proposal of 3V-remission [2-3]. However, the significance of PtGA as a complement to the limitations of the 28-joint assessment has been forgotten.ObjectivesThis study aimed to evaluate the discriminative power of PtGA for the presence of joint findings outside the 28 joints within the framework of Boolean2.0 and 3V-remission in the real-world setting.MethodsWe analyzed 8,684 patients with rheumatoid arthritis who achieved 3V-remission (28-tender joint count (TJC), 28-swollen joint count (SJC) and C-reactive protein (mg/dL) all ≤1) registered in the National Database of Rheumatic Diseases in Japan (NinJa) in 2020, a large observational database. Based on TJC68 and SJC66, patients were divided into two groups of patients with and without joint findings outside the 28 joints (JFO28). The values and distributions of PtGA were compared between the two groups, and the positive likelihood ratio for no findings outside the 28 joints was calculated, varying cutoff values of PtGA. Receiver Operating Characteristic (ROC) analysis was performed to assess the discriminative power of PtGA for the presence of JFO28 and optimal cut-off value.ResultsAmong 8,684 patients, 6,901 were patients without JFO28 and 1,783 were patients with JFO28. The values of PtGA were significantly higher in patients with JFO28 (the difference of 25% trimmed mean, 1.12 [95% CI, 1.01 to 1.24]). However, the distribution of PtGA was largely overlapping (Figure 1). About 12%, 15%, and 21% of patients had JFO28 when the cutoff values for PtGA were 1.0, 2.0 (Boolean2.0), and none (3V-remission), respectively. The positive likelihood ratios were 1.90 and 1.44 when the cutoff values of PtGA were 1.0 and 2.0, respectively. The area under the ROC curve was 0.68 [95% CI, 0.66 to 0.69], indicating low discriminative power. The optimal cut-off value was 1.0 based on Youden index.Figure 1.The distribution of PtGA in patients with and without JFO28ConclusionA cutoff value of 1.0 for PtGA seems reasonable in terms of 68/66 joint findings. It may be pragmatic to evaluate PtGA and joint findings separately in accordance with the concept of dual target therapy because PtGA has low discriminative power for the presence of JFO28 in patients achieving 3V-remission. However, our results suggested that there is a need to extend the criteria for joint assessment in 3V-remission to 68/66 joints, considering not a few patients had JFO28 even if they had reached 3V-remission.References[1]Felson DT, et al. Arthritis Rheum 2011;63(3):573-86.[2]Studenic P, et al. Ann Rheum Dis 2023;82(1):74-80.[3]Ferreira RJO, et al. Ann Rheum Dis 2021;80(3):293-303.AcknowledgementsThe authors would like to acknowledge all investigators in the National Database of Rheumatic Diseases in Japan (NinJa) in 2020. We also acknowledge Akiko Komiya, who curated the NinJa database, and Satomi Hanawa, who assisted administrative work.Disclosure of InterestsTakahiro Nishino: None declared, Shigeto Tohma Speakers bureau: Pfizer Japan inc., Abbie Japan Co., Ltd., Eisai Co., LTD., Janssen Pharmaceutical K. K., Celltrion healthcare Japan Co., Ltd., Consultant of: Mitsubishi-Tanabe Pharma Co., Grant/research support from: Chugai Pharmaceutical Co., LTD., Mitsubishi-Tanabe Pharma Co., Abbie Japan Co., Ltd., Toshihiro Matsui Speakers bureau: AbbVie, Asahikasei Pharma Corp., Astellas, Chugai Pharmaceutical Co, Ltd., Eisai Co., Ltd. Eli Lilly Japan, Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Grant/research support from: Asahikasei Pharma Corp., Chugai Pharmaceutical Co, Ltd.

Background:In recent years, the number of patients with late-onset rheumatoid arthritis (LORA) has been increasing [1]. LORA patients are often subject to various treatment restrictions due to their advanced age from the time of onset, and it has been reported that rheumatologists tend to hesitate to treat older patients aggressively [2]. However, no treatment strategy or treatment recommendation that takes age of onset into consideration has been proposed. Furthermore, it is suggested that there is diversity within LORA due to differences in the age of onset.Objectives:To compare the patient attributes, treatment approach and disease activity during the early stages of onset between late-onset rheumatoid arthritis (LORA) and younger-onset rheumatoid arthritis (YORA), and to clarify the differences between younger-onset LORA (“early LORA”) and older-onset LORA (“late LORA”).Methods:Among the 17,181 patients registered in NinJa (National Database of Rheumatic Diseases in Japan) [3], a nationwide RA database in Japan) in 2021, 1,154 patients with onset of disease less than 2 years were extracted. They were divided into three groups based on the age of onset: those under 65 years old in the YORA group (491 cases), those between 65 and 74 years old in the early LORA group (336 cases), and those over 75 years old in the late LORA group (327 cases). Their characteristics, disease activity, remission rates, and drugs used were compared.Results:The ages (mean [SD]) of the YORA, early LORA, and late LORA groups were 51.4 [10.3] years, 70.4 [2.8] years, and 81.1 [3.9] years. The proportion of men (24.2% in YORA, 37.8% in early LORA, and 33.0% in late LORA) was higher in LORA groups than in YORA, with BMI (22.8 [4.2], 22.9 [3.5], 22.2 [2.9]) and current plus past smoking rate (47.8 %, 48.7%, 33.0%) were significantly lower in late LORA. The mean estimated glomerular filtration rate (mL/min/1.73m2) (80.3 [16.0], 71.5 [16.0], 61.0 [17.7]), rheumatoid factor positive rate (69.3%, 61.5%, 58.8%) and anti-cyclic citrullinated peptide antibody positive rate (71.1%, 57.0%, 50.0%) showed a significant difference between YORA and LORA groups. No significant difference was observed in the mean values of DAS28-ESR (2.84 [1.27], 3.06 [1.37], 3.04 [1.23]) and CDAI (7.10 [7.44], 7.43 [8.60], 6.23 [7.30]). The remission rate evaluated by DAS28-ESR (2.84 [1.27], 3.06 [1.37], 3.04 [1.23]) was not different among groups, but that by CDAI (35.0%, 37.8%, 44.3%) was significantly higher in late LORA than in YORA. MTX usage rate (76.4%, 66.8%, 58.7%), any csDMARDs usage rate other than MTX (39.9%, 43.0%, 55.5%), corticosteroid usage rate (31.2%, 40.8%, 47.0%), and NSAIDs usage rate (41.1%, 38.6%, 29.3%) showed significant differences between groups. No significant difference was observed in total biologics usage (12.6%, 11.7%, 11.3%), non-TNF inhibitors usage (5.5%, 7.0%, 8.5%), and JAK inhibitors usage (3.4%, 4.4%, 6.0%), however, there was a significant difference in the TNF inhibitors usage (7.1%, 4.7%, 2.8%) and the selection rate of non-TNF inhibitors among biologics users (43.6%, 59.5%, 75.0%).Conclusion:During the early stage of disease onset, LORA achieved disease activity control equivalent to that of YORA, but the treatment content differed significantly. Furthermore, differences were observed in patient attributes and treatment content between early LORA and late LORA, clarifying that there is also diversity within LORA.REFERENCES:[1] Int J Rheum Dis. 2017; 20:839-45.[2] J Rheumatol. 2018; 45:590-594.[3] Expert Rev Clin Immunol. 2012; 8:455-65.Acknowledgements:NIL.Disclosure of Interests:Toshihiro Matsui AbbVie, AsahiKASEI, Astellas, Chugai, Eisai, Eli Lilly, Ono, Pfizer, AsahiKASEI, Chugai, Tomoya Yoshida: None declared, Takahiro Nishino: None declared, Shigeto Tohma AsahiKASEI, Pfizer, AbbVie, Chugai, Mitsubishi Tanabe.

Background:Both in Japan and global, the aging is advancing at an unprecedented pace. With aging, there is a concomitant increase in exercise-related diseases, such as falls and fractures, giving rise to serious health concerns. Fractures not only compromise activities of daily living and the quality of life, but also have a detrimental impact on life prognosis, presenting a significant challenge. Rheumatoid arthritis (RA) is encompassed within the Fracture Risk Assessment Tool (FRAX), a methodology developed by the World Health Organization (WHO) for evaluating fracture risks. The disease itself poses a substantial risk of fractures.Objectives:Given that unmodifiable risk factors for fractures in RA patients—such as age, sex, disease duration, disease activity, physical dysfunction, and oral corticosteroid use—persist over the long-term and are challenging to address or improve, we hypothesized that delineating short-term fracture risk could be more efficacious for fracture prevention. This approach allows for the implementation of targeted preventive measures. Our research leverages the National Database of Rheumatic Diseases in Japan (NinJa), a nationwide multicenter observation database of patients with RA. It was founded in 2002 and the number of registered patients is increasing year by year. It collects clinical data for RA patients annually. Recently, we collected data > 15,000 patients per year. Of those, about 90% will be followed continuously for 1 year after enrollment.Among the irreparable risk factors for fractures in patients with RA, we will clarify the risk of fractures, with a particular focus on physical dysfunction. Physical dysfunction is treated with modified Health Assessment Questionnaire(mHAQ), which is an item of NinJa.Methods:We examined changes in mHAQ in RA patients suffering from fracture who were enrolled in NinJa from 2002 to 2020 and had mHAQ data for the 4 consecutive years prior to fracture onset.Then, we extracted all RA patients data registered continuously from 2002 to 2020, spanning 4 consecutive years and including mHAQ data. The change in mHAQ from the 1st-3rd year was categorized based on whether it increased or not. Subsequently, the fracture incidence rate in the 4th year was calculated.Fractures were estimated from NinJa entries, utilizing details from hospitalizations and surgeries. The chi-square test was employed to compare fracture occurrences between the 2 groups, with a significance level set at 0.05.Results:A total of 740 cases with RA had mHAQ data for 4 consecutive years prior to the onset of fracture. In the 2 years leading up to the fracture, mHAQ increased compared to the previous year. This study focuses on changes in mHAQ over 2 years and the incidence of fractures in all RA patients over the subsequent 1 year.In the results of the following study, a total of 68,151 RA cases had data for 4 consecutive years. The fracture rate in the group with increasing mHAQ at years 1-2 was higher (272 fractures in 17,105 cases, 1.59%) compared to the non- increasing group (459/51,046, 0.90%) (p < 0.0001). And the fracture rate in the group with increasing mHAQ at years 2-3 was higher (298/17,474, 1.71%) compared to the non- increasing group (433/50,677, 0.85%) (p < 0.0001).The change in mHAQ at 1-3 years yielded fracture rates of 2.11% (88/4,163) for those increasing for 2 consecutive years, 1.44% (187/13,023) for those increasing only in the 1-2 years, 1.57% (205/13,018) for those increasing only in the 2-3 years, and 0.66% (251/37,947) for those not increasing for 2 consecutive years. Fracture incidence was significantly higher in the group increasing for 2 consecutive years compared to the groups increasing only in the 1st-2nd year (p = 0.0038) and the 2nd- 3rd year (p = 0.0314).Conclusion:Patients with elevated mHAQ were significantly more predisposed to fractures in the subsequent year, with a notably higher risk observed in those with elevated mHAQ for 2 consecutive years compared to those without. This research sheds light on the critical link between mHAQ changes and fracture risk, providing valuable insights for targeted fracture prevention strategies in RA patients.Table 1.Figure 1.Acknowledgements:NIL.Disclosure of Interests:None declared.

The boreal summer of 2008 was unusual for the Indian monsoon, featuring exceptional heavy loading of dust aerosols over the Arabian Sea and northern-central India, near normal all-India rainfall, but excessive heavy rain, causing disastrous flooding in the Northern Indian Himalaya Foothills (NIHF) regions, accompanied by persistent drought conditions in central and southern India. Using the NASA Unified-physics Weather Research Forecast (NUWRF) model with fully interactive aerosol physics and dynamics, we carried out three sets of 7-day ensemble model forecast experiments: (1) control with no aerosol, (2) aerosol radiative effect only and (3) aerosol radiative and aerosol-cloud-microphysics effects, to study the impacts of aerosol-monsoon interactions on monsoon variability over the NIHF during the summer of 2008. Results show that aerosol-radiation interaction (ARI), i.e ., dust aerosol transport, and dynamical feedback processes induced by aerosol-radiative heating, plays a key role in altering the large-scale monsoon circulation system, reflected by an increased north-south tropospheric temperature gradient, a northward shift of heavy monsoon rainfall, advancing the monsoon onset by 1–5 days over the HF, consistent with the EHP hypothesis (Lau et al. in Clim Dyn 26(7–8):855–864, 2006 ). Additionally, we found that dust aerosols, via the semi-direct effect, increase atmospheric stability, and cause the dissipation of a developing monsoon onset cyclone over northeastern India/northern Bay of Bengal. Eventually, in a matter of several days, ARI transforms the developing monsoon cyclone into meso-scale convective cells along the HF slopes. Aerosol-Cloud-microphysics Interaction (ACI) further enhances the ARI effect in invigorating the deep convection cells and speeding up the transformation processes. Results indicate that even in short-term (up to weekly) numerical forecasting of monsoon circulation and rainfall, effects of aerosol-monsoon interaction can be substantial and cannot be ignored.

Background:COVID-19 pandemic was world-wide disaster. Not only COVID-19 infection itself but also the risk of infection and public health policy influenced the human behavior and motivation. RA management recommendation based on robust scientific evidence is well known by all rheumatologists, however, under the pandemic of COVID-19, the therapeutic decision might become defensive.Objectives:To assess changes of therapeutic decision of bDMARDs or tsDMARDs (molecular targeted therapy (MTT)) by rheumatologists between before under COVID-19 pandemic (pandemic).Methods:NinJa is the largest RA registry in Japan. Clinical data of 15,000 over patients for 10 years from 49 hospitals in Japan were accumulated. From this database two datasets were created: from NinJa2018 to 2019 (before pandemic (BP); 12965 cases) and from NinJa2019 to 2020 (under pandemic (UP); 12195 cases). As the therapeutic decision of MTT, three options were picked up. New indication of MTT(1); the patients who have not ever used MTT were extracted from two groups(BP; 8962 vs UP; 8132 cases) and compared on the proportion of initial induction of MTT. Changes(2) or discontinuation(3) of MTT; the patients who have already used MTT were extracted from two groups and compared on the proportion of changes or discontinuation of MTT(BP; 4003 vs UP; 4063 cases).Other than pandemicc, age of onset, disease duration, sex, smoking habit, anxiety, depression, CDAI, DAS28(ESR), Boolean remission, HAQ-DI and dose of MTX and prednisolone were collected as major contributing factors in therapeutic decisions, After Fisher’s exact test, multiple logistic regression analysis was performed to estimate the effect of COVID-19 pandemic on each therapeutic decision. Based on disease duration (Early; <2yr, Established; 2-10yr, Long-standing; >11yr), stratified analysis was also conducted.Results:(1)New indication of MTT; 5.4% of BP group and 4.3% of UP group were newly started MTT(p=0.0017). OR; 0.79 [0.69-0.92](2)Changes of MTT; MTT were changed in 12.5% of BP group and 8.9% of UP group (p=0.00000011). OR; 0.68 [0.59-0.79](3)Discontinuation of MTT: MTT were withdrawn in 5.4% of BP group and 5.6% of UP group (P=0.63). OR; 1.05 [0.86-1.28]. Main reasons for discontinuation were insufficiency or adverse effects of MTT.Results of multiple logistic regression analysis are shown in Table 1.Stratified Analysis:(1)Pandemic suppressed the new indication of MTT only in established RA, not in early and long-standing RA.(2)Except long-standing RA, pandemic suppressed the change of MTT in early and established RA.Pandemic did not affect the discontinuation of MTT in any subgroups.Conclusion:Under COVID-19 pandemic, the therapeutic decision on the new indication of MTT was properly made based on RA management recommendation in early RA. However, new indication of MTT in established RA and the change of MTT were significantly affected by pandemic.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background and aims: Immunosuppressive therapy with intravenous ciclosporin is an alternative treatment option to total colectomy for patients with ulcerative colitis (UC), while the benefits of oral administration of tacrolimus are not well defined and are based on reports of several uncontrolled studies. Methods: Patients with refractory active UC were randomly assigned to a high trough concentration (10–15 ng/ml) group (HT group) (n = 21), low trough concentration (5–10 ng/ml) group (LT group) (n = 22), or placebo group (n = 20). Patients received an initial oral dose of 0.05 mg/kg tacrolimus or placebo twice daily. Efficacy was evaluated in 60 patients based on a disease activity index (DAI) score. Fifty eight patients had additional treatment with tacrolimus and were evaluated for efficacy in a 10 week open label extension. Results: An improvement in DAI score (⩾4 points, all categories improved) was observed for 68.4% of cases in the HT group compared with 10.0% in the placebo group (p<0.001). In the HT group, 20.0% of patients had clinical remission and 78.9% had mucosal healing. In the open label extension, 55.2% of all patients had an improved DAI score at week 10. Mean dose of prednisolone was reduced from 19.7 mg/day at study entry to 7.8 mg/day at week 10. The incidence of side effects in the HT group was significantly higher than that of the placebo group (p = 0.043). The most common event was mild finger tremor. Conclusions: Our findings demonstrate dose dependent efficacy and safety of oral tacrolimus for remission-induction therapy of refractory UC. The optimal target range appears to be 10–15 ng/ml in terms of efficacy with two week therapy.

We examined the relationship between morphological characteristics of anthers and fertility in japonica rice cultivars subjected to high temperature (37·5/26 °C day/night) at flowering. Percentage fertility was negatively correlated with the number of cell layers that separated the anther locule from the lacuna that formed between the septum and the stomium. The cell layers consisted of the remaining septum and degraded tapetum, and serve to keep the adjacent two locules closed. Anther dehiscence therefore requires the rupture of the cell layers. We conclude that the tight closure of the locules by the cell layers delayed locule opening, and decreased fertility at high temperatures.

Epithelial–mesenchymal transition (EMT) has a major role in cancer progression, as well as normal organ development and human pathology such as organ fibrosis and wound healing. Here, we performed a gene expression array specialized in EMT of colorectal cancer (CRC). From a comprehensive gene expression analysis using epithelial- and mesenchymal-like CRC cell lines, and following the ontology (GO) analysis, SIX1 gene was identified to be an EMT-related gene in CRC. Using SW480 cells stably transfected with a SIX1 expression construct and their control counterparts, we demonstrated that SIX1 overexpression represses CDH1 expression and promotes EMT in CRC. SIX1 -induced CDH1 repression and EMT in CRC cells were correlated at least in part with posttranscriptional ZEB1 activation and miR-200 -family transcriptional repression. In primary tumors of CRC, in accord with the functional findings, aberrant expression of SIX1 in cancer cells was observed at the disruption of the basement membrane and at the tumor invasive front, where tumor cells underwent EMT in vivo . Taken together, SIX1 overexpression is suggested to occur in carcinogenesis, and contribute to repression of CDH1 expression and promotion of EMT partly through repression of miR-200 -family expression and activation of ZEB1 in CRC.

During cardiopulmonary resuscitation, securing intravenous access for medication delivery can be problematic due to the size of the patient and vasoconstriction due to hypotension. The osseous route is a promising alternative to the intravenous route. The proximal humerus and proximal tibia are two commonly utilized sites in dogs. While some studies have reported the superiority of the proximal humerus route over the proximal tibia route for drug delivery in humans, there is a lack of knowledge on this topic in dogs. This study evaluated the difference in intraosseous vasopressin effect between the proximal humerus and proximal tibia in dogs. Seven healthy dogs were under general isoflurane anesthesia and intraosseous access was achieved in a crossover design. 0.05 U/kg vasopressin was administered and perfusion index (PI), heart rate (HR), and mean arterial blood pressure (MAP) were recorded. PI and HR decreased more dramatically when vasopressin was injected into the proximal humerus than into the proximal tibia, and MAP increased more distinctly when vasopressin was injected into the proximal humerus than into the proximal tibia. These results suggest that vasopressin is more effectively delivered when injected into the proximal humerus than into the proximal tibia. We performed histopathologic exploration of the humerus and tibia and found the difference in the distribution of vessels with cell composition of the bone marrow, and this would be a factor to affect the drug absorption of the each site. These results support the opinion that humerus is a superior intraosseous route for the administration of vasopressin.