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Approximately 20%-30% of infants cry excessively and exhibit sleep difficulties for no apparent reason, causing parental stress and even triggering impulsive child maltreatment in a small number of cases.

This study proposes to make effective use of plutonium transmuted from minor actinides (MA) by fusion reactors as fertile fuel in a light water reactor (LWR). The plutonium transmuted from MA, particularly Pu-238, has a large neutron capture cross section and becomes fissile Pu-239 by the reaction. If the plutonium transmuted from MA is loaded into LWR appropriately, there is a possibility to maintain a constant effective multiplication factor. This study evaluated the effects of the plutonium transmuted from MA on a full MOX boiled water reactor (BWR) core by Monte Carlo-based neutron transport and burnup calculation. We revealed that some fuel assemblies achieved the effective multiplication factor is greater than 1.0 and its decrease was significantly small (−0.013) during 400 days operation. However, under this condition, the power peaking factor was 1.4, which should be unacceptable from the viewpoint of thermal design. Inventories of heavy nuclides in fuel cycles was evaluated using a simple diagram and its result indicated that the accumulation of MA in the fuel cycle was reduced by introducing the MA transmutation and the Pu recycle system. Furthermore, the amount of MA production and MA transmutation are balanced by introducing two fusion reactors with 3 GW thermal output into the fuel cycle, and the MA inventory was equilibrated.

Tumor-associated macrophages are associated with more malignant phenotypes of esophageal squamous cell carcinoma (ESCC) cells. Previously, an indirect co-culture assay of ESCC cells and macrophages was used to identify several factors associated with ESCC progression. Herein, a direct co-culture assay of ESCC cells and macrophages was established, which more closely simulated the actual cancer microenvironment. Direct co-cultured ESCC cells had significantly increased migration and invasion abilities, and phosphorylation levels of Akt and p38 mitogen-activated protein kinase (MAPK) compared with monocultured ESCC cells. According to a cDNA microarray analysis between monocultured and co-cultured ESCC cells, both the expression and release of S100 calcium binding protein A8 and A9 (S100A8 and S100A9), which commonly exist and function as a heterodimer (herein, S100A8/A9), were significantly enhanced in co-cultured ESCC cells. The addition of recombinant human S100A8/A9 protein induced migration and invasion of ESCC cells via Akt and p38 MAPK signaling. Both S100A8 and S100A9 silencing suppressed migration, invasion, and phosphorylation of Akt and p38 MAPK in co-cultured ESCC cells. Moreover, ESCC patients with high S100A8/A9 expression exhibited significantly shorter disease-free survival (P = 0.005) and cause-specific survival (P = 0.038). These results suggest that S100A8/A9 expression and release in ESCC cells are enhanced by direct co-culture with macrophages and that S100A8/A9 promotes ESCC progression via Akt and p38 MAPK signaling pathways.

Direct numerical simulations have been performed for heat and momentum transfer in internally heated turbulent shear flow with constant bulk mean velocity and temperature, $u_{b}$ and $\theta_{b}$, between parallel, isothermal, no-slip and permeable walls. The wall-normal transpiration velocity on the walls $y=\pm h$ is assumed to be proportional to the local pressure fluctuations, i.e. $v=\pm \beta p/\rho$ (Jim\'enez et al., J. Fluid Mech., vol. 442, 2001, pp.89-117). The temperature is supposed to be a passive scalar, and the Prandtl number is set to unity. Turbulent heat and momentum transfer in permeable-channel flow for $\beta u_{b}=0.5$ has been found to exhibit distinct states depending on the Reynolds number $Re_b=2h u_b/\nu$. At $Re_{b}\lesssim 10^4$, the classical Blasius law of the friction coefficient and its similarity to the Stanton number, $St\approx c_{f}\sim Re_{b}^{-1/4}$, are observed, whereas at $Re_{b}\gtrsim 10^4$, the so-called ultimate scaling, $St\sim Re_b^0$ and $c_{f}\sim Re_b^0$, is found. The ultimate state is attributed to the appearance of large-scale intense spanwise rolls with the length scale of $O(h)$ arising from the Kelvin-Helmholtz type of shear-layer instability over the permeable walls. The large-scale rolls can induce large-amplitude velocity fluctuations of $O(u_b)$ as in free shear layers, so that the Taylor dissipation law $\epsilon\sim u_{b}^{3}/h$ (or equivalently $c_{f}\sim Re_b^0$) holds. In spite of strong turbulence promotion there is no flow separation, and thus large-amplitude temperature fluctuations of $O(\theta_b)$ can also be induced similarly. As a consequence, the ultimate heat transfer is achieved, i.e., a wall heat flux scales with $u_{b}\theta_{b}$ (or equivalently $St\sim Re_b^0$) independent of thermal diffusivity, although the heat transfer on the walls is dominated by thermal conduction., Comment: 13 pages, 7 figures

Introduction Recent advances in the treatment for esophageal cancer have improved the prognosis after esophagectomy, but they have led to an increased incidence of gastric tube cancer. In most patients who underwent retrosternal reconstruction, median sternotomy is performed; it is associated with a risk of postoperative bleeding and osteomyelitis, and pain often negatively affects respiration. Here, we report the first case of thoracoscopic retrosternal gastric conduit resection in the supine position (TRGR-S). Materials and surgical technique A 75-year-old male patient was placed in the supine position. Four ports were placed in the left chest wall. The gastric tube was separated from the epicardium, sternum, and left brachiocephalic vein. Because of adhesions between the gastric tube and the right pleura, combined resection of the right pleura was performed. The dorsal side of the gastric tube was dissected before the ventral side, enabling the gastric tube to be suspended from the back of the sternum and, thus, making it easier to expose the surgical field. Next, pedicled jejunal reconstruction via the presternal route was performed. There were no postoperative complications. The pathological diagnosis was signet ring cell carcinoma (pT1b, pN0, M0, pStage I), indicating R0 resection. Discussion TRGR-S does not require sternotomy, reducing the risk of postoperative bleeding and osteomyelitis. In the presence of adhesions, TRGR-S is safe and provides a good surgical view. It is also reliable procedure for resection of retrosternal gastric tube cancer, and it is ergonomic for surgeons.

Growing interest has been paid to bis(tricyclic) aromatic enes as key components of functional organic materials such as molecular switches and charge-transporting materials. Currently, the synthetic approaches to the overcrowded alkenes are limited to McMurry coupling and Barton–Kellog olefination. This communication reports that palladium-catalyzed double cross-coupling reaction of phenazastannines with 9-(dibromomethylene)fluorene, -xanthene, -thioxanthene, and -thioxanthene-S,S-dioxide serves as a facile synthetic approach to bis(tricyclic) aromatic enes such as 9-(9H-fluoren-9-ylidene)acridines, 9-(9H-oxanthen-9-ylidene)acridines, 9-(9H-thioxanthen-9-ylidene)acridines, and 9-(10,10-dioxido-9H-thioxanthen-9-ylidene)acridines.

Takayasu arteritis (TA) is a large vessel vasculitis of unknown aetiology characterized by chronic inflammatory changes of the aorta and its major branches. We report the active TA case who had severe heart failure due to acute myocardial infarction and aortic regurgitation. Bentall procedure was successfully performed, but he had severely depressed left ventricular function and muscle wasting together with vascular inflammation. The treatment with tocilizumab, an interleukin‐6 receptor monoclonal antibody, in addition to prednisolone and standard heart failure therapy led to prompt remission of TA activity and improvement of left ventricular function and muscle wasting. Taken together with possible involvement of interleukin‐6 in the pathogenesis of heart failure and muscle wasting, inhibition of interleukin‐6 receptor signalling by tocilizumab may be a safe and reasonable approach in the treatment of active TA with heart failure and muscle wasting.

To clarify cytokines involved in the development of systemic juvenile idiopathic arthritis (s-JIA) associated macrophage activation syndrome (MAS) and to identify the serum biomarkers for the diagnosis of s-JIA associated MAS, we employed an antibody array that simultaneously detects 174 cytokines. Fifteen s-JIA patients including 5 patients receiving tocilizumab (TCZ) were analyzed. The levels of five cytokines were significantly elevated in MAS phase compared to those in the active phase of s-JIA. CXCL9 showed the most significant increase following the development of s-JIA associated MAS. Next, to confirm clinical significance of serum CXCL9 levels as a biomarker for s-JIA associated MAS, serum CXCL9 levels in 56 patients with s-JIA including 20 with MAS were analyzed. Results were compared with the clinical features of s-JIA associated MAS. Serum CXCL9 levels correlated positively with disease activity. Monitoring of serum CXCL9 is useful for the evaluation of disease activity in s-JIA associated MAS.

To investigate whether serum leucine-rich α2-glycoprotein (LRG) levels are useful as a marker of disease activity in systemic juvenile idiopathic arthritis (s-JIA), we determined serum LRG levels in fifty-nine s-JIA patients, 15 with other subtypes of JIA, 7 with Kawasaki disease (KD), 7 with influenza A infection (flu), 7 with enterohemorrhagic Escherichia coli (EHEC) infection, and 20 healthy controls (HC). Results were compared with the clinical features of s-JIA and serum cytokine levels including interleukin- (IL-) 6, IL-18, and soluble tumor necrosis factor receptors I and II. Serum LRG levels in active s-JIA were higher compared to those in other subtypes of JIA, EHEC, flu patients, and HC. Serum LRG levels were normalized in the inactive s-JIA phase after treatment. Serum LRG levels were positively correlated with serum C-reactive protein and ferritin levels. Serum LRG levels reflected s-JIA disease activity and thus may be useful for monitoring s-JIA disease activity.

We report herein that 4,5-bis(diarylamino)phthalimides exhibit efficient solid-state emission. The phthalimides were easily prepared from dimethyl 4,5-bis(diarylamino)phthalates or commercially available 4,5-dichlorophthalic acid via a few steps. The absorption spectra of the phthalimides in toluene showed strong bands at 337–374 nm and weak bands possessing two shoulders at 378–455 nm. Toluene solutions of the phthalimides fluoresced in the greenish blue to orange-yellow region with good-to-high quantum yields. In contrast, the phthalimides showed no emission in DMSO. Based on the observation, phthalimide was demonstrated to serve as a turn-on type fluorescent probe for hydrazine. The phthalimides dispersed in a thin film of poly(methyl methacrylate) and in powder form fluoresced in the blue-to-green and green-to-orange region, respectively, with high quantum yields. As the electron-donating ability of the diarylamino moieties increased, the emission spectra in solution and the solid states were red-shifted. The density functional theory calculations confirm that the photo-excitation involves an intramolecular charge transfer from diarylamino groups to imide-carbonyl moieties.

The design of light-responsive fluorescent assembly systems with a variety of photochemical and photophysical properties is important for the fundamental understanding of the assembly–disassembly process as well as for applications such as optical information storage and fluorescence sensing. A major obstacle in constructing such photofunctional materials is the lack of a molecular design strategy for photoswitchable organic chromophores with aggregation-induced emission/aggregation-induced emission enhancement (AIE/AIEE) characteristics. Herein, we describe a new trigonal azobenzene framework showing AIE/AIEE characteristics and excellent photoisomerization (∼90%) from the C3-symmetric to asymmetric (including a bent-shaped cis-azobenzene) form. NMR experiments demonstrate light-induced molecular structure changes, which cause drastic symmetry breaking. The trigonal chromophores assemble into red fluorescent microspheres and their fluorescence intensity increases by ∼10-fold, confirming the AIE/AIEE characteristics. Importantly, scanning electron microscopy (SEM), optical microscopy (OM), and fluorescence optical microscopy (FOM) images substantiate that a noticeable light-driven melting occurs simultaneously with a marked fluorescence switching from on to off. Moreover, the fluorescent spheres are successfully applied in optical information storage and fluorescence sensing in a non-contact fashion.

We prepared dimethyl and diaryl 2,5-dialkoxytere-phthalates from dimethyl 2,5-dihydroxyterephthalate in good-to-high yields via alkylation or a sequence of alkylation, hydrolysis, chlorination, and condensation. The absorption spectra of the dialkoxyterephthalates contain a small band at 332-355 nm, which could be assigned to intramolecular charge-transfer transition from the alkoxy to alkoxycarbonyl groups on the basis of theoretical calculations using density functional theory. The dialkoxyterephthalates exhibited blue fluorescence with moderate-to-excellent quantum yields not only in solution but also in the solid state, such as a poly(methyl methacrylate) (PMMA) film and a powder. The solid-state quantum yields of the diisopropoxy-substituted terephthalates were similar or considerably higher than those of the dimethoxy-substituted counterparts. Copolymerization of 2,5-diisopropoxyterephthaloyl chloride and 1,4-butanediol with or without terephthaloyl chloride gave brilliantly blue fluorescent polymers, whose quantum yields were 0.72 and 0.71 in toluene and 0.46 and 0.40 in the neat film, respectively. Furthermore, white emission was achieved when a fluorescent yellow 2,5-diaminoterephthalate was doped into the thin film of the blue fluorescent polymer at 0.4 wt %.

We found a multi-scale steady solution of the Boussinesq equations for Rayleigh–Benard convection in a three-dimensional periodic domain between horizontal plates with a constant temperature difference. This was realised using a homotopy from the wall-to-wall optimal transport solution provided by Motoki et al. (J. Fluid Mech., vol. 851, 2018, R4). A connected steady solution, which is a consequence of bifurcation from a thermal conduction state at Rayleigh number scaling law with a consistent prefactor, and the energy transfer to small scales with a nearly constant flux in the wavenumber space is in accordance with the turbulent energy transfer.

This article takes a look back over our research on the development of organic fluorophores that efficiently emit light in the solid state and precious-metal-free phosphors that emit light at room temperature. In particular, we place an emphasis on the prehistory of each project and the relationship between the established molecular designs. Our story starts from the serendipitous discovery of a luminophore with a single benzene core and follows the molecular design and characterization of 2,5-dipiperidyl-1,4-bis(acceptor-substituted ethenyl)benzenes that exhibit solid-state fluorescence with high-to-excellent quantum yields in the blue-to-red region. In addition, the design concepts, luminescence characteristics, and applications of eight novel classes of fluorophores are described, and the discovery, design, and luminescent properties of precious-metal-free compounds that show efficient room-temperature phosphorescence are presented.

Objective The acylcarnitine profile is analyzed in dried blood spots (DBS) to screen for inborn errors of metabolism. Hematocrit (Ht) is known to affect the result of quantitative analyses of DBS samples; however, the effects of Ht on the acylcarnitine profiles in DBS have not been studied in actual samples from newborns. Study Design The acylcarnitine profiles in DBS for newborn screening tests and Ht levels of very-low-birth-weight infants were obtained from medical records. We investigated the relationship between Ht and each acylcarnitine using Pearson's correlation coefficient (r). Results We examined 77 newborns in this study. There was a significantly positive correlation between Ht and C0, C2, C12, C16, C18, C18:1, and C18:1-OH, respectively (p Conclusion This study clarifies that Ht and C0, C2, C12, C16, C18, C18:1, and C18:1-OH are significantly correlated in DBS, which is consistent with previous studies. Hence, the effect of Ht should be considered when interpreting the results of acylcarnitine profiles in DBS. Key Points

We retrospectively investigated the use of oral hydromorphone for cancer pain. Nineteen patients treated for cancer pain with oral hydromorphone were reviewed in this study. Cancers had occurred in the gastrointestinal (n=4), lung(n=3), breast(n=2), bone and soft tissue(n=2), hematological(n=2), and others(n=6). The administered opioids before switching to hydromorphone were morphine, oxycodone, and tapentadol. The mean oral morphine equivalent daily dose (OMEDD)was 89.3 mg. The average dose of hydromorphone administered was 16.4 mg/day, and average NRS 10(numerical rating scale: 0-10)scores of cancer pain before and after switching were 4.1 and 3.8, respectively, showing no significant differences. In this study, switching from other opioids to oral hydromorphone was feasible with an approved conversion ratio, ie, an oral hydromorphone-to-oral morphine ratio of 1:5. No severe adverse effects were observed. The oral hydromorphone extended-release formulation was administered every 24 h, as a tiny tablet formulation that is preferable owing to easy administration and adherence.

In line with Pomeau's conjecture about the relevance of directed percolation (DP) to turbulence onset/decay in wall-bounded flows, we propose a minimal stochastic model dedicated to the interpretation of the spatially intermittent regimes observed in channel flow before its return to laminar flow. Numerical simulations show that a regime with bands obliquely drifting in two stream-wise symmetrical directions bifurcates into an asymmetrical regime, before ultimately decaying to laminar flow. The model is expressed in terms of a probabilistic cellular automaton evolving von Neumann neighbourhoods with probabilities educed from a close examination of simulation results. It implements band propagation and the two main local processes: longitudinal splitting involving bands with the same orientation, and transversal splitting giving birth to a daughter band with orientation opposite to that of its mother. The ultimate decay stage observed to display one-dimensional DP properties in a two-dimensional geometry is interpreted as resulting from the irrelevance of lateral spreading in the single-orientation regime. The model also reproduces the bifurcation restoring the symmetry upon variation of the probability attached to transversal splitting, which opens the way to a study of the critical properties of that bifurcation, in analogy with thermodynamic phase transitions., 21 pages, 16 figures. Identical to the published version except for the format and the spelling, here kept British but changed to American by the publisher

Objectives: Genetic analysis of TNFRSF1A can confirm the diagnosis of tumor necrosis factor receptor-associated periodic syndrome (TRAPS), but interpretation of the pathogenesis of variants of unknown significance is sometimes required. The aim of this study was to evaluate the clinical significance of serum soluble tumor necrosis factor receptor type I (sTNFR-I)/II ratio to differentiate TRAPS from other autoinflammatory diseases. Methods: Serum sTNFR-I and sTNFR-II levels were measured using an enzyme-linked immunosorbent assay in patients with TRAPS (n = 5), familial Mediterranean fever (FMF) (n = 14), systemic juvenile idiopathic arthritis (s-JIA) (n = 90), and Kawasaki disease (KD) (n = 37) in the active and inactive phase, along with healthy controls (HCs) (n = 18). Results: In the active phase, the serum sTNFR-I/II ratio in patients with s-JIA, KD, and FMF was significantly elevated compared with that in HCs, whereas it was not elevated in patients with TRAPS. In the inactive phase, the serum sTNFR-I/II ratio in patients with s-JIA and FMF was significantly higher compared with that in HCs, and the ratio was lower in TRAPS patients than in patients with s-JIA and FMF. Conclusions: Low serum sTNFR-I/II ratio in the active and inactive phase might be useful for the differential diagnosis of TRAPS and other autoinflammatory diseases.

Objective To investigate the clinical significance of serum IL-18 levels for the diagnosis of systemic JIA (s-JIA) and to predict the disease course of s-JIA. Methods Overall, 116 patients with s-JIA, 151 with other diseases and 20 healthy controls were analysed. Serum IL-18 levels were measured longitudinally in 41 patients with s-JIA from active phase through remission phase. Serum IL-18 levels were quantified via enzyme-linked immunosorbent assay and the results were compared with clinical features and the disease course of s-JIA. Results The serum IL-18 level cut-off value for differentiation of s-JIA from other diseases was 4800 pg/ml. In patients with a monocyclic course, serum IL-18 levels steadily decreased during the inactive phase and low levels were sustained during remission. In contrast, in patients with a chronic course, elevated serum IL-18 levels were sustained even during the inactive phase. In patients with a polycyclic course, serum IL-18 levels were elevated during disease flares and normalized during the inactive phase. The serum IL-18 level cut-off value for diagnosis of remission in s-JIA was 595 pg/ml, Conclusion Serum IL-18 levels of >4800 pg/ml may be useful for differentiating between s-JIA and other diseases. Monitoring of serum IL-18 levels might be useful for predicting the disease course and assessing remission in s-JIA.

To assess the efficacy and safety of canakinumab in Japanese patients with systemic juvenile idiopathic arthritis (sJIA). This was an open-label, single-arm active treatment study. sJIA patients, aged ≥2 to

To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P=4.94E-20, odds ratio (OR) =1.90) and TNFSF15 (rs6478109, P=2.54E-8, OR=0.72) regions achieved genome-wide significance and were replicated in Korean, South Asian and African populations. Trans-ethnic meta-analyses including Japanese, Korean, South Asian, African, European, Hispanic and Maghrebian populations confirmed the significant associations of variants in NPHS1-KIRREL2 (P(meta)=6.71E-28, OR=1.88) and TNFSF15 (P(meta)=5.40E-11, OR=1.33) loci. Analysis of the NPHS1 risk alleles with glomerular NPHS1 mRNA expression from the same person revealed allele specific expression with significantly lower expression of the transcript derived from the risk haplotype (Wilcox test p=9.3E-4). Because rare pathogenic variants in NPHS1 cause congenital nephrotic syndrome of the Finnish type (CNSF), the present study provides further evidence that variation along the allele frequency spectrum in the same gene can cause or contribute to both a rare monogenic disease (CNSF) and a more complex, polygenic disease (SSNS).

Direct numerical simulations have been performed for turbulent thermal convection between horizontal no-slip, permeable walls with a distance $H$ and a constant temperature difference $\Delta T$ at the Rayleigh number $Ra=3\times10^{3}-10^{10}$. On the no-slip wall surfaces $z=0$, $H$ the wall-normal (vertical) transpiration velocity is assumed to be proportional to the local pressure fluctuation, i.e. $w=-\beta p'/\rho, +\beta p'/\rho$ (Jim\'enez et al., J. Fluid Mech., vol. 442, 2001, pp. 89-117), and the property of the permeable wall is given by the permeability parameter $\beta U$ normalised with the buoyancy-induced terminal velocity $U={(g\alpha\Delta TH)}^{1/2}$, where $\rho$, $g$ and $\alpha$ are mass density, acceleration due to gravity and volumetric thermal expansivity, respectively. A zero net mass flux through the wall is instantaneously ensured, and thermal convection is driven only by buoyancy without any additional energy inputs. The critical transition of heat transfer in convective turbulence has been found between the two $Ra$ regimes for fixed $\beta U=3$ and fixed Prandtl number $Pr=1$. In the subcritical regime at lower $Ra$ the Nusselt number $Nu$ scales with $Ra$ as $Nu\sim Ra^{1/3}$, as commonly observed in turbulent Rayleigh-B\'enard convection. In the supercritical regime at higher $Ra$, on the other hand, the ultimate scaling $Nu\sim Ra^{1/2}$ is achieved, meaning that the wall-to-wall heat flux scales with $U\Delta T$ independent of the thermal diffusivity, although the heat transfer on the wall is dominated by thermal conduction. The physical mechanisms of the achievement of the ultimate heat transfer are presented.

Objectives To compare the cytokines involved in the development of macrophage activation syndrome (MAS) in different background rheumatic diseases and to identify serum biomarkers for MAS diagnosis. Methods Serum neopterin, IL-6, IL-18 and soluble TNF receptor (sTNFR) type I (sTNFR-I) and type II (sTNFR-II) levels were determined using ELISA in 12 patients with SLE, including five with MAS; 12 patients with JDM, including four with MAS; 75 patients with Kawasaki disease (KD), including six with MAS; and 179 patients with systemic JIA (s-JIA), including 43 with MAS. These results were compared with the clinical features of MAS. Results Serum neopterin, IL-18 and sTNFR-II levels were significantly higher during the MAS phase than during the active phase in patients with all diseases. Furthermore, serum sTNFR-I levels were significantly higher during the MAS phase than during the active phase in patients with SLE, KD and s-JIA. Receiver operating characteristic (ROC) curve analysis revealed that serum sTNFR-I levels for SLE, serum IL-18 levels for JDM, and serum sTNFR-II levels for KD and s-JIA had the highest areas under the ROC curve. Serum levels of these cytokines were significantly and positively correlated with serum ferritin levels. Conclusions Overproduction of IFN-γ, IL-18 and TNF-α might be closely related to the development of MAS. Serum levels of sTNFR-I for SLE, IL-18 for JDM, and sTNFR-II for KD and s-JIA might be useful diagnostic markers for the transition from active phase to MAS.

We aimed to assess the kinetics of the release of proinflammatory cytokines and to clarify clinical usefulness as an indicator of the disease activity in human parechovirus type 3 virus (HPeV3)-induced sepsis-like syndrome. We measured serum levels of neopterin, interleukin (IL)-6 and the soluble forms of tumor necrosis factor (TNF) receptor types I (sTNF-RI) and II (sTNF-RII). Serum samples were obtained from 12 patients with HPeV3-induced sepsis-like syndrome and 28 healthy children. Disease course after onset was divided into 3 phases: early (day 1-2), peak (day 3-6) and recovery (day 9-16) phases. Serum IL-6 levels rapidly and markedly elevated in early phase and gradually decreased to those in healthy children in recovery phase. Furthermore, serum neopterin, sTNFR-I and sTNFR-II levels increased rapidly and markedly in onset phase and remained elevated in peak phase. These levels gradually decreased in recovery phase. Serum IL-18 levels increased from onset phase to peak phase and decreased in recovery phase. These results indicate that proinflammatory cytokines, in particular, interferon gamma, TNF-α and IL-18 are closely related to the development of HPeV3-induced sepsis-like syndrome. Serum levels of these cytokines might be a useful indicator of the disease activity.

Background This study aimed to determine the influence of tocilizumab (TCZ) in modifying the clinical and laboratory features of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (s-JIA). Furthermore, we assessed the performance of the 2016 MAS classification criteria for patients with s-JIA-associated MAS while treated with TCZ. Methods A panel of 15 pediatric rheumatologists conducted a combination of expert consensus and analysis of real patient data. Clinical and laboratory features of s-JIA-associated MAS in 12 TCZ-treated patients and 18 untreated patients were evaluated. Possible MAS was defined as having characteristic laboratory features but lack of clinical features of MAS, or atypical MAS, or early treatment that prevented full-blown MAS. Results Clinically, the TCZ-treated patients with s-JIA-associated MAS were less likely febrile and had significantly lower ferritin, triglyceride, and CRP levels than the untreated patients with s-JIA-associated MAS. Other laboratory features of MAS including lower platelet counts and lower fibrinogen were more pronounced in TCZ-treated patients. The TCZ-treated patients with s-JIA-associated MAS were less likely to be classified as MAS based on the MAS classification criteria (25% vs 83.3%, p Conclusion TCZ could modify the clinical and laboratory features of s-JIA-associated MAS. When evaluating the s-JIA patients while treated with TCZ, it is not applicable to use MAS classification criteria. Care must be taken to not underdiagnose MAS based on the MAS classification criteria.

Made available in DSpace on 2021-06-25T10:38:01Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-11-01 Healthway Objective. To develop a composite disease activity score for systemic JIA (sJIA) and to provide preliminary evidence of its validity. Methods. The systemic Juvenile Arthritis Disease Activity Score (sJADAS) was constructed by adding to the four items of the original JADAS a fifth item that aimed to quantify the activity of systemic features. Validation analyses were conducted on patients with definite or probable/possible sJIA enrolled at first visit or at the time of a flare, who had active systemic manifestations, which should include fever. Patients were reassessed 2 weeks to 3 months after baseline. Three versions were examined, including ESR, CRP or no acute-phase reactant. Results. A total of 163 patients were included at 30 centres in 10 countries. The sJADAS was found to be feasible and to possess face and content validity, good construct validity, satisfactory internal consistency (Cronbach's alpha 0.64-0.65), fair ability to discriminate between patients with different disease activity states and between those whose parents were satisfied or not satisfied with illness outcome (P < 0.0001 for both), and strong responsiveness to change over time (standardized response mean 2.04-2.58). Overall, these properties were found to be better than those of the original JADAS and of DAS for RA and of Puchot score for adult-onset Still's disease. Conclusion. The sJADAS showed good measurement properties and is therefore a valid instrument for the assessment of disease activity in children with sJIA. The performance of the new tool should be further examined in other patient cohorts that are evaluated prospectively. UOC Clinica Pediatrica e Reumatologia IRCCS Istituto Giannina Gaslini Dipartimento di Neuroscienze Riabilitazione Oftalmologia Genetica e Scienze Materno-Infantili (DiNOGMI) Università degli Studi di Genova Dipartimento di Epidemiologia e Biostatistica IRCCS Istituto Giannina Gaslini Faculty of Medicine Ain Shams University Pediatric Rheumatology Division Institute of Child Health Section of Pediatric Rheumatology SRCC Children's Hospital Rheumatology Division Pediatric Department Faculty of Medicine Ramathibodi Hospital Mahidol University Pediatric Rheumatology Clinic R G Kar Medical College Division of Rheumatology IRCCS Ospedale Pediatrico Bambino Gesù Division of Pediatric Rheumatology Institute of Child Health Sir Ganga Ram Hospital Faculty of Medicine Benha University Faculty of Medicine Alexandria University Faculty of Medicine Tanta University Faculty of Medicine Cairo University Pediatric Rheumatology Division Adolescent Health Care Unit Universidade do Estado do Rio de Janeiro Department of Internal Medicine Universidade Federal do Rio de Janeiro Servicio de Inmunología y Reumatología Hospital de Pediatría Garrahan Department of Clinical Sciences and Community Health University of Milan Division of Rheumatology University Hospital Meyer Rheumatology Division National Medical Research Center of Children's Health Sechenov First Moscow State Medical University Department of Immunology Rheumatology and Allergy Queen Rania Children's Hospital Saint-Petersburg State Pediatric Medical University UOC Pediatria a Media Intensità di Cure Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Rheumatology Department Faculty of Medicine Suez Canal University Department of Pediatrics King Faisal Specialist Hospital and Research Center Dipartimento Promise G. D'Alessandro Università degli Studi di Palermo Pediatric Department Hospital das Clínicas Botucatu Medicine University UNESP UOC Pediatria Servizio di Immuno-Reumatologia Pediatrica Azienda Ospedaliera Universitaria Gaetano Martino Messina UO Nefrologia e Reumatologia Pediatrica Azienda Ospedaliera Universitaria Gaetano Martino Department of Pediatrics School of Medicine Institute of Medical Pharmaceutical and Health Sciences Kanazawa University Pediatric Unit Ospedale Vito Fazzi Pediatric Unit AON SS Antonio e Biagio e Cesare Arrigo Children's Hospital Pediatric Department Hospital das Clínicas Botucatu Medicine University UNESP

Background. Kawasaki disease (KD) is typically characterized by fever, oral cavity erythematous changes, bilateral bulbar conjunctival injection, skin rash, erythema and edema of the hands and feet, and cervical lymphadenopathy. Some atypical patients with KD initially develop cervical and pharyngeal cellulitis; however, an initial presentation with inguinal cellulitis is extremely rare. In addition, to our knowledge, no report has documented the cytokine profile in a KD patient with cellulitis. Case presentation. A previously healthy 8-year-old Japanese girl was hospitalized following a 2-day history of fever and a 5-day history of pain and erythema in the left inguinal region. She was diagnosed with bacterial inguinal cellulitis and was administered antibiotics. The next day, a polymorphous rash emerged on her trunk. After 3 days of antibiotics, however, her fever continued and the cellulitis had spread over the entire lower abdomen. Simultaneously, the bilateral bulbar conjunctival injection without exudate became more prominent and her lips became erythematous. In addition, erythematous changes on her palms appeared a few hours later, which led to the diagnosis of KD. Since she had a high risk score that predicted no response to initial intravenous immunoglobulin (IVIG) at the initiation of treatment, she was treated with IVIG, intravenous prednisolone (PSL), and oral aspirin. The KD symptoms improved the next day, but the cellulitis did not completely resolve until 2 months after discharge. The patient’s serum cytokine profile at admission had an IL-6 dominant pattern which was consistent with that of patients with KD despite her initial lack of KD symptoms, and the pattern observed at admission was sustained until IVIG and PSL administration. Conclusion. KD should be included in the differential diagnosis for patients presenting with inguinal cellulitis who are unresponsive to initial empiric antibiotics.

Background Cognitive function and physical function are important predictors of mortality. Aim To investigate whether or not reaction time (RT) as a cognitive function and grip strength (GS) as a physical function were associated, alone or in combination, with mortality from heart disease or stroke. Methods The subjects included 4901 Adult Health Study participants in Hiroshima who had undergone RT and GS measurements, were 35-74 years old at baseline (1970-1972) and were followed until the end of 2007. Results After adjustment for other potential risk factors, RT was positively and GS was negatively associated with mortality from both heart disease and stroke. These associations were persistent in the model when adjusting simultaneously for RT, GS and other factors, but hazard ratios were attenuated. When we evaluated the associations by baseline age and gender, we found the greater hazard ratios for RT in the younger cohort, but no clear modification by age for GS. The interaction between RT and GS was statistically significant (P = 0.012) for stroke mortality. In the stratified analyses divided using the age-specific median value of RT or GS, the estimated hazard ratio of stroke mortality for RT was significant in participants with weak or strong GS but greater in the former, and for GS, it was only significant in participants with slow RT. Conclusion RT and GS, alone and in combination, predicted heart disease and stroke mortalities. Interventions for both cognitive function and physical function may be beneficial for the prevention of cardiovascular disease mortality.

Juvenile idiopathic arthritis (JIA) is the most common disease in pediatric rheumatism. There is no specific symptom or examination finding for JIA, and the diagnosis is made by exclusion and differentiation. Because non-pediatric rheumatologists are sometimes involved in medical care, 'proposal for JIA guidance on diagnosis and treatment for primary care pediatricians and non-pediatric rheumatologists' was first published in 2007. In these 10 years, a number of new findings on pathophysiology and treatment of JIA have been published; therefore, we propose this guidance of 2018th edition aiming at updating and standardization of JIA medical care in Japan. This edition included the management of uveitis, macrophage activation syndrome, infectious diseases before and during treatment. Moreover, details of biologics are also described. Although this guidance is tailored to adaptation of examinations and drugs, we do not purpose to limit the physicians' discretion in clinical practice. This guidance should be viewed as recommendations and be individualized according to the condition of the patient. We hope that medical care for JIA will advance and more patients will get benefit based on this guidance. Then, further revisions are needed due to changes in future conditions.

This study aims to investigate the clinical significance of serum soluble CD163 (sCD163) levels as a predictor of the disease activity of systemic juvenile idiopathic arthritis (s-JIA). In this study, we examined 63 patients with s-JIA, four with Epstein-Barr virus-induced hemophagocytic lymphohistiocytosis (EBV-HLH), and seven with Kawasaki disease (KD), along with 14 healthy controls. We quantified serum cytokine levels (sCD163, neopterin, IL-18, IL-6) by enzyme-linked immunosorbent assay and compared the results with the clinical features of s-JIA. Serum sCD163 levels were significantly elevated in patients with s-JIA associated macrophage activation syndrome (MAS) and EBV-HLH compared to those in patients with acute-phase s-JIA and KD. In addition, serum sCD163 levels profoundly increased with the progress of MAS and correlated positively with the disease activity of s-JIA, even in patients receiving tocilizumab. Furthermore, serum sCD163 levels significantly decreased in the inactive phase compared to those in the active phase and normalized in remission. The correlation between macrophage activation and serum sCD163 levels might be a unique indicator of the disease activity and a potential diagnostic laboratory criterion for clinical remission in patients with s-JIA, including those receiving tocilizumab.

To investigate the clinical significance of serum soluble tumor necrosis factor receptor (sTNFR) II level and sTNFR II/I ratio as indicators of the development of coronary artery lesions (CALs) in Kawasaki disease (KD), we measured levels of serum sTNFR I and II, interleukin (IL)-6, IL-18, and neopterin in 63 patients with KD, including nine patients with CALs and 20 healthy controls. At the time of diagnosis of KD before intravenous immunoglobulin (IVIG) treatment, serum sTNFR I and II levels were found to be significantly higher in non-responders to IVIG treatment than in responders. On the contrary, serum sTNFR II levels and sTNFR II/I ratio were significantly higher in patients with KD having CALs than in those without CALs. Longitudinal observation in a patient with KD who is unresponsive to IVIG revealed sustained elevation of serum sTNFR II level, and elevated sTNFR II/I ratio was linked to the CALs development. Increase in serum sTNFR II level and elevated sTNFR II/I ratio may be promising indicators of the development of CALs in KD.

Exploration of novel organic luminophores that exhibit thermally activated delayed fluorescence (TADF) in the aggregated state is very crucial for advance of delayed luminescence-based applications such as time-gated bio-sensing and temperature sensing. We report herein that synthesis, photophysical properties, molecular and crystal structures, and theoretical calculations of 2,6-bis(diarylamino)benzophenones. Absorption spectra in solution and calculations using density functional theory (DFT) method revealed that the optical excitation took place through intramolecular charge-transfer from one diarylamino moiety to an aroyl group. While the benzophenones did not luminesce in solution, the solids of the benzophenones emitted green light with moderate-to-good quantum yields. Thus, the benzophenones exhibit aggregation-induced emission. Based on the lifetime measurement, the green emission of the solids was found to include TADF. The emergence of the TADF is supported by the small energy gap between the excited singlet and triplet states, which was estimated by time-dependent DFT calculations. Thin films of poly(methyl methacrylate) doped by the benzophenones also showed green prompt and delayed fluorescence whose lifetimes were in the order of microseconds. Linear correlation between logarithm value of TADF lifetime and temperature was observed with the benzophenone in powder, suggesting that the benzophenones can serve as molecular thermometers workable under aqueous conditions.

Objective To validate whether the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA) is practical in the real world. Methods A combination of expert consensus and analysis of real patient data was conducted by a panel of 15 pediatric rheumatologists. A total of 65 profiles comprised 18 patients with systemic JIA-associated MAS and 47 patients with active systemic JIA without evidence of MAS. From these profiles, 10 patient data points for full-blown MAS, 11 patient data points for MAS onset, and 47 patient data points for acute systemic JIA without MAS were evaluated. Results Evaluation of the classification criteria to discriminate full-blown MAS from acute systemic JIA without MAS showed a sensitivity of 1.000 and specificity of 1.000 at the time of full-blown MAS. Sensitivity was 0.636 and specificity was 1.000 at the time of MAS onset. The number of measurement items that fulfilled the criteria increased in full-blown MAS compared to that at MAS onset. At MAS onset, the positive rates of patients who met the criteria for platelet counts and triglycerides were low, whereas those for aspartate aminotransferase were relatively high. At full-blown MAS, the number of patients who met the criteria for each measurement item increased. Conclusion The classification criteria for MAS complicating systemic JIA had a very high diagnostic performance. However, the diagnostic sensitivity for MAS onset was relatively low. For the early diagnosis of MAS in systemic JIA, the dynamics of laboratory values during the course of MAS should be further investigated.

The objective of this study is to identify risk factors for hypersensitivity reaction (HSR) to tocilizumab (TCZ) in systemic juvenile idiopathic arthritis (sJIA).Clinical records of 40 patients with sJIA administered TCZ at one center were retrospectively reviewed. Patients were divided into HSR or non-HSR groups depending on the presence of HSR between the first and third TCZ administrations; clinical and laboratory assessments, including serum cytokine profile, were compared.Five patients displayed HSR following the third TCZ administration. They were significantly younger, shorter, and lighter, with a higher peak body temperature than non-HSR patients following the third administration. Their serum C-reactive protein (CRP) level was undetectable following the first administration but detectable by the third administration. Before the third administration, the white blood cell counts and serum levels of CRP and sTNFRII were significantly higher in the HSR group than in the non-HSR group. The serum levels of interleukin-18 and -6 before the third TCZ administration were higher and lower than those before the first administration in the HSR and non-HSR groups, respectively.Patients with sJIA having a younger age, shorter stature, and lighter weight and those showing increased disease activity in the early period of TCZ administration may be at higher risk of TCZ-induced HSR.

To estimate target of treatment for long-term efficacy of the first biologic agent used to treat polyarticular juvenile idiopathic arthritis (pJIA).A retrospective cohort of patients with pJIA treated at six medical institutions in Japan between 1 March 2005 and 31 October 2014 was identified. The patients were divided by 2-year treatment periods with the first biologic agent into continuous treatment group and switching group. Three markers were examined: matrix metalloproteinase-3 (MMP-3), erythrocyte sedimentation rate (ESR), and disease activity score (DAS) 28-ESR.Thirty-two pJIA patients (8 boys, 24 girls) from 43 recruited patients were included in this study. The treatment periods with the first biologic agent in continuous treatment group (24 patients, 75%) was 40 months (median, range 24-119) and switching group (8 patients; 25%) was 9.5 months (median, 6-18). Markers [odds ratio (95% confidence interval)] at 3 months were MMP-3 [1.02 (0.99-1.05), p = .219], ESR [1.00 (0.78-1.30), p = .998], and DAS28-ESR [13.9 (2.08-409.82), p = .035]. The cut-off point for DAS28-ESR at 3 months to distinguish the two groups was 2.49 (sensitivity, 87.5%; specificity, 87.5%).DAS28-ESR of 2.49 at 3 months after initiating the first biologic agent can be a target of sustained treatment in pJIA patients.

We designed and characterized 1,4-diaroyl-2,5-bis(silylmethoxy)benzenes as precious-metal-free organic luminophores that efficiently phosphoresce at room temperature. The benzene derivatives in crystals emit green phosphorescence with quantum yields up to 0.45 under ambient conditions. The luminescence quantum yield increases with increasing number of intermolecular interactions in the crystal, such as hydrogen bonding and CH–π interactions. The luminescence lifetimes are inversely proportional to temperature over the −80 to 80 °C range, demonstrating the potential of the benzene derivatives as materials for temperature sensing. Poly(methyl methacrylate) films doped with these luminophores also exhibit intense green phosphorescence at room temperature under vacuum, while they emit very faint blue fluorescence under ambient conditions. Electron spin resonance spectroscopy of a UV-excited diphenylmethylsilyl-derivative in toluene at 77 K reveals a triplet diradical species, whose electronic distribution is similar to that of naphthalene, indicating that the triplet diradical is distributed over almost ten atoms.

An antiparallel double-strand of a BODIPY–zinc–porphyrin dyad was assembled via geometrical complementarity of an unusual B–F⋯Zn coordination bonding interaction.