Dispersion-corrected density functional theory (DFT) calculations examined energetically preferable hybrid structures between 13cycloparaphenylene (13CPP) and an armchair (m,m) tube (5 ≤ m ≤ 9). ...Tube-in-ring and ring-on-tube structures, denoted by (m,m)@13CPP and 13CPP–(m,m), respectively, were considered. DFT-based energy-decomposition analyses revealed that the key factors determining the stability of the hybrid structures are attractive long-range interactions between 13CPP and the (m,m) tube and the energy penalty required for the deformation of 13CPP. The long-range interactions in (m,m)@13CPP become more significant with an increase in the tube diameter. The 13CPP deformation in (m,m)@13CPP varies with the degree of deviation between the radius difference between 13CPP and a tube (Δr) and the van der Waal contact distance between two carbon atoms (3.35 Å). Accordingly, the stability of (m,m)@13CPP depends on the tube diameter. Particularly, (8,8)@13CPP, whose Δr is close to 3.35 Å, is highly stabilized among (m,m)@13CPP because of a negligible energy penalty for the 13CPP deformation. In contrast, the stability of 13CPP–(m,m) is less sensitive to the tube-diameter, and their attractive long-range interactions are weaker than those in (m,m)@13CPP. Consequently, a tube-in-ring structure whose radius difference is close to 3.35 Å is the most preferable among hybrid structures between 13CPP and an (m,m) tube.
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IJS, KILJ, NUK, PNG, UL, UM
This multi-center, retrospective study aimed to clarify the factors affecting drug retention of the Janus kinase inhibitors (JAKi) including baricitinib (BAR) and tofacitinib (TOF) in patients with ...RA. Patients were as follows; females, 80.6%; age, 60.5 years; DAS28-ESR, 4.3; treated with either BAR (n = 166) or TOF (n = 185); bDMARDs- or JAKi-switched cases (76.6%). The reasons for drug discontinuation were classified into four major categories. The drug retention was evaluated at 24 months using the Kaplan-Meier method and multivariate Cox proportional hazards modelling adjusted by confounders. Discontinuation rates for the corresponding reasons were as follows; ineffectiveness (22.3%), toxic adverse events (13.3%), non-toxic reasons (7.2%) and remission (0.0%). Prior history of anti-interleukin-6 receptor antibody (aIL-6R) ineffectiveness significantly increased the risk of treatment discontinuation due to ineffectiveness (p = 0.020). Aging (≥ 75 years) (p = 0.028), usage of PSL ≥ 5 mg/day (p = 0.017) and female sex (p = 0.041) significantly increased the risk of treatment discontinuation due to toxic adverse events. Factors not associated with treatment discontinuation were: number of prior bDMARDs or JAKi, concomitant MTX usage, difference of JAKi, and prior use of TNF inhibitor, CTLA4-Ig or other JAKi.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Inserting a guidewire into an extremely angulated side branch (SB) is difficult. Reverse wire technique (RWT) method was developed to specifically overcome this challenging situation, and it has ...become common among operators performing percutaneous coronary intervention. The first step of RWT involves the delivery of a reverse wire (RW) beyond the bifurcation, together with dual lumen catheter (DLC). This step is sometimes difficult, due to the stenosis proximal to bifurcation. Balloon dilatation of the stenosis is sometimes required to make space for the RW passage, but this lesion modification involves a potential risk of vessel damage, plaque shift, or carina shift, which results in the occlusion of the target SB. Streamlined RWT is a novel method we developed to facilitate RW delivery. It consists of the following three steps: (a) Advancing a DLC alone beyond the occlusion and inserting a preshaped RW into a non‐target SB distal to the bifurcation. (b) Adjusting the position of the bending part of RW and the exit port of DLC together at the ostium of the non‐target SB. (c) Advancing the RW and DLC simultaneously, while holding them both together. All procedures subsequent to the delivery of RW are the same as those required in conventional RWT. This technique enables us to deliver a RW through severe stenosis without the risk of either vessel injury or the occlusion of target SB. It also helps us to save time and effort in accomplishing SB access, even during the treatment of complex bifurcated lesions.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The purpose of this study was to evaluate the retention and discontinuation reasons of seven biological disease-modifying antirheumatic drugs (bDMARDs) in a real-world setting of patients with ...rheumatoid arthritis (RA). 1,037 treatment courses with bDMARDs from 2009 to 2016 female, 81.8%; baseline age, 59.6 y; disease duration 7.8 y; rheumatoid factor positivity 81.5%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR), 4.4; concomitant prednisolone 43.5% and methotrexate 68.6%; Bio-naïve, 57.1%; abatacept (ABT), 21.3%; tocilizumab (TCZ), 20.7%; golimumab (GLM), 16.9%; etanercept (ETN), 13.6%; adalimumab (ADA), 11.1%; infliximab (IFX), 8.5%; certolizumab pegol (CZP), 7.9% were included in this multi-center, retrospective study. Drug retention and discontinuation reasons at 36 months were estimated using the Kaplan-Meier method and adjusted by potent confounders using Cox proportional hazards modeling. As a result, 455 treatment courses (43.9%) were stopped, with 217 (20.9%) stopping due to inefficacy, 113 (10.9%) due to non-toxic reasons, 86 (8.3%) due to toxic adverse events, and 39 (3.8%) due to remission. Drug retention rates in the adjusted model were as follows: total retention (ABT, 60.7%; ADA, 32.7%; CZP, 43.3%; ETN, 51.9%; GLM, 45.4%; IFX, 31.1%; and TCZ, 59.2%; P < 0.001); inefficacy (ABT, 81.4%; ADA, 65.7%; CZP, 60.7%; ETN, 71.3%; GLM, 68.5%; IFX, 65.0%; and TCZ, 81.4%; P = 0.015), toxic adverse events (ABT, 89.8%; ADA, 80.5%; CZP, 83.9%; ETN, 89.2%; GLM, 85.5%; IFX, 75.6%; and TCZ, 77.2%; P = 0.50), and remission (ABT, 95.5%; ADA, 88.1%; CZP, 91.1%; ETN, 97.5%; GLM, 94.7%; IFX, 86.4%; and TCZ, 98.4%; P < 0.001). In the treatment of RA, ABT and TCZ showed higher overall retention, and TCZ showed lower inefficacy compared to IFX, while IFX showed higher discontinuation due to remission compared to ABT, ETN, GLM, and TCZ in adjusted modeling.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The introduction of calcium imaging has rendered cnidarians, such as Hydra vulgaris, valuable model organisms for investigating neuronal activity and behavior. Here, we present a comprehensive ...protocol to image and manipulate neuronal activity and behavior of Hydra. We describe steps for wide-field imaging and two-photon simulation and ablation of neurons. We then detail imaging behavior and post-ablation analysis. We address challenges that may arise during the preparation and execution of the experiments.
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•Calcium imaging of neuronal activity in behaving Hydra•Selective two-photon activation and ablation of neurons•Behavioral effects of neuronal activity manipulation
Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
The introduction of calcium imaging has rendered cnidarians, such as Hydra vulgaris, valuable model organisms for investigating neuronal activity and behavior. Here, we present a comprehensive protocol to image and manipulate neuronal activity and behavior of Hydra. We describe steps for wide-field imaging and two-photon simulation and ablation. We then detail imaging behavior and post-ablation analysis. We address challenges that may arise during the preparation and execution of the experiments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objectives: Sarcopenia is characterized by loss of muscle strength and mass, leading to falls and adverse health outcomes. Our aim was to determine the prevalence of sarcopenia in patients with ...rheumatoid arthritis (RA) and to identify factors associated with sarcopenia in these patients.
Methods: A cross-sectional study of 388 consecutive women with RA was conducted, assessing muscle mass and strength, and walking speed. Falls and bone fractures sustained over the prior year were evaluated. The association between sarcopenia and RA characteristics, falls, and bone fractures was evaluated using logistic regression analyses.
Results: The prevalence of sarcopenia was 37.1% (14.7%, severe sarcopenia; 22.4%, sarcopenia), with 49.0% classified as having low muscle mass. The incidence of falls, fractures, and lower bone mineral density was higher in patients with than without sarcopenia. Age, RA duration, Steinbrocker's stage, the high Mini-Nutritional Assessment-Short Form score and the use of biological disease-modifying anti-rheumatic drugs (bDMARDs) were independent factors associated with sarcopenia.
Conclusion: We confirmed that sarcopenia develops in a significant proportion of patients with RA. Age, longer disease duration, joint destruction and malnutrition were positively associated with sarcopenia, with the use of bDMARDs being negatively associated.
Rheumatoid arthritis causes joint inflammation due to immune abnormalities, resulting in joint pain and swelling. In recent years, there have been considerable advancements in the treatment of this ...disease. However, only approximately 60% of patients achieve remission. Patients with multifactorial diseases shift between states from day to day. Patients may remain in a good or poor state with few or no transitions, or they may switch between states frequently. The visualization of time-dependent state transitions, based on the evaluation axis of stable/unstable states, may provide useful information for achieving rheumatoid arthritis treatment goals. Energy landscape analysis can be used to quantitatively determine the stability/instability of each state in terms of energy. Time-series clustering is another method used to classify transitions into different groups to identify potential patterns within a time-series dataset. The objective of this study was to utilize energy landscape analysis and time-series clustering to evaluate multidimensional time-series data in terms of multistability. We profiled each patient's state transitions during treatment using energy landscape analysis and time-series clustering. Energy landscape analysis divided state transitions into two patterns: "good stability leading to remission" and "poor stability leading to treatment dead-end." The number of patients whose disease status improved increased markedly until approximately 6 months after treatment initiation and then plateaued after 1 year. Time-series clustering grouped patients into three clusters: "toward good stability," "toward poor stability," and "unstable." Patients in the "unstable" cluster are considered to have clinical courses that are difficult to predict; therefore, these patients should be treated with more care. Early disease detection and treatment initiation are important. The evaluation of state multistability enables us to understand a patient's current state in the context of overall state transitions related to rheumatoid arthritis drug treatment and to predict future state transitions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Sarcopenia is an age-related disease with an increased risk of mortality. It is emerging that low serum 25-hydroxyvitamin D 25(OH)D affects the sarcopenic state in general, but in rheumatoid ...arthritis (RA), these associations are not understood although the prevalence of vitamin D insufficiency is high in RA. We conducted a cross-sectional study of older female outpatients from our cohort (KURAMA) database. We measured skeletal muscle mass, handgrip strength, and gait-speed to diagnose severe sarcopenia. The serum 25(OH)D concentration was measured using electrochemiluminescence immunoassay. A total of 156 female patients with RA (sarcopenia:44.9%, severe sarcopenia: 29.5%, and without sarcopenia: 25.6%) were enrolled. Classification of vitamin D status at a cutoff point of median 25(OH)D concentration revealed that low 25(OH)D status was associated with a high prevalence of severe sarcopenia and with low measured values of muscle mass, handgrip, and gait speed. Furthermore, multivariable logistic regression analysis identified that low 25(OH)D status was associated with a high prevalence of severe sarcopenia (OR 6.00; 95% CI 1.99-18.08).The same association was observed when the cut-off value was set at 20 ng/ml. In components of sarcopenia, both low physical performance and muscle mass were associated with low 25(OH)D status. In conclusion, vitamin D status was inversely associated with severe sarcopenia, low physical performance, and low skeletal muscle mass. Modification of vitamin D status including vitamin D supplementation should be investigated as a therapeutic strategy for sarcopenic patients with RA.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The aim of this study is to evaluate the retention rates and reasons for discontinuation for seven biological disease-modifying antirheumatic drugs (bDMARDs) in a real-world setting of patients with ...rheumatoid arthritis (RA).
This multi-center, retrospective study assessed 4466 treatment courses of 2494 patients with bDMARDs from 2009 to 2017 (females, 82.4%; baseline age, 57.4 years; disease duration 8.5 years; rheumatoid factor positivity 78.6%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate, 4.3; concomitant prednisolone (PSL) 2.7 mg/day (43.1%) and methotrexate (MTX) 5.0 mg/week (61.8%); and 63.6% patients were bio-naïve). Treatment courses included tocilizumab (TCZ; n = 895), etanercept (ETN; n = 891), infliximab (IFX; n = 748), abatacept (ABT; n = 681), adalimumab (ADA; n = 558), golimumab (GLM; n = 464), and certolizumab pegol (CZP; n = 229). Drug retention rates and discontinuation reasons were estimated at 36 months using the Kaplan-Meier method and adjusted for potential confounders (age, sex, disease duration, concomitant PSL and MTX, and switched number of bDMARDs) using Cox proportional hazards modeling.
A total of 56.9% of treatment courses were stopped, with 25.8% stopping due to lack of effectiveness, 12.7% due to non-toxic reasons, 11.9% due to toxic adverse events, and 6.4% due to disease remission. Drug retention rates for each discontinuation reason were as follows: lack of effectiveness from 65.5% (IFX) to 81.7% (TCZ); with significant differences between groups (Cox P < 0.001), toxic adverse events from 81.8% (IFX) to 94.0% (ABT), Cox P < 0.001, and remission from 92.4% (ADA and IFX) to 97.7% (ETN), Cox P < 0.001. Finally, overall retention rates excluding non-toxic reasons and remission for discontinuation ranged from 53.4% (IFX) to 75.5% (ABT) (Cox P < 0.001).
TCZ showed the lowest discontinuation rate by lack of effectiveness, ABT showed the lowest discontinuation rate by toxic adverse events, ADA and IFX showed the highest discontinuation rate by remission, and ABT showed the highest overall retention rates (excluding non-toxic reasons and remission) among seven bDMARDs in the adjusted model.
Frailty is a geriatric syndrome characterized by anabolic-catabolic imbalance and multisystem dysregulation resulting in increased adverse health outcomes, and is closely related with dietary habits ...in the general population. Although chronic inflammatory diseases are thought to accelerate development of frailty, correlations between rheumatoid arthritis (RA), frailty and dietary habits have not been examined. We performed a cross-sectional study using our cohort database (KURAMA cohort), and classified 306 participants into three groups (robust, prefrail and frail) according to the Study of Osteoporotic Fracture (SOF) criteria. Multivariate logistic analysis revealed that the presence of frailty/prefrailty was significantly correlated with the disease activity score (DAS28-ESR) (OR 1.70 (1.30-2.22), p < 0.0001). Additional analyses of frailty and food intake showed that 5 foods (fish, meat, milk, vegetables and fruits) of 20 groups on the questionnaire were inversely associated with the prevalence of frail/prefrail categories. In multivariate analysis with the five nutrients, fish intake (> two times a week) was an independent covariate negatively correlated with frailty/prefrailty (OR 0.35 (0.19-0.63), p = 0.00060). In conclusion, habitual fish intake may play a key role in nutritional intervention to prevent progression of frailty and RA.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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