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The dispersal processes of anatomically modern humans in Asia during the late Middle to early Upper Paleolithic periods have been a focus of intensive research in recent years through interdisciplinary approaches including genetic, paleoanthropological, and archeological studies. However, sparse datasets, often only available from limited time-space contexts have not produced a satisfactory picture of the vast geographic extension of this continent. This study investigated how the chrono-spatial patterning of lithic technological records, which are widely available across Asia, might contribute to our better understanding of the population dynamics in this period. The study is based on a large database (PaleoAsiaDB) recently developed by the authors to accommodate the relevant datasets, including geographical coordinates of each site and available radiometric dates, for the Middle and Upper Paleolithic periods in Asia. Each of the 895 lithic assemblages was characterized in terms of the presence/absence of 24 lithic modes/submodes that were adapted from the work of John Shea to fit our research objective. The dataset was analyzed using exploratory statistical methods, including principal component analysis. The results revealed marked spatiotemporal patterns in technological variability from the late Middle to early Upper Paleolithic periods. Some can be interpreted as a result of modern human dispersal, whereas others are better explained from ecological and other perspectives rather than authorships. Although this study has obvious limitations due to its reliance on the information sourced from the literature, it provides a global synthesis of lithic variability in the crucial period of the dispersals of modern humans on a continental scale for the first time. The results serve as a guide to be tested with evidence from other research strategies, such as genetics and fossil studies.

In this paper, we propose a novel radiochromic film (RCF)-based computed tomography (CT) dosimetry method, which is different from the method based on CT dose index. RCF dosimetry using Gafchromic QA2 films was performed using two lengths of film-folding phantoms. The phantom was exposed to X-ray CT through a single scan, while the RCF was sandwiched between the phantoms. We analysed the dose profile curve in two directions to investigate the dose distribution. We observed a difference in the dose distribution as the phantom size changed. Our results contradict with the results of previous studies such as Monte Carlo simulation or direct measurement. The ability to visually evaluate 2D dose distributions is an advantage of RCF dosimetry over other methods. This research investigated the ability of 2D X-ray CT dose evaluation using RCF and film-folding phantom.

Although the "drug lag"-namely, the delay in drug approval time in Japan relative to the United States and/or European Union (US/EU)-has been shortened for drugs approved in Japan, there remain many new drugs that have been approved in the US/EU, but not in Japan. To assess the possibility of a future drug lag, this study has examined the current lag in drug development in Japan based on "ClinicalTrials.gov" data from multiregional clinical trials (MRCTs) conducted in the US/EU and East Asia. Among 828 MRCTs registered as of April 5th, 2021, the percentage of MRCTs in which Japan participated (jMRCTs) was 57.1%. jMRCTs were common for some diseases such as "nervous system" and "visual system" disorders, but less common for "neoplasm," infection," "mental," and "circulatory" disorders. Regarding the investigational drugs in non-jMRCTs (i.e., MRCTs without Japanese participation) in the latter four therapeutic areas (i.e., neoplasm, infection, mental and circulatory disorders), approximately 80% (313/399) of drugs were not being developed in Japan. Furthermore, many of these drugs were being developed by the top 50 pharmaceutical companies by sales, and the majority would be recognized as a new active ingredient with a new mode of action in Japan. This study has highlighted the possibility of a future drug lag in Japan, especially in the therapeutic areas of neoplasm, infection, mental, and circulatory disorders. Such a lag may arise not only between Japan and the US/EU, but also between Japan and other countries in the East Asian region.

Spot Vision Screener (SVS) can conduct refraction tests for both eyes within a short period. This study aims to evaluate the refraction and pupil diameters of 3-year- and 1-month-old Japanese children using SVS in regular medical checkup. We examined 2438 eyes of 1219 children (age: 3-year- and 1-month) in Fujieda (Shizuoka, Japan) to assess their refraction and pupil diameters and eye-position screening conducted by SVS. SVS successfully measured 1217 children (99.8%). Regarding the right eye refraction, the spherical power was +0.70 ± 0.55 D (median, +0.75 D), and the cylindrical power was −0.67 ± 0.49 D (median, −0.50 D). The pupil diameter of the right eyes was 5.57 ± 0.79 (median, 5.60) mm. we could obtain a large number of basic data for 3-year- and 1-month-old Japanese children. However, refraction and pupil diameter of children were not normally distributed, so careful handling of children’s basic data on the eye is necessary.

Objectives: To analyze the effects of tocilizumab on peripheral B-cell subpopulation and its ability to produce anti-cyclic citrullinated peptide (CCP) antibody in patients with rheumatoid arthritis (RA). Methods: Thirteen consecutive RA patients initiated with tocilizumab were enrolled in our prospective study. Anti-CCP antibody titers and clinical parameters were evaluated during treatment. Peripheral blood B-cell subsets were analyzed using flow cytometry according to the Human Immunology Project. Results: Disease activity was significantly improved and anti-CCP antibody titers significantly decreased at week 24 compared to baseline. The percentages of post-switch memory B cells in CD19+ cells transiently increased at week 12, but there was no significant difference in any of the investigated B-cell subpopulations at week 24 compared to baseline. The ratios of post-switch memory to naïve B cells (post-switch/naïve) correlated negatively with anti-CCP antibody titers regardless of the time-points. Conclusion: Our study indicated that tocilizumab has a potential to reduce anti-CCP antibody production presumably by affecting post-switch/naïve ratio, and that anti-CCP antibody titers reflect B-cell distribution/subpopulation. As anti-CCP antibodies are produced in lymph nodes or ectopic lymphoid structures in synovial tissues, not in circulation, transient increment of post-switch memory B cells after tocilizumab treatment may reflect the altered balance of B-cell distribution between circulation and arthritic joints, resulting in suppressed production of anti-CCP antibody in situ.

To identify the subpopulation of rheumatoid arthritis (RA) non-responders to Janus kinase inhibitors (JAKis) using cluster analysis.This retrospective study enrolled RA patients who had been treated with JAKis (tofacitinib or baricitinib) between July 2013 and September 2019 in six centres. The endpoint was set as inadequate response to JAKis (JAKis-IR), defined as either non-response to JAKis or their intolerance. Non-response to JAKis was defined as achieving neither American College of Rheumatology 20% response nor Disease Activity Score (ΔDAS28-CRP)1.2 at 12 weeks. Withdrawal time point included earlier than after 12 weeks from baseline. A hierarchical cluster analysis was performed with variables related with clinical and serological parameters at baseline.The 132 RA patients enrolled were classified into four groups (Group A-D). Groups consisted of three components defined at baseline, as seropositivity, advanced joint destruction, interstitial lung disease presumably associated with RA (RA-ILD). Group A (n=32): seronegative, presence of advanced joint destruction, absence of RA-ILD. Group B (n=35): seropositive, absence of advanced joint destruction and RA-ILD. Group C (n=20): seropositive, absence of advanced joint destruction, presence of RA-ILD. Group D (n=45): seropositive, presence of advanced joint destruction and RA-ILD. The rate of JAKis-IR in four groups was as follows: A, 34.3%; B, 17.1%; C, 20.0%; and D, 8.9%. The difference in JAKis-IR rate between group A and D was statistically significant.A subpopulation of RA patients with a combination of the following three components, seronegativity, advanced joint destruction and absence of RA-ILD, was identified as being prone to JAKis-IR.

A stone chamber is a stone burial facility built inside a mounded tomb (Kofun). A corridor-style stone chamber is a stone chamber built on the side of a Kofun. A corridor-style stone chamber is composed of a main burial chamber for storing a body and a tunnel-shaped passageway to the chamber of a mounded tomb. Many corridorstyle stone chambers have basically the same structure. However, many of stone chambers are different in shapes such as the number of beams in the main burial chamber, and the shapes have been changed after stone on the ceiling is collapsed and sediment is accumulated inside. Archaeologists have been attempting to store and record 3D-measured digital data of stone chambers to protect and manage them1. In [1], a depth sensor in a smartphone is used for 3D measurement, and multiple stone chambers are measured. In addition, the shape similarity between the measured point clouds is visually compared by any 3D CG Viewing software. Meanwhile, the visual comparison is based on subjective and qualitative observation approaches; thus a method for objectively evaluating the similarity is required. A matching method using the scaling iterative closest point (sICP) algorithm is one of the methods for evaluating the similarity between the point clouds. It enables distance minimization of closest point pairs between the point clouds after adjusting the point clouds in a same scale. Then the similarity between the point clouds can be evaluated as this obtained minimum distance. When a corridor-style stone chamber is measured, however, not only the stone chamber in the ground but also the ground surface part will be obtained together as a point cloud. The difference of the ground surface shapes makes shape matching difficult. Owing to the above-mentioned issue, this paper proposes an examination of the stone chamber extraction. It is the base of similarity evaluation between 3D-measured corridor-style stone chambers.

We report the development of a superconducting acousto-optic phase modulator fabricated on a lithium niobate substrate. A titanium-diffused optical waveguide is placed in a surface acoustic wave resonator, where the electrodes for mirrors and an interdigitated transducer are made of a superconducting niobium titanium nitride thin film. The device performance is evaluated as a substitute for the current electro-optic modulators, with the same fiber coupling scheme and comparable device size. Operating the device at a cryogenic temperature (T=8K), we observe the length-half-wave-voltage (length-$V_\pi$) product of 1.78 V$\cdot$cm. Numerical simulation is conducted to reproduce and extrapolate the performance of the device. An optical cavity with mirror coating on the input/output facets of the optical waveguide is tested for further enhancement of the modulation efficiency. A simple extension of the current device is estimated to achieve an efficient modulation with $V_\pi=$ 0.27 V., Comment: 9 pages, 4 figures

Trapped-ion quantum technologies have been developed for decades toward applications such as precision measurement, quantum communication and quantum computation. Coherent manipulation of ions' oscillatory motions in an ion trap is important for quantum information processing by ions, however, unwanted decoherence caused by fluctuating electric-field environment often hinders stable and high-fidelity operations.. One way to avoid this is to adopt pulsed laser ablation for ion loading, a loading method with significantly reduced pollution and heat production. Despite the usefulness of the ablation loading such as the compatibility with cryogenic environment, randomness of the number of loaded ions is still problematic in realistic applications where definite number of ions are preferably loaded with high probability. In this paper, we demonstrate an efficient loading of a single strontium ion into a surface electrode trap generated by laser ablation and successive photoionization. The probability of single-ion loading into a surface electrode trap is measured to be 82\,\%, and such a deterministic single-ion loading allows for loading ions into the trap one-by-one. Our results open up a way to develop more functional ion-trap quantum devices by the clean, stable, and deterministic ion loading., Comment: 6 pages, 4figures, 1 table

Background Endoscopic removal of colorectal adenoma is considered an effective treatment for reducing the mortality rates associated with colorectal cancer. Warfarin, a type of anticoagulant, is widely used for the treatment and prevention of thromboembolism; however, bleeding may increase with its administration after polypectomy. In recent times, a high incidence of bleeding after endoscopic polypectomy has been reported in patients receiving heparin bridge therapy. However, previous studies have not compared the bleeding rate after endoscopic colorectal polypectomy between patients who continued with anticoagulant therapy and those who received heparin bridge therapy. We hypothesised that endoscopic colorectal polypectomy under the novel treatment with continuous warfarin is not inferior to endoscopic colorectal polypectomy under standard treatment with heparin bridge therapy with respect to the rate of postoperative bleeding. This study aims to compare the efficacy of endoscopic colorectal polypectomy with continuous warfarin administration and endoscopic colorectal polypectomy with heparin bridge therapy with respect to the rate of postoperative bleeding. Methods We will conduct a prospective multicentre randomised controlled non-inferiority trial of two parallel groups. We will compare patients scheduled to undergo colorectal polypectomy under anticoagulant therapy with warfarin. There will be 2 groups, namely, a standard treatment group (heparin bridge therapy) and the experimental treatment group (continued anticoagulant therapy). The primary outcome measure is the rate of postoperative bleeding. On the contrary, the secondary outcomes include the rate of cumulative bleeding, rate of overt haemorrhage (that does not qualify for the definition of haemorrhage after endoscopic polypectomy), incidence of haemorrhage requiring haemostasis during endoscopic polypectomy, intraoperative bleeding during endoscopic colorectal polypectomy requiring angiography, abdominal surgery and/or blood transfusion, total rate of bleeding, risk factors for postoperative bleeding, length of hospital stay, incidence of thromboembolism, prothrombin time-international ratio (PT-INR) 28 days after the surgery, and incidence of serious adverse events. Discussion The results of this randomised controlled trial will provide valuable information for the standardisation of management of anticoagulants in patients scheduled to undergo colorectal polypectomy. Trial registration UMIN-CTR UMIN000023720. Registered on 22 August 2016

The rapid development in designs and fabrication techniques of superconducting qubits has helped making coherence times of qubits longer. In the near future, however, the radiative decay of a qubit into its control line will be a fundamental limitation, imposing a trade-off between fast control and long lifetime of the qubit. In this work, we successfully break this trade-off by strongly coupling another superconducting qubit along the control line. This second qubit, which we call a Josephson quantum filter (JQF), prevents the qubit from emitting microwave photons and thus suppresses its relaxation, while faithfully transmitting large-amplitude control microwave pulses due to the saturation of the quantum filter, enabling fast qubit control. We observe an improvement of the qubit relaxation time without a reduction of the Rabi frequency. This device could potentially help in the realization of a large-scale superconducting quantum information processor in terms of the heating of the qubit environments and the crosstalk between qubits., Comment: 22 pages, 13 figures, 1 table

Whispering gallery modes (WGMs), circulating modes near the surface of a spheroidal material, have been known to exhibit high quality factors for both acoustic and electromagnetic waves. Here, we report an electro-optomechanical system, where the overlapping WGMs of acoustic and optical waves along the equator of a dielectric sphere strongly couple to each other. The triple-resonance phase-matching condition provides a large enhancement of the Brillouin scattering only in a single sideband, and conversion from the input radio-frequency signal exciting the acoustic mode to the output optical signal is observed., 13 pages, 10 figures

Hybrid quantum devices expand the tools and techniques available for quantum sensing in various fields. Here, we experimentally demonstrate quantum sensing of the steady-state magnon population in a magnetostatic mode of a ferrimagnetic crystal. Dispersively coupling the magnetostatic mode to a superconducting qubit allows the detection of magnons using Ramsey interferometry with a sensitivity on the order of $10^{-3}$ $\text{magnons}/\sqrt{\text{Hz}}$. The protocol is based on dissipation as dephasing via fluctuations in the magnetostatic mode reduces the qubit coherence proportionally to the number of magnons., Comment: 5 pages, 4 figures, Supplementary Material (23 pages, 14 figures)

The strength and density change of the ultraviolet (UV) ray of Gafchromic EBT2 were investigated. Previous studies suggested that UV-A rays can be substituted for the x-ray double-exposure technique to correct Gafchromic EBT2’s non-uniformity error. In this study, we aimed to determine the appropriate strength of UV-A rays for irradiating an active layer that would correct the non-uniformity error of Gafchromic EBT2. UV-A rays with a wavelength of 375 nm were used to irradiate Gafchromic EBT2 in various durations, and the resulting density change was investigated. To correct Gafchromic EBT2’s non-uniformity error, a pre-irradiation with a UV-A lamp was conducted at a distance of 72 cm for 30 min. To determine the most appropriate irradiation duration, a UV light-emitting diode generating UV-A of 375 nm was used to irradiate the Gafchromic EBT2 film with varying durations of 1, 2, 3, 4, 5, 10, 15, 20, 25, and 30 min at a distance of 5.3 cm. A 12.7 diameter region of interest was set by the irradiation area, and a histogram of pixel values was created. The condition options were decided based on two important requirements: 1) no zero values of the mode and seconds exist, and 2) the 1/10 value of the mode intersects both histogram sleeves. In the case of Gafchromic EBT2, the irradiation strength was 85.43 mJ/cm2 for one minute in which the pixel value of mean ± SD was 255.34 ± 213.29. The irradiation duration of 4 min was the border duration of the above two conditions. When a UV ray of 375 nm wavelength is used to irradiate Gafchromic EBT2 as a substitute for x-ray exposure, the 4-min pre-irradiation duration (341.74 mJ/cm2) is demonstrably sufficient.

BACKGROUND Synovitis, which is a hallmark of rheumatoid arthritis (RA), needs to be precisely quantified to determine the treatment plan. Time-intensity curve (TIC) shape analysis is an objective assessment method for characterizing the pixels as artery, inflamed synovium, or other tissues using dynamic contrast-enhanced MRI (DCE-MRI). PURPOSE/HYPOTHESIS To assess the feasibility of our original arterial mask subtraction method (AMSM) with mutual information (MI) for quantification of synovitis in RA. STUDY TYPE Prospective study. SUBJECTS Ten RA patients (nine women and one man; mean age, 56.8 years; range, 38-67 years). FIELD STRENGTH/SEQUENCE 3T/DCE-MRI. ASSESSMENT After optimization of TIC shape analysis to the hand region, a combination of TIC shape analysis and AMSM was applied to synovial quantification. The MI between pre- and postcontrast images was utilized to determine the arterial mask phase objectively, which was compared with human subjective selection. The volume of objectively measured synovitis by software was compared with that of manual outlining by an experienced radiologist. Simple TIC shape analysis and TIC shape analysis combined with AMSM were compared in slices without synovitis according to subjective evaluation. STATISTICAL TESTS Pearson's correlation coefficient, paired t-test and intraclass correlation coefficient (ICC). RESULTS TIC shape analysis was successfully optimized in the hand region with a correlation coefficient of 0.725 (P

Gafchromic films have been used to measure X-ray doses in diagnostic radiology such as computed tomography. The double-exposure technique is used to correct non-uniformity error of Gafchromic EBT2 films. Because of the heel effect of diagnostic x-rays, ultraviolet A (UV-A) is intended to be used as a substitute for x-rays. When using a UV-A light-emitting diode (LED), it is necessary to determine the effective optimal UV wavelength for the active layer of Gafchromic EBT2 films. This study evaluated the relation between the increase in color density of Gafchromic EBT2 films and the UV wavelengths. First, to correct non-uniformity, a Gafchromic EBT2 film was pre-irradiated using uniform UV-A radiation for 60 min from a 72-cm distance. Second, the film was irradiated using a UV-LED with a wavelength of 353-410 nm for 60 min from a 5.3-cm distance. The maximum, minimum, and mean ± standard deviation (SD) of pixel values of the subtraction images were evaluated using 0.5 inches of a circular region of interest (ROI). The highest mean ± SD (8915.25 ± 608.86) of the pixel value was obtained at a wavelength of 375 nm. The results indicated that 375 nm is the most effective and sensitive wavelength of UV-A for Gafchromic EBT2 films and that UV-A can be used as a substitute for x-rays in the double-exposure technique.

Late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) is a well-known finding indicative of cardiac involvement in systemic sclerosis (SSc heart). However, few studies have reported the precise histopathology at the site of LGE. We present an autopsy report of a 51-year-old man diagnosed with diffuse cutaneous SSc according to a systematic diagnostic workup, including skin biopsy. CMR indicated left ventricular (LV) dilatation and broadly distributed subendocardial LGE in the LV walls. The patient was treated with methylprednisolone pulse therapy because of multiple episodes of ventricular tachycardia, whereas he subsequently died of left heart failure. An autopsy study revealed broad subendocardial replacement fibrosis, concomitant with the distribution of LGE on CMR, without inflammatory or edematous changes. Notably, myocardial fibrosis was evident around the intramural coronary arteries, although the arteries themselves were intact. These findings demonstrated that broad subendocardial LGE on CMR reflected replacement myocardial fibrosis in a patient with diffuse cutaneous SSc. These clinicopathological observations suggested that spasms in the intramyocardial arteries or the cardiac Raynaud’s phenomenon may have provoked broad subendocardial fibrosis of the LV walls.

Previous studies have shown that ferromanganese crusts in the Pacific Ocean commonly record paleomagnetic reversals and that the reversal patterns can be used to estimate growth rates. In order to investigate the applicability of the magnetostratigraphic method, we conducted paleomagnetic measurements of crust samples recovered from five locations in the northwest Pacific. A series of thin slices, with thicknesses of 0.5–1.0 mm, was prepared for each sample, and a paleomagnetic polarity was determined for each slice. In all five samples, we found a consistent reversal pattern of N1–R1–N2–R2–N3 from the surface to the inner part of the crust. In three samples, another polarity interval (R3) was recognized below the N3 section of the crust. These data suggest that ferromanganese crusts in the northwest Pacific recorded paleomagnetic reversals and that reversal patterns can be used for ocean-scale correlations. The magnetostratigraphic method suggests constant growth rates of 1.49, 2.54, 3.56 and 3.67 mm/Ma for four samples, three of which are consistent with those estimated using 10 Be/ 9 Be dating at the 2σ (standard deviation) level.

Ferromanganese crusts record long-term deep-sea environmental changes. Thus, providing their reliable high-resolution age models is important. We applied a magnetostratigraphic technique to estimate the growth rate of a ferromanganese crust using scanning SQUID (superconducting quantum interference device) microscope (SSM). SSM is designed to map the magnetic field across thins sections with sub-millimeter resolution. The crust sample was taken from the Takuyo–Daigo Seamount, northwestern Pacific, and recorded a limited supply of dust and sediment from continents. After drift correction and removal of spike noises, the magnetic field values were stacked within the areas of high signal-to-noise ratios. By correlating the obtained profiles with a standard geomagnetic polarity timescale, we obtained an average growth rate of 3.37 ± 0.06 mm/m.y., which is consistent with that obtained by 10Be/9Be geochronology (2.93 ± 0.15 mm/m.y.). S-ratio mapping shows low values after ~3 Ma, associated with voids between columnar structures.

Background Topical corticosteroid and calcineurin inhibitor have similar therapeutic benefits in atopic dermatitis (AD), but the differences in therapeutic mechanisms of action of these agents against AD symptoms are not fully understood. Objective This study was performed to examine the different effects of topical betamethasone valerate (BMV), clobetasol propionate (CBP), and tacrolimus (TAC) on itch-related behavior and dermatitis in NC/Nga mice with AD-like symptoms. Methods AD-like dermatitis was induced in the dorsal skin of NC/Nga mice by repeated topical application of Dermatophagoides farinae body (Dfb) ointment twice weekly for three weeks. Mice with dermatitis scores over 5 were divided into five groups with equal dermatitis scores and treated with BMV, CBP, TAC, or Vaseline (Vas) once daily for two consecutive days, or were not treated (NT). Scratching behavior was analyzed using a SCLABA ® -Real system. Transepidermal water loss (TEWL) before and after treatment was measured using a Tewameter ® TM210. Skin collected from each group was analyzed histologically. Results After the second treatment, dermatitis showed significantly greater improvement in the CBP and TAC-treated groups than in the Vas-treated and NT groups. The numbers of scratching bouts were significantly lower in CBP and TAC-treated mice than in Vas-treated mice. TEWL was significantly lower in TAC-, but not in CBP-, treated mice than in Vas-treated mice. Immunohistochemical examination showed that BMV, CBP and TAC did not reduce the increased densities of epidermal protein gene product 9.5- and substance P-immunoreactive fibers. The numbers of dermal CD4-immunoreactive T cells were significantly lower in BMV and CBP-treated mice than in Vas-treated and NT mice. The numbers of dermal eosinophils were significantly lower in BMV, CBP and TAC-treated mice than in Vas-treated and NT mice, with CBP showing the strongest effect. CBP significantly reduced epidermal thickness compared with Vas and NT. There were no significant differences in the numbers of interleukin-31-immunoreactive cells and mast cells, or in expression of epidermal thymic stromal lymphopoietin among all five groups. Conclusion The therapeutic potency of TAC against AD-like symptoms, including pruritus, is equal to that of the corticosteroid CBP. Epidermal innervation of sensory nerves itself might not be related to the therapeutic effects of topical tacrolimus and corticosteroids in its early phase.

Background Despite the advantages of ultrasound (US) in the management of rheumatoid arthritis (RA) patients, power Doppler (PD) US may be highly dependent on the type of US machine used. Purpose To present a method to calibrate the PD signal of two models of US machines by use of a flow phantom and finger joints of patients with RA. Material and Methods For the phantom study, the PD signal count was measured in the flow phantom perfusing blood mimicking fluid at various injection rates and pulse repetition frequencies (PRFs). The quantitative PD index was calculated with ImageJ. For the clinical study, the second and third metacarpophalangeal joints of five consecutive patients with RA were examined. The quantitative PD index was measured at various PRFs by use of two models of machine (the same models as the phantom study). Results For the phantom and clinical studies, negative correlations were found between the PRF and the quantitative PD index when the flow velocity was constant and positive correlations between flow velocity and the quantitative PD index at constant PRF. There was a significant difference in the depiction performance of synovial blood flow between the two models, which can be calibrated by adjusting the PRF values derived from the phantom study in each model. Conclusion Signal calibration of pannus vascularity between US machines may be possible by adjusting the PRF value according to flow phantom data. Different US machines can thus provide equivalent examination results concerning the pannus vascularity.

To clarify the efficacy and safety of calcineurin inhibitors (CNI) for treating adult-onset Still's disease (AOSD).This multicentre historical cohort study enrolled the consecutive patients with AOSD according to Yamaguchi classification criteria. The endpoints were set as the time from the initiation of treatment to events, the persistency rate of CNI and safety. Based on the recurrent event data analysis, these endpoints were evaluated for each event. We divided the events into two groups according to the treatment that included CNI or conventional therapy without CNI.One hundred seventy-eight patients with 247 events were analysed. CNI were predominantly used in 72 events with a recurrent history, typical skin rash, high ferritin levels, and/or severe complications such as macrophage activation syndrome, disseminated intravascular coagulation, serositis, meningitis. CNI led to a significantly longer event-free survival (hazard ratio: 0.57, 95% confidential interval: 0.32-0.99) after adjustment of concomitant medications. Subgroup analysis showed that CNI were effective for AOSD patients with high ALT level (hazard ratio: 0.11, 95% confidential interval: 0.02-0.59) and severe complications (hazard ratio: 0.11, 95% confidential interval: 0.01-0.94). The persistency rate of CNI was 71% at 5th year. Adverse events occurred more frequently in the CNI group (18% versus 8%, p=0.02); however, CNI did not involve in increased risk of adverse events, including nephrotoxicity, after adjustment (p=0.23).Our retrospective analysis suggested that CNI could be an effective and safe option for treating AOSD.

Background Adult-onset Still’s disease (AOSD) is a systemic inflammatory disorder generally responsive to corticosteroid (CS) therapy, whereas cases not responding CS monotherapy are frequently found in clinical practice. In such cases, methotrexate and/or biologics including TNF-α, IL-1, or IL-6 inhibitors are used [1]. However, further treatment options are required for refractory AOSD patients who are intolerant to methotrexate and/or biologics. Calcineurin inhibitors (CNI) downregulate T cell activation through inhibiting IL-2 transcription and signal transduction. Therefore, they are reasonable therapeutic medication for AOSD considering T cells and subsequently activated macrophages play a pathophysiological role in AOSD [2]. Nevertheless, only a few case series have indicated effects of CNI for difficult AOSD. Objectives To evaluate the efficacy of CNI in patients with AOSD. Methods This is a multi-centre historical cohort study comprised the consecutive patients with AOSD in accordance with Yamaguchi classification criteria. The primary endpoint was set as the time from the initiation of treatment to event defined as death of any causes or relapse of AOSD requiring an increase of CS dose. Secondary endpoints were set as persistency rate of CNI and safety. Based on the recurrent event data analysis, these endpoints were evaluated for each event. We compared the frequency of events between two groups according to the treatment that included calcineurin inhibitors (CNI+) or conventional therapy without calcineurin inhibitors (CNI-). Results One hundred seventy-eight patients were enrolled in this study. Mean age was 46 year-old, and median follow-up period 36 months. Seventy-one events in 56 patients were treated with therapeutic regimen including CNI (CNI+, cyclosporine: 14, tacrolimus: 60), and 176 events in 138 patients were treated with the conventional therapy excluding CNI (CNI-). CNI were used in AOSD patients with recurrent history, high ferritin level, serositis, hemophagocytic syndrome (HPS) and/or disseminated intravascular coagulation (DIC). The CNI+ group had longer event-free survival than the CNI- group (83% versus 75% at 5th year). The hazard ratio (HR) was 0.57 (95% CI, 0.32-0.99) after adjustment of initial dose of CS and other concomitant medications. Subgroup analysis showed that CNI were more effective for AOSD patients with high ALT levels (≥ 80 IU/L) and/or severe complications such as HPS and DIC. The persistency rate of CNI was 71% at 5th year. Adverse events occurred more frequently in the CNI+ group than in the CNI- group (18% versus 8%, p = 0.04); however, serious adverse events did not increase in the CNI+ group (3% versus 2%). AOSD-related mortality had never been found in the observation period. One patient had a fatal course due to septic shock in the CNI+ group. Conclusion Our retrospective analysis suggested that CNI could be an additional option for treating AOSD with acceptable safety. References [1] Efthimiou P, et al. Diagnosis and management of adult onset Still’s disease. Ann Rheum Dis. 2006. [2] Chen DY, et al. Predominance of Th1 cytokine in peripheral blood and pathological tissues of patients with active untreated adult onset Still’s disease Ann Rheum Dis. 2004. Disclosure of Interests Masato Tarumi: None declared, Hiroyuki Nakamura: None declared, Yuichiro Fujieda: None declared, Hirohiko Kitagawa: None declared, Ryo Hisada: None declared, Yuka Shimizu: None declared, Ikuma Nakagawa: None declared, Akito Tsutsumi: None declared, Takashi Kurita: None declared, Hiroshi Kataoka: None declared, Masaya Mukai: None declared, Hideki Kasahara: None declared, Atsushi Noguchi: None declared, Yoshiharu Amasaki: None declared, Tetsuya Horita: None declared, Tatsuya Atsumi Grant/research support from: Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co. Ltd., Otsuka Pharmaceutical Co., Ltd. and Pfizer Inc., Alexion Inc., Bayer Yakuhin, Ltd,Otsuka Pharmaceutical Co., Ltd. Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Eisai Co., Ltd., Bristol-Myers Squibb Co., Daiichi Sankyo Co. Ltd., Mitsubishi Tanabe Pharma Co., Asahi Kasei Pharma Co., Consultant for: ONO PHARMACEUTICAL CO., LTD Sanofi K.K. Daiichi Sankyo Co., Ltd. Pfizer Inc., Speakers bureau: Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd., Pfizer Inc.,Daiichi Sankyo Co. Ltd., Bristol-Myers Squibb Co., Eli Lilly Japan K.K.