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Objectives The aim of this AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial subgroup analysis was to examine rivaroxaban monotherapy benefits and their relation to the time between stenting and enrollment among patients after coronary stenting. Background Of 2,215 patients with atrial fibrillation and stable coronary artery disease in the AFIRE trial, rivaroxaban monotherapy was noninferior to rivaroxaban plus antiplatelet therapy (combination therapy) in terms of efficacy and superior for safety endpoints. However, thrombotic risk after antiplatelet therapy cessation remained a concern among 1,444 patients who had undergone coronary stenting >1 year before enrollment. Methods The benefits of rivaroxaban monotherapy in coronary stenting subgroups were assessed for efficacy (a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death of any cause), safety (major bleeding defined according to International Society on Thrombosis and Haemostasis criteria), ischemic endpoints, net adverse clinical event, and time between stenting and enrollment. Results Efficacy and safety endpoints for monotherapy were superior to combination therapy, with HRs of 0.70 for efficacy (95% CI: 0.50-0.98; P = 0.036) and 0.55 for safety (95% CI: 0.33-0.92; P = 0.019). For ischemic endpoints, the HR was 0.82 (95% CI: 0.58-1.15; P = 0.240). The HR became smaller with longer time between stenting and enrollment (efficacy, P for interaction = 0.158; safety, P = 0.097). Conclusions In patients with atrial fibrillation after coronary stenting, the benefits of rivaroxaban monotherapy for efficacy and safety endpoints were consistent with those in the whole AFIRE trial population. The benefits became apparent with longer time between stenting and enrollment. (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease Study [AFIRE]; UMIN000016612 , NCT02642419 )

Nakajo‐Nishimura syndrome (NNS) is an autoinflammatory disorder caused by a homozygous mutations in the PSMB8 gene. The administration of systemic corticosteroids is partially effective, but continuous treatment causes severe side effects. We previously established a pluripotent stem cell (PSC)‐derived NNS disease model that reproduces several inflammatory phenotypes, including the overproduction of monocyte chemoattractant protein‐1 (MCP‐1) and interferon gamma‐induced protein‐10 (IP‐10). Here we performed high‐throughput compound screening (HTS) using this PSC‐derived NNS model to find potential therapeutic candidates and identified CUDC‐907 as an effective inhibitor of the release of MCP‐1 and IP‐10. Short‐term treatment of CUDC‐907 did not induce cell death within therapeutic concentrations and was also effective on primary patient cells. Further analysis indicated that the inhibitory effect was post‐transcriptional. These findings suggest that HTS with PSC‐derived disease models is useful for finding drug candidates for autoinflammatory diseases., High‐throughput screening using pluripotent stem cell‐derived monocytic cell lines was performed to identify potential therapeutic candidates of Nakajo‐Nishimura syndrome. The hit compound, CUDC‐907 effectively inhibits the overproduction of inflammatory chemokines, monocyte chemoattractant protein‐1, and interferon gamma‐induced protein‐10.

ObjectivesTo collect clinical information and NOD2 mutation data on patients with Blau syndrome and to evaluate their prognosis.MethodsFifty patients with NOD2 mutations were analysed. The activity of each NOD2 mutant was evaluated in HEK293 cells by reporter assay. Clinical information was collected from medical records through the attending physicians.ResultsThe study population comprised 26 males and 24 females aged 0–61 years. Thirty-two cases were sporadic, and 18 were familial from 9 unrelated families. Fifteen different mutations in NOD2 were identified, including 2 novel mutations (p.W490S and D512V); all showed spontaneous nuclear factor kappa B activation, and the most common mutation was p.R334W. Twenty-six patients had fever at relatively early timepoints in the disease course. Forty-three of 47 patients had a skin rash. The onset of disease in 9 patients was recognised after BCG vaccination. Forty-five of 49 patients had joint lesions. Thirty-eight of 50 patients had ocular symptoms, 7 of which resulted in blindness. After the diagnosis of Blau syndrome, 26 patients were treated with biologics; all were antitumour necrosis factor agents. Only 3 patients were treated with biologics alone; the others received a biologic in combination with methotrexate and/or prednisolone. None of the patients who became blind received biologic treatment.ConclusionsIn patients with Blau syndrome, severe joint contractures and blindness may occur if diagnosis and appropriate treatment are delayed. Early treatment with a biologic agent may improve the prognosis.

Importance: Sodium glucose cotransporter 2 inhibitors reduce morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Clinicians may find estimates of the projected long-term benefits of sodium glucose cotransporter 2 inhibitors a helpful addition to clinical trial results when communicating the benefits of this class of drug to patients. Objective: To estimate the projected long-term treatment effects of dapagliflozin in patients with HFrEF over the duration of a patient’s lifetime. Design, Setting, and Participants: Exploratory analysis was performed of Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF), a phase 3 randomized, placebo-controlled clinical trial conducted at 410 sites in 20 countries. Patients with an ejection fraction less than or equal to 40% in New York Heart Association functional classification II to IV and elevated plasma levels of N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Mean (SD) duration of follow-up was 17.6 (5.2) months. Interventions: Dapagliflozin, 10 mg, once daily vs placebo in addition to standard therapy. Main Outcomes and Measures: The primary composite outcome was time to first hospitalization for heart failure, urgent heart failure visit requiring intravenous therapy, or cardiovascular death. The trial results were extrapolated to estimate the projected long-term treatment effects of dapagliflozin over the duration of a patient’s lifetime for the primary outcome and the secondary outcome of death from any cause. Results: A total of 4744 patients (1109 women [23.4%]; 3635 men [76.6%]) were randomized in DAPA-HF, with a mean (SD) age of 66.3 (10.9) years. The extrapolated mean event-free survival for an individual aged 65 years from a primary composite end point event was 6.2 years for placebo and 8.3 years for dapagliflozin, representing an event-free survival time gain of 2.1 years (95% CI, 0.8-3.3 years; P = .002). When considering death from any cause, mean extrapolated life expectancy for an individual aged 65 years was 9.1 years for placebo and 10.8 years for dapagliflozin, with a gain in survival of 1.7 years (95% CI, 0.1-3.3; P = .03) with dapagliflozin. Similar results were seen when extrapolated across the age range studied. In analyses of subgroups of patients in DAPA-HF, consistent benefits were seen with dapagliflozin on both event-free and overall survival. Conclusions and Relevance: These findings indicate that dapagliflozin provides clinically meaningful gains in extrapolated event-free and overall survival. These findings may be helpful in communicating the benefits of this treatment to patients with HFrEF. Trial registration: ClinicalTrials.gov Identifier: NCT03036124.

An investigation of the utilization of water quality monitors at water purification plants throughout Japan was conducted via questionnaire from August to October 2015. The number of types of monitors installed at more than one water purification plant was 34. Chlorine, high sensitivity turbidity, pH, and turbidity monitors were (highly) recommended for installation in four water purification processes (rapid sand filtration, chlorination only, slow sand filtration and membrane treatment), except for high sensitivity turbidity of chlorination only. The number of installations of the monitors recommended and their installation points were dependent upon the processes. Highly recommended points of turbidity were raw water and sedimentation points, which were set for (critical) control points in water safety plans. That of high sensitivity turbidity was the rapid sand filtration point for confirmation of Cryptosporidium control. Chlorine monitors were applied for automatic control, regardless of the water purification processes. Some interesting monitors, such as those for musty odor compounds and trihalomethane, were newly developed and utilized. The results of this study showed that water quality monitors were important for water quality management systems based on water safety plans in Japan.

Autoinflammatory diseases are a disease entity caused by the dysregulation of innate immune cells. Typical autoinflammatory diseases are monogenic disorders and often very rare. As a result, there is a relative lack of understanding of the pathogenesis, poor diagnosis and little available treatment. Induced pluripotent stem (iPS) cells are a new technology being applied to in vitro disease modeling. These models are especially useful for the analysis of rare and intractable diseases including autoinflammatory diseases. In this review, I will provide a general overview of iPS cell models for autoinflammatory diseases and a brief description of the results obtained from individual reports.

Blau Syndrome, or early-onset sarcoidosis, is hereditary juvenile-onset systemic granulomatosis. Clinical symptoms appear before the age of four years and mainly affect the skin, joints, and eyes. The symptoms are progressive and cause severe complications, such as joint destruction and blindness. Although tumor necrosis factor alpha (TNFα) antagonists are effective for controlling some of the symptoms of Blau Syndrome, there is no specific curative treatment. Heterozygous mutations in nucleotide-binding oligomerization domain 2 (NOD2) were identified as the cause of Blau Syndrome onset. NOD2 is an intracellular pathogen recognition receptor, the ligand of which is muramyl dipeptide (MDP) found in bacterial cell walls. Upon binding to MDP, NOD2 activates the NF-κB pathway, which leads to upregulation of proinflammatory cytokines. However, the detailed molecular mechanisms by which disease associated NOD2 mutations lead to autoinflammation and granuloma formation are still unclear. To clarify the relationship between disease associated NOD2 mutations and the inflammatory response, we established induced pluripotent stem (iPS) cells from Blau Syndrome patients. Functional analyses using these iPS cells suggested that IFNγ is a critical mediator of the inflammatory manifestations in this disease. This experimental finding is supported by the clinical observation that bacillus Calmette-Guesrin (BCG) vaccination is sometimes associated with disease onset, since IFNγ is a major cytokine associated with BCG-mediated immune responses. Further investigation of NOD2 signaling and accumulation of clinical cases are essential to elucidate the mechanisms of Blau Syndrome and develop an effective treatment for patients.

Background Blau syndrome (BS) is an autoinflammatory disease associated with mutations in nucleotide-binding oligomerization domain 2. Although treatments with anti-TNF agents have been reported to be effective, the underlying molecular mechanisms remain unclear. Objective We aimed to elucidate the mechanisms of autoinflammation in patients with BS and to clarify how anti-TNF treatment controls the disease phenotype at the cellular level in clinical samples. Methods Macrophages were differentiated from monocytes of 7 BS patients, and global transcriptional profiles of 5 patients were analyzed with or without IFN-γ stimulation. Macrophages were also generated from BS-specific induced pluripotent stem cells (iPSCs), and their transcriptome was examined for comparison. Results Aberrant inflammatory responses were observed upon IFN-γ stimulation in macrophages from untreated BS patients, but not in those from patients treated with anti-TNF. iPSC-derived macrophages carrying a disease-associated mutation also showed IFN-γ–dependent accelerated inflammatory responses. Comparisons of peripheral blood– and iPSC-derived macrophages revealed the upregulation of nuclear factor kappa–light-chain enhancer of activated B cells (NF-κB) targets in unstimulated macrophages as a common feature. Conclusions IFN-γ stimulation is one of the key signals driving aberrant inflammatory responses in BS-associated macrophages. However, long-term treatment with anti-TNF agents ameliorates such abnormalities even in the presence of IFN-γ stimulation. Our data thus suggest that preexposure to TNF or functionally similar cytokines inducing NF-κB–driven proinflammatory signaling during macrophage development is a prerequisite for accelerated inflammatory responses upon IFN-γ stimulation in BS.

Nakajo-Nishimura syndrome (NNS) is an autoinflammatory disorder caused by a homozygous mutations in PSMB8 gene. The administration of systemic corticosteroids is partially effective, but continuous treatment causes severe side effects. We previously established a pluripotent stem cell (PSC)-derived NNS disease model that reproduces several inflammatory phenotypes including the overproduction of monocyte chemoattractant protein-1 (MCP-1) and interferon gamma-induced protein-10 (IP-10). Here we performed high-throughput compound screening (HTS) using this PSC-derived NNS model to find potential therapeutic candidates and identified CUDC-907 as an effective inhibitor of the release of MCP-1 and IP-10. CUDC-907 did not induce cell death within therapeutic concentrations and was also effective on primary patient cells. Further analysis indicated that the inhibitory effect was post-transcriptional. These findings suggest that HTS with PSC-derived disease models is useful for finding drug candidates for autoinflammatory diseases.Significance statementIn this study, we identified a histone deacetylase inhibitor CUDC-907 as a potential effective compound for ameliorating overproduction of inflammatory chemokines in an autoinflammatory disease named Nakajo-Nishimura syndrome. We performed high-throughput screening using pluripotent stem cell-derived monocytic cell lines. Our data prove the validity of screening system as a versatile platform for seeking candidate compounds for the treatment of congenital immunological disorders associated with monocytic lineage cells.

Purpose/Objective(s) Radiotherapy (RT) is performed not only to reduce pain but also to prevent pathological fractures due to bone metastases of the spine. However, it is unclear to what extent radiotherapy increases bone strength. Bone density is sometimes used as a marker for assessment of local response to RT in spinal bone metastases. The purpose of this study was to evaluate the changes of bone strength using CT-based finite element (FE) methods in radiotherapy for metastases at the lumber vertebra in comparison with bone density. Materials/Methods Five patients with metastases to the lumber vertebra who could be followed for more than 6 months were included. Primary lesions were lung cancer in all patients. All patients had osteolytic changes of the bone cortex in the vertebral body. Median radiation dose was 37.8 Gy in 14 fractions. CT images were taken before and at 1, 3, 6, 9 and 12 months after irradiation. Bone density was measured in Hounsfield units (HU) in each CT scan. The regions of interest were set to include the whole vertebral body of the metastatic spine and that of a non-irradiated unaffected neighboring spine used for reference. The 3-dimensional FE models of the same vertebrae were constructed from each CT image. The models consisted of 1- or 2-mm linear tetrahedral elements and the cortical shell with a thickness of 0.1 mm. A uniaxial compressive load with uniform distribution was applied on the upper surface of the vertebral body with the lower surface completely restrained. The predicted fracture load was defined to be present when at least one element or cortical shell failed. The ratios of the values on the follow-up CT to the values on the pre-irradiation CT were calculated, and single regression equations were determined for these ratios. Results At one month after irradiation, the bone density decreased in all except one case of the affected vertebral bodies, and the predicted fracture load decreased in all except one case of the unaffected vertebral bodies. In the affected vertebral bodies, the slopes of the single regression equations of bone density were positive in 4 out of 5 cases. The slopes of those of predicted fracture loads were negative in 3 out of that 4 cases. In the unaffected vertebral bodies, the slopes of the single regression equations of bone density were positive in 3 out of 5 cases. The slopes of predicted fracture loads were positive in those 3 cases. Conclusion The bone strength might not improve in one month after irradiation. The predicted fracture load did not necessarily increase even if the bone density increased in the irradiated affected vertebral bodies. Bone density alone might not be sufficient as an indicator of bone strength. The FE method could evaluate the changes in bone strength in radiotherapy for bone metastases based on predicted fracture loads.

Nanothick TiO2 channel-thin film transistors (TFTs) are examined as UV and gas sensors. The TiO2 thin films were deposited by atomic layer deposition on thermally oxidized n+ Si substrates with deposition thicknesses from 17 to 42 nm, where the channel length and width were fixed at 60 μm and 1 mm, respectively. The titanium drain and source electrodes were fabricated on the TiO2 channel and the n+ Si substrate was used as the gate electrode. The nanothick TiO2-channel TFT exhibits an extremely high drain current modulation of ∼20 μA in the atmosphere with a UV exposure of 1.6 × 10−5 W cm−2 and a wavelength of 278 nm. This corresponds to a UV sensitivity of 2 × 103 A W−1. The strong drain current modulation by the UV light is explained not only with the direct absorption of the UV photons in the channel but also with the surface interactions with gas molecules in the atmosphere. In the course of the mechanism study about the UV sensing, we confirm the strong modulation of the drain current with various ambience of air, dry air, N2, and vacuum, suggesting a possibility as the gas sensor in the dark. The operation mechanism of the nanothick TiO2 TFT is discussed in this paper.

Objective Organosiloxanes are prevalent in personal care products (PCPs) due to the desired properties they impart in the usage and application of such products. However, the European Chemical Agency (ECHA) has recently published restriction proposals on the amount of two cyclic siloxanes, octamethylcyclotetrasiloxane (D4) and decamethylcyclotetrasiloxane (D5) allowed in wash off products such as shampoos and conditioners which are discharged down the drain during consumer use. This legislation will require that reliable analytical methods are available for manufacturers and government agencies to use in documenting compliance with the restrictions. This paper proposes a simple analytical method to enable accurate measurement of these compounds down to the circa 0.1 weight percent level in PCPs. Methods While gas chromatography methods are reported in the literature for quantitation of D4 and D5 in several matrices including PCPs, the potential for generation of false positives due to contamination, co-elution, and in-situ generation of cyclic volatile methylsiloxanes (cVMS) is always present and needs to be controlled. This report demonstrates the applicability of using a combination of emulsion break, liquid-liquid extraction and silylation sample preparation followed by GC-FID analysis as a suitable means of analyzing PCPs for specific cVMS. Results The reliability and limitations of such methodology was demonstrated through several round robin studies conducted in the laboratories of a consortium of silicone manufacturers. In addition, this report presents examples of false positives encountered during development of the method and presents a comparative analysis between this method and a published QuEChERS sample preparation procedure to illustrate the potential for generation of false positives when an inappropriate approach is applied to determination of cVMS in personal care products. Conclusion This report demonstrates that an approach to determine cVMS levels in personal care products is to perform an emulsion break on the sample, isolate the nonpolar phase from the emulsion break and treat with a silylation reagent to abate potential in situ formation of cyclics during the course of GC-FID analysis. Round robin studies conducted in laboratories representing multiple siloxane manufacturers demonstrated the reliability of the GC-FID method when measuring cVMS in PCPs down to circa 0.1%. This article is protected by copyright. All rights reserved.

To the editor: The central nervous system (CNS) is a key site of extramedullary disease in pediatric acute lymphoblastic leukemia (ALL),[1][1] and prior to the development of contemporary risk-adapted treatment strategies, CNS involvement was inevitable in most cases.[1][1] However, the biology of

Objective To elucidate the genetic background of a patient with neonatal-onset multisystem inflammatory disease (NOMID) who does not carry any NLRP3 mutation. Methods A Japanese male diagnosed as NOMID was recruited. The patient had no NLRP3 mutation even as low frequency mosaicism. We performed whole exome sequencing (WES) of the patient and his parents. Induced pluripotent stem cells (iPSCs) were established from the fibroblasts of the patient. iPSCs were then differentiated into monocytic lineage to evaluate the cytokine profile. Results We established multiple iPSC clones from an NOMID patient and incidentally found that the phenotype of monocytes from iPSC clones were heterogeneous, and could be grouped into “diseased” and “normal” phenotype. Because each iPSC clone was derived from a single somatic cell, we hypothesized the patient had somatic mosaicism of an IL-1β-related gene. WES of both representative iPSC clones and patient's blood identified a novel heterozygous NLRC4 mutation, p.T177A (c.529A>G), as a specific mutation in “diseased” iPSC clones. Knockout of the NLRC4 gene using CRISPR/Cas9 system in a mutant iPSC clone abrogated the pathogenic phenotype. Conclusion We concluded the patient as having somatic mosaicism of a novel NLRC4 mutation. To our knowledge, this is the first case showing somatic NLRC4 mutation causes autoinflammatory symptoms compatible to NOMID. The present study demonstrates the significance of prospective genetic screening combined with iPSC-based phenotypic dissection for individualized diagnoses. This article is protected by copyright. All rights reserved.

Background. Acute Atrial Fibrillation (AF) is common in critically ill patients, with significant morbidity and mortality; however, its incidence and severity in Intensive Care Units (ICUs) from low-income countries are poorly studied. Additionally, impact of vasoactive drugs on its incidence and severity is still not understood. This study aimed to assess epidemiology and risk factors for acute new-onset AF in critically ill adult patients and the role of vasoactive drugs. Method. Cohort performed in seven general ICUs (including cardiac surgery) in three cities in Paraná State (southern Brazil) for 45 days. Patients were followed until hospital discharge. Results. Among 430 patients evaluated, the incidence of acute new-onset AF was 11.2%. Patients with AF had higher ICU and hospital mortality. Vasoactive drugs use (norepinephrine and dobutamine) was correlated with higher incidence of AF and higher mortality in patients with AF; vasopressin (though used in few patients) had no effect on development of AF. Conclusions. In general ICU patients, incidence of new-onset AF was 11.2% with a high impact on morbidity and mortality, particularly associated with the presence of Acute Renal Failure. The use of vasoactive drugs (norepinephrine and dobutamine) could lead to a higher incidence of new-onset AF-associated morbidity and mortality.

Background Leukotriene receptor antagonists have been used to prevent virus-induced asthma exacerbations in autumn. Its efficacy, however, might differ with age and sex. Objective This study aimed to investigate whether pranlukast added to usual asthma therapy in Japanese children during autumn, season associated with the peak of asthma, reduces asthma exacerbations. It was also evaluated the effect of age and sex on pranlukast's efficacy. Methods A total of 121 asthmatic children aged 1 to 14 years were randomly assigned to receive regular pranlukast or not according to sex, and were divided in 2 age groups, 1-5 years and 6-14 years. The primary outcome was total asthma score calculated during 8 weeks by using a sticker calendar related to the days in which a child experienced a worsening of asthma symptoms. This open study lasted 60 days from September 15 to November 14, 2007. Results Significant differences in pranlukast efficacy were observed between sex and age groups. Boys aged 1 to 5 years had the lower total asthma score at 8 weeks (p = 0.002), and experienced fewer cold episodes (p = 0.007). There were no significant differences between pranlukast and control group in total asthma score at 8 weeks (p = 0.35), and in the days in which a child experienced a worsening of asthma symptoms (p = 0.67). Conclusion There was a substantial benefit of adding pranlukast to usual therapy in asthmatic children, especially in boys aged 1 to 5 years, during autumn season.

Background Sustained ventricular arrhythmias (VAs) and death are feared events post myocardial infarction (post-MI). Patients with heart failure post-MI have higher risk of VAs, compared to those without heart failure. Although the risk of sudden cardiac arrest and death post-MI isn't small, previous clinical trials have failed to demonstrate the benefit of early use of implantable cardioverter defibrillators. Moreover, little is known about the relationship between the acute phase and the late phase VAs in patients with heart failure post-MI. Purpose The aim of this study was to determine the predictors of the late phase VAs in patients with heart failure post MI. Methods We retrospectively analyzed our database of MI patients from January 2012 to September 2016. Results A total of consecutive 460 post-MI patients were included in this study (age, 67±12 year-old; male, 336 (73%); STEMI, 281 (61%)). All the patients underwent primary percutaneous coronary intervention. Of those, 90 patients (20%) had depressed left ventricular ejection fraction (LVEF) ≤35%. After a mean follow up period of 30±16 months, 45 patients (50%) had VAs after MI. Among them, 35 patients (78%) had VAs within 48 hours after MI onset, 8 patients (18%) within 7 days 48 hours later, and 21 patients (47%) more than 7 days. Cox-regression analysis showed that VAs within 7 days 48 hours later after MI onset was significantly related to sustained VAs more than 7 days after MI onset (Hazard Ratio, 4.97; 95% Confidence Interval, 1.31–18.9; p=0.019). Conclusions VAs in the sub-acute phase after MI predicted sustained VAs in the late phase in this population. Prompt initiation of aggressive antiarrhythmic therapies, including catheter ablation, after MI should be considered to reduce the mortality.

Objectives We show that deep learning can be used to create high accuracy cells classifiers that can support cytologists in their work. Two deep learning models are presented. The first model is used for cervical cancer cytology negative/positive prescreening and we show its high specificity at 100% Negative Predict Value (NPV). The second model is used to predict among 15 categories common to cervical analysis, as listed in figure 1(b). Our classifiers include Grad-Cam visualizations that show both models concentrate on relevant areas of images. Methods Classifiers are based on deep convolutional networks. The crucial aspects in achieving high accuracy are data augmentation and focal loss. Grad-Cam visualizations are used to explain models’ reasoning. Results Prescreening model, based on 2700 samples, achieves 95.89% overall accuracy and 91.62% specificity at 100% NPV (figure 1(a)) ; second stage screening model, based on approximately 9500 samples, achieves 92.03% overall accuracy (figure 1(b)). Grad-Cam visualizations show that both models concentrate on relevant areas of the image when making predictions (figure 1(c)). Conclusions We show that deep learning based classifiers can be useful in supporting cytologist in their work. Approximately 92% of samples that cytologist screen for cervical cancer are negative. With our model cytologists can concentrate their efforts on only positive samples and a small number of false positives predictions.

Acute Atrial Fibrillation (AF) is common in critically ill patients, with significant morbidity and mortality; however, its incidence and severity in Intensive Care Units (ICUs) from low-income countries are poorly studied. Additionally, impact of vasoactive drugs on its incidence and severity is still not understood. This study aimed to assess epidemiology and risk factors for acute new-onset AF in critically ill adult patients and the role of vasoactive drugs.Cohort performed in seven general ICUs (including cardiac surgery) in three cities in Paraná State (southern Brazil) for 45 days. Patients were followed until hospital discharge.Among 430 patients evaluated, the incidence of acute new-onset AF was 11.2%. Patients with AF had higher ICU and hospital mortality. Vasoactive drugs use (norepinephrine and dobutamine) was correlated with higher incidence of AF and higher mortality in patients with AF; vasopressin (though used in few patients) had no effect on development of AF.In general ICU patients, incidence of new-onset AF was 11.2% with a high impact on morbidity and mortality, particularly associated with the presence of Acute Renal Failure. The use of vasoactive drugs (norepinephrine and dobutamine) could lead to a higher incidence of new-onset AF-associated morbidity and mortality.

AIM To evaluate the clinicopathological and computed tomography (CT) and magnetic resonance imaging (MRI) findings of steatohepatitic hepatocellular carcinoma (SH-HCC). MATERIALS AND METHODS Clinicopathological and radiological features were evaluated in 20 patients with SH-HCC. The diagnosis of SH-HCC was made histologically if the tumour had four of the following five characteristics: steatosis (>5% tumour cells), ballooning, Mallory–Denk bodies, interstitial fibrosis, and inflammation. All patients underwent dynamic CT and MRI. CT and MRI images were reviewed for morphological features including tumour size, presence, and distribution of fat, and patterns and degree of contrast enhancement. RESULTS Obesity, hypertension, and history of heavy alcohol intake were common clinical findings observed in 10 (50%), 13 (65%), and 11 (55%) of the 20 patients, respectively. Steatosis and steatohepatitis were pronounced in the background liver in 12 (60%) and 10 (50%) patients, respectively. SH-HCC was moderately differentiated in 18 patients (90%) and well differentiated in two (10%). Pathologically, steatohepatitic features were diffuse in 12 (60%) of the 20 tumours and focal in eight (40%). Tumour size and the percentage of intratumoural steatosis were not correlated (r=0.17, p=0.47). On CT, 16 (80%) patients showed arterial phase enhancement and delayed washout. On MRI, 16 (80%) of 20 tumours showed prominent fatty deposition (10 diffusely, six focally) with arterial phase enhancement. CONCLUSIONS SH-HCC is likely to show prominent fatty deposits with arterial phase enhancement on CT and MRI. A hypervascular lesion with prominent fatty change should raise the diagnostic suspicion of SH-HCC.

A helicon wave was tested for coupling at low power in the KSTAR, and high-power coupling has also been tried. When RF is applied to the antenna system, the reflected power gradually increases on a sub-millisecond timescale. A slower process than usual arcing suggests that a multipactor discharge causes the reflection. It is essential to mitigate or eliminate the multipactor discharge to apply a high-power helicon wave to the tokamak plasmas. A new VFT is fabricated following a design that focuses on the reduced total RF electric field and zero axial electric field on TiN-coated alumina and conductor surfaces. The unmatched impedance caused by the 1-cm-thick alumina is compensated by the series matching element positioned in the pressurized section. Particle in cell codes are used to predict the effects of secondary electrons caused by electrons emitted in the high-power RF transmissions. Different coating conditions are compared, and it is calculated that the designed VFT is free from multipacting. Thermomechanical stress and deformation due to the RF loss is also analyzed. The RF characteristics of the fabricated VFT agrees well with the design. Currently, a megawatt-level high-power test with the KSTAR helicon antenna in a vacuum is being prepared.

The inner tracker of the ATLAS detector is scheduled to be replaced by a completely new silicon-based inner tracker (ITk) for the Phase-II of the CERN LHC (HL-LHC). The silicon strip detector covers the volume 40 R 100 cm in the radial and | z | 300 cm in the longitudinal directions. The silicon sensors for the detector will be fabricated using the n + -on-p 6-inch wafer technology, for a total of 22,000 wafers. Intensive studies were carried out on the final prototype sensors ATLAS17LS fabricated by Hamamatsu Photonics (HPK). The charge collection properties were examined using penetrating 90Sr β -rays and the ALIBAVA fast readout system for the miniature sensors of 1 cm × 1 cm in area. The samples were irradiated by protons in the 27 MeV Birmingham Cyclotron, the 70 MeV CYRIC at Tohoku University, and the 24 GeV CERN-PS, and by neutrons at Ljubljana TRIGA reactor for fluence values up to 2 × 1015 n eq /cm 2 . The change in the charge collection with fluence was found to be similar to the previous prototype ATLAS12, and acceptable for the ITk. Sensors with two active thicknesses, 300 μ m (standard) and 240 μ m (thin), were compared and the difference in the charge collection was observed to be small for bias voltages up to 500 V. Some samples were also irradiated with gamma radiation up to 2 MGy, and the full depletion voltage was found to decrease with the dose. This was caused by the Compton electrons due to the 60Co gamma radiation. To summarize, the design of the ATLAS17LS and technology for its fabrication have been verified for implementation in the ITk. We are in the stage of sensor pre-production with the first sensors already delivered in January of 2020.

Parkinson's disease is associated with progressive degeneration of mesolimbic dopaminergic neurons that are involved in reward-based behavior learning, including rewarding effects of food consumption and drugs of abuse. The importance of this pathway in development of addictive behaviors led us to hypothesize that medical disorders related to poor impulse control may occur less frequently among patients with Parkinson's disease than those with other progressive neurodegenerative disorders such as Alzheimer's disease. Retrospective cross-sectional study of all patients treated for Parkinson's disease and Alzheimer's disease in a community based clinic during a two-year period. Associations were summarized using odds ratios (OR) and 95% confidence intervals (95% CI) estimated from logistic regression models, adjusted for differences in gender distribution between the groups. A total of 106 patients with Parkinson's disease and 72 patients with Alzheimer's disease were included. Patients with Parkinson's disease were less likely to have either past substance use (adjusted OR = 0.035, 95% CI = 0.009 - 0.130) or presence of co-morbid medical conditions related to poor dietary choices (adjusted OR = 0.157, 95% CI = 0.062 - 0.397). Co-morbid medical conditions related to poor impulse control occur less frequently among those with Parkinson's disease than those with Alzheimer's disease. These findings are consistent with dysfunction of dopamine dependent pathways involved in addiction during the presymptomatic phase of Parkinson's disease and support a biological basis for addiction.

Micro pixel chambers (μ-PICs), which are a type of the micro-pattern gas chambers, are usually manufactured using the printed-circuit-board (PCB) technology. However, recent application projects have begun to require higher gas gains and finer position resolution than those obtainable with current μ-PICs. It is difficult to improve the electrode structure to achieve these improvements because PCB technology limits the precision of electrode fabrication and the thickness of the substrate. We have therefore adopted micro-electro-mechanical-systems (MEMS) technology and developed the first prototype of a through-glass-via (TGV) μ-PIC. This prototype TGV μ-PIC worked well, achieving a maximum gain of approximately 20,000 and an energy resolution of 20.6% (FWHM) at 5.9 keV over the whole 5 × 5 cm2 detection area.

The purpose of this 4-year longitudinal study was to identify the effects of consumption of various food groups on incidence of decline of activities of daily living (ADL) in community-dwelling older women in Japan. The study included 1,111 women aged 75–85 years without ADL disability at the baseline examination, who were available for follow-up 4 years later. The association between the self-reported frequency of consumption of food groups (seafood, meat, egg, milk, soy products, colored vegetables, seaweeds, potatoes, fruits, fats and oils) at baseline and the incidence rate of ADL decline during the follow-up period was examined using logistic regression analyses, incorporating baseline age, body weight, and years of education as covariates. The incidence rate of ADL decline was 7.6%. The odds ratio (OR) of the incidence of ADL decline for those who consumed soy products twice per week or less relative to those who consumed them almost every day was 2.4 (95% CI = 1.4–4.1). The OR for those who consumed colored vegetables twice per week or less relative to those who consumed them almost every day was 2.7 (95% CI = 1.3–5.6). The OR for those who consumed fats and oils twice per week or less relative to those who consumed them almost every day was 2.1 (95% CI = 1.2–3.4). These results suggest that daily consumption of soy products, colored vegetables, and fats and oils may help prevent ADL decline in community-dwelling older women in Japan.

To establish imaging spectroscopy of cosmic gamma-rays from a few hundreds of keV to a few tens MeV, we developed an electron-tracking Compton camera (ETCC). The ETCC consists of a time projection chamber (TPC) and pixelated scintillator arrays (PSAs). The ETCC is superior to conventional gamma-ray imaging detectors of this energy band in that the arrival direction of an incident gamma-ray is firmly determined at one point and realizes high noise rejection efficiency. We performed a campaign to demonstrate the gamma-ray imaging performance of the ETCC at balloon altitude via the sub-MeV gamma-ray imaging loaded-on-balloon experiment 2+ (SMILE-2+). The balloon was launched on April 7, 2018, at 6:26 ACST (UTC +9:30) from Alice Springs, Australia. We performed a level flight for 26 hours at an altitude of 39.6 km. The main observation targets were the Galactic Center region and the Crab Nebula and we succeeded in observing them without any critical problems. The configuration of the flight model ETCC and the housekeeping data are described in detail.

Background Nakajo-Nishimura syndrome (NNS) is an immunoproteasome-associated autoinflammatory disorder caused by a mutation of PSMB8 gene.1 Although dysfunction of immunoproteasome causes various cellular stresses attributed to the overproduction of inflammatory cytokines and chemokine in NNS, precise underlying mechanisms of autoinflammation are still largely unknown. Objectives We aim to investigate and understand the detailed mechanisms and signal pathways in NNS and to seek potential therapeutic candidates. Methods We established a panel of isogenic pluripotent stem cell (PSC) lines with the homozygous G201V mutation in PSMB8 gene using CRISPR/Cas9- mediated genome editing system. Myeloid cell lines (MLs) were established from each clone and used for functional analysis.2 3 Results Immunoproteasome activity of PSMB8-mutant PSC-derived MLs (MTMLs) reduced even without stimulation, compared to that of the isogenic wild-type counterparts. When stimulated, MT-MLs showed overproduction of inflammatory cytokines and chemokines, with elevated reactive oxygen species (ROS). The levels of phosphorylated p38 MAPK and STAT1 also increased. Treatment with a p38 MAPK inhibitor, a JAK inhibitor and anti-oxidants dose-dependently decreased the abnormal production of cytokines and chemokines in MT-MLs. Both unstimulated and stimulated MT-MLs showed distinct transcriptional profiles, indicating the ML-MLs were already in a ‘primed’ state before stimulation. Conclusions The current PSC models revealed a specific ROS-mediated inflammatory pathway and provide a platform for studying the pathophysiology of NNS and searching for the alternative therapeutic options for NNS and related immunoproteasome disorders. References [1] Arima K, et al. PNAS2011;108(36):14914–9. [2] Kawasaki Y, et al. Arthritis Rheum2017;69(2):447–459. [3] Takada S, et al. J Allergy Clin Immunol2018;141(1):339–349. Acknowledgements We thank Dr. Fumiko Honda-Ozaki and Ms Madoka Terashima for conducting researdch. We also thank Drs. Nobuo Kanazawa, Akira Niwa, Masakatsu Yanagimachi, Akitsu Hotta and Tatsutoshi Nakahata, and Ms. Haruna Ito for percitipating. Funding was provided by Japan Agency for Medical Research and Development, Tokyo, Japan. Disclosure of Interest None declared

Newly developed ion cyclotron range of frequencies (ICRF) antennas were fabricated and installed in the Large Helical Device (LHD). The antennas, called field-aligned-impedance-transforming (FAIT) antennas, were designed based on former handshake form (HAS) antennas for high power and steady-state operation. The FAIT antennas demonstrated higher loading resistance and lower temperature on ceramic feed-through than HAS antennas. Antenna impedance and injected power were measured precisely using a directional coupler installed between the impedance matching device and antenna. It was shown that an injection power of 1.8 MW or a power density of 15 MW/m2 would be possible for short-pulse discharges. The mutual coupling between two FAIT antennas is small enough, since any current phase is possible without adjusting the impedance matching device. Although the FAIT antennas are aligned in a poloidal direction, a high heating efficiency of 85% was achieved with the proper minority concentration ratio.