All-Microwave Manipulation of Superconducting Qubits with a Fixed-Frequency Transmon Coupler.

All-microwave control of fixed-frequency superconducting quantum computing circuits is advantageous for minimizing the noise channels and wiring costs. Here we introduce a swap interaction between two data transmons assisted by the third-order nonlinearity of a coupler transmon under a microwave drive. We model the interaction analytically and numerically and use it to implement an all-microwave controlled-Z gate. The gate based on the coupler-assisted swap transition maintains high drive efficiency and small residual interaction over a wide range of detuning between the data transmons.

Clinical features of atlantoaxial involvement in patients with rheumatoid arthritis using 18F-fluorodeoxyglucose-positron emission tomography with computed tomography.

INTRODUCTION/OBJECTIVES: Cervical spine involvement is one of the most serious complications in rheumatoid arthritis (RA). The study aim was to assess the clinical significance of atlantoaxial (AA) joint involvement detected by 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) with computed tomography (CT) in patients with RA. METHOD: A prospective cross-sectional study was conducted to evaluate AA joint involvement detected by FDG-PET/CT in consecutive RA patients from December 2017 to February 2022. We investigated the relationship between AA joint involvement and clinical data, including disease activity and patients' cervical symptoms. RESULTS: Among 48 patients enrolled, abnormal FDG uptake at AA joint was detected in 13 (27%). Rheumatoid factor titre, initial disease activity score 28-erythrocyte sedimentation rate and total standardized uptake value were significantly higher in the 13 patients than in the others (P = 0.004, P < 0.001 and P = 0.001, respectively). All patients with abnormal FDG uptake at AA joint had some cervical symptoms regardless of cervical spine X-ray abnormalities. Neck pain on movement and at rest were more frequent in the 13 patients than in the others (P = 0.001 and P = 0.004, respectively). The most sensitive symptom associated with AA joint involvement was neck pain on movement (sensitivity, 69%), and the most specific symptom was neck pain at rest (specificity, 100%). CONCLUSIONS: AA joint involvement was commonly observed by FDG-PET/CT in patients with active RA, independent of radiographic findings. Specific cervical symptoms can be important surrogate markers for detection of potential AA synovitis associated with active RA. Key Points • AA joint involvement was frequently seen in RA with high disease activity independent of radiographic findings. • Neck pain was a hallmark of AA joint involvement reflecting disease activity, and resting pain was highly specific.

Potential Future Drug Development Lag in Japan Based on an Analysis of Multiregional Clinical Trials in the US, Europe, and East Asia.

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.

Prediction of the intolerance or non-responder to Janus kinase inhibitors in patients with rheumatoid arthritis: a preliminary retrospective study with integrative cluster analysis.

OBJECTIVES: To identify the subpopulation of rheumatoid arthritis (RA) non-responders to Janus kinase inhibitors (JAKis) using cluster analysis. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Superconducting acousto-optic phase modulator.

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 = 8 K), we observe the length-half-wave-voltage (length-Vπ) product of 1.78 V·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 Vπ = 0.27 V.

Functional expression of the reverse transcriptase αß heterodimer from avian myeloblastosis virus in Escherichia coli.

The α subunit of avian myeloblastosis virus reverse transcriptase (AMV-RT) is generated from the ß-subunit by proteolysis, and the αß heterodimer represents the active form. The codon-optimized gene was expressed in Escherichia coli, and an active αß heterodimer was generated. The RNA amplification activity of the purified recombinant AMV-RT αß heterodimer was similar to that of the native one.

THE CONCEPT OF X-RAY CT DOSE EVALUATION METHOD USING RADIOCHROMIC FILM AND FILM-FOLDING PHANTOM.

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.

Continuous warfarin administration versus heparin bridging therapy in post colorectal polypectomy haemorrhage: a study protocol for a multicentre randomised controlled trial (WHICH study).

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.

Single-photon quantum regime of artificial radiation pressure on a surface acoustic wave resonator.

Electromagnetic fields carry momentum, which upon reflection on matter gives rise to the radiation pressure of photons. The radiation pressure has recently been utilized in cavity optomechanics for controlling mechanical motions of macroscopic objects at the quantum limit. However, because of the weakness of the interaction, attempts so far had to use a strong coherent drive to reach the quantum limit. Therefore, the single-photon quantum regime, where even the presence of a totally off-resonant single photon alters the quantum state of the mechanical mode significantly, is one of the next milestones in cavity optomechanics. Here we demonstrate an artificial realization of the radiation pressure of microwave photons acting on phonons in a surface acoustic wave resonator. The order-of-magnitude enhancement of the interaction strength originates in the well-tailored, strong, second-order nonlinearity of a superconducting Josephson junction circuit. The synthetic radiation pressure interaction adds a key element to the quantum optomechanical toolbox and can be applied to quantum information interfaces between electromagnetic and mechanical degrees of freedom.

Calcineurin inhibitors for adult-onset Still's disease: a multicentre retrospective cohort study.

OBJECTIVES: To clarify the efficacy and safety of calcineurin inhibitors (CNI) for treating adult-onset Still's disease (AOSD). METHODS: 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. RESULTS: 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). CONCLUSIONS: Our retrospective analysis suggested that CNI could be an effective and safe option for treating AOSD.

Anti-cyclic citrullinated peptide antibody titers decrease in rheumatoid arthritis patients treated with tocilizumab: A pilot study.

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.

Refraction and pupil diameter in 3-year- and 1-month-old children as measured by Spot Vision Screener.

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.

Antifibrotic efficacy of nintedanib in a cellular model of systemic sclerosis-associated interstitial lung disease.

OBJECTIVES: Nintedanib is approved for the treatment of idiopathic pulmonary fibrosis (IPF) and was demonstrated to slow disease progression in patients with IPF by reducing decline in forced vital capacity by 50%. Recently, nintedanib has been reported to exert anti-fibrotic activity on systemic sclerosis (scleroderma, SSc) skin fibroblasts and to diminish skin and lung fibrosis in mouse models. The goal of the present study was to determine the effects of nintedanib on a cellular model of SSc-associated interstitial lung disease (ILD). METHODS: Study was performed using lung fibroblasts (LF) isolated from five patients with SSc-ILD and from three control subjects. RESULTS: Nintedanib inhibited LF proliferation and migration in a concentration- and time-dependent manner. The proliferation rate of LF stimulated with PDGF in the presence of nintedanib was reduced 1.9-fold within 24 h as compared to cells stimulated with PDGF alone. Migration of SSc-ILD LF incubated with 100 nM nintedanib was reduced from 62.8±12.5% to 39.1±9.0% in the presence of PDGF and from 38.2±7.9% to 26.6±7.2% in serum-free medium. Nintedanib attenuated PDGF-induced Ca2+ efflux, reduced α-SMA promoter activity and α-SMA protein expression. Furthermore, nintedanib blocked PDGF-induced differentiation of normal LF to myofibroblasts, reduced production of collagen and fibronectin, and decreased contractility of SSc-ILD LF in both floating and fixed collagen gels. CONCLUSIONS: Our data demonstrate significant antifibrotic efficacy of nintedanib in SSc-ILD LF suggesting that nintedanib has the potential not only to prevent but also to reverse the increased activity of LF consequently attenuating excessive lung fibrosis observed in SSc-ILD.

Effect of Posterior Corneal Vesicles on Corneal Endothelial Cell Density and Anisometropic Amblyopia.

PURPOSE: To evaluate the effect of corneal vesicles in patients with posterior corneal vesicles (PCV) on corneal endothelial cell (CEC) density and the acquisition of amblyopia. METHODS: In this retrospective study of patients with PCV (18 eyes of 14 patients), CEC density was examined by noncontact specular microscopy during each follow-up examination. Best-corrected visual acuity and the objective refractive error were also examined. RESULTS: Of the 14 total patients, 10 were diagnosed with PCV and 4 were diagnosed with bilateral suspected PCV or posterior polymorphous corneal dystrophy (PPCD), and in all patients, no ocular abnormality other than corneal vesicles was observed. In patients with PCV and patients with bilateral suspected PCV or PPCD, mean CEC density was 1131 ± 338 and 1095 ± 492 cells/mm, respectively. In both PCV group and the bilateral suspected PCV or PPCD-group patients who were followed for 164.2 ± 25.4 months (range: 123-186 months), CEC density tended not to decrease. In patients with PCV, the mean best-corrected visual acuity of the unaffected eyes was significantly higher than that of the affected eyes with corneal vesicles (-0.10 ± 0.06 and 0.05 ± 0.13, respectively, P = 0.012). Four of 9 affected eyes (1 eye was excluded because of retinal atrophy) exhibited amblyopia, and all 4 eyes had astigmatism higher than 2 diopters. CONCLUSIONS: Although CEC density of patients with PCV in this study was found to be stable over a long-term follow-up period, strict attention should be given to the possibility of amblyopia in eyes with PCV.

Quantification of hand synovitis in rheumatoid arthritis: Arterial mask subtraction reinforced with mutual information can improve accuracy of pixel-by-pixel time-intensity curve shape analysis in dynamic MRI.

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 < 0.01) with the results of manual assessment regarded as ground truth. Objective selection utilizing MI had substantial agreement (ICC = 0.734) with subjective selection. Correlation of synovial volumetry in combination with TIC shape analysis and AMSM with manual assessment was excellent (r = 0.922, P < 0.01). In addition, negative predictive ability in slices without synovitis pixels was significantly increased (P < 0.01). DATA CONCLUSIONS: The combination of TIC shape analysis and image subtraction reinforced with MI can accurately quantify synovitis of RA in the hand by eliminating arterial pixels. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.

Autologous haematopoietic stem cell transplantation for Japanese patients with systemic sclerosis: Long-term follow-up on a phase II trial and treatment-related fatal cardiomyopathy.

OBJECTIVES: The objective of this study is to elucidate the efficacy and safety of autologous haematopoietic stem cell transplantation (HSCT) for Japanese patients with systemic sclerosis (SSc). METHODS: A phase II clinical trial included SSc patients diagnosed within the last three years having at least one of the following clinical features: diffuse skin sclerosis with modified Rodman total thickness skin score (mRSS) ≥ 15, refractory digital ulcer or interstitial lung disease (ILD). HSCT were performed after conditioning using cyclophosphamide. RESULTS: Fourteen patients were enrolled and underwent HSCT. Median follow-up period was 137 months. Overall survival or event-free survival rate was 93% or 40% at 10 years, respectively. Eight patients (57%) achieved more than a 50% decrease in mRSS from baseline within six months after HSCT. Six patients (43%) required additional immunosuppressive treatments due to progression of diffuse skin sclerosis and/or ILD during follow-up period. Adverse events related to HSCT occurred in six patients (43%). Severe cardiomyopathy occurred in two patients, and one of them had a fatal course. CONCLUSION: HSCT is a feasible treatment bringing favourable results to more than half of our patients with SSc. Careful selection of the patients is essential for whom benefited from HSCT, considering the risk-benefit balance of the treatment.

Qubit-Assisted Transduction for a Detection of Surface Acoustic Waves near the Quantum Limit.

We demonstrate ultrasensitive measurement of fluctuations in a surface-acoustic-wave (SAW) resonator using a hybrid quantum system consisting of the SAW resonator, a microwave (MW) resonator, and a superconducting qubit. The nonlinearity of the driven qubit induces parametric coupling, which up-converts the excitation in the SAW resonator to that in the MW resonator. Thermal fluctuations of the SAW resonator near the quantum limit are observed in the noise spectroscopy in the MW domain.

Establishment of an indirect ELISA for detection of the novel antifibrotic peptide M10.

OBJECTIVE: M10 is a ten amino acid peptide generated from the intracellular cytoplasmic tail of the hepatocyte growth factor (HGF) receptor c-Met following cleavage by caspase-3. Recently we reported that M10 interacts with Smad2 and demonstrates antifibrotic properties in vitro and in vivo and can be advanced into a novel antifibrotic remedy. The current study was undertaken to develop an immunoassay to measure M10 concentration in biological specimens. EXPERIMENTAL DESIGN: An Indirect Enzyme-Linked Immunosorbent Assay (ELISA) for detection of M10 in biological fluids was developed using pharmaceutical grade synthetic M10 as a calibrator and commercially available anti-c-Met C12 antibody. RESULTS: M10 ELISA specifically detected in plasma M10, but not a scrambled peptide, following a single intraperitoneal administration of M10 (1mg/kg) to mice. The detection limit was 9.6 ng/ml, and the measuring limit was between 15 ng/ml and 200 ng/ml. The recovery limits of M10 were between 80% and 120%; intra-assay coefficient of variation was between 5.3% and 6.3%; inter-assay coefficient of variation was between 5.0% and 8.0% over the buffer concentration tested in the range from 15 ng /ml to 250 ng /ml. The peak of M10 concentration following a single intraperitoneal injection (1mg/kg) was achieved within 6 hours and declined to minimal levels by 48 hours. The experimentally obtained half-life for M10 was comparable to the theoretically predicted half-life for M10. CONCLUSIONS: We have established a highly sensitive ELISA to detect the antifibrotic peptide M10 in plasma samples, which should prove to be a novel tool to study the pharmacokinetics and efficacy of M10 in the treatment of fibroproliferative disorders.