A Case With Typical Clinical Manifestations of Kawasaki Disease and Multisystem Inflammatory Syndrome in Children Temporally Associated With SARS-CoV-2 Infection.

Whether Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) temporally associated with SARS-CoV-2 infection are two distinct syndromes or part of the same spectrum is not fully understood. In this report, we present the case of a five-year-old boy who fully satisfied the diagnostic criteria for both KD and MIS-C associated with SARS-CoV-2 infection. He tested positive for SARS-CoV-2 on an oropharyngeal swab antigen test approximately four weeks before the onset of symptoms. He had severe abdominal pain. Abdominal ultrasound showed ascites. He improved with initial (2 g/kg) and additional (1 g/kg) intravenous immunoglobulin (IVIG) therapy and intravenous methylprednisolone (initial dose, 2 mg/kg/day). Our case may lead to clarification of the pathogenesis of both diseases. Additionally, the recent history of SARS-CoV-2 infection for children with prolonged fever and no clear focus of infection should be checked, and, if present, clinicians should consider MIS-C temporally associated with SARS-CoV-2 infection. IVIG therapy is important for children with MIS-C who meet the diagnostic criteria for KD, even if diagnosed with MIS-C.

Prediction Models for Intravenous Immunoglobulin Resistance in Kawasaki Disease: A Meta-analysis.

CONTEXT: Approximately 10% to 20% of patients with Kawasaki disease (KD) are refractory to initial intravenous immunoglobulin (IVIG) therapy. KD is mainly associated with coronary artery abnormalities. OBJECTIVES: To identify and evaluate all developed prediction models for IVIG resistance in patients with KD and synthesize evidence from external validation studies that evaluated their predictive performances. DATA SOURCES: PubMed Medline, Dialog Embase, the Cochrane Central Register of Controlled Trials, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov were searched from inception until October 5, 2021. STUDY SELECTION: All cohort studies that reported patients diagnosed with KD who underwent an initial IVIG of 2 g/kg were selected. DATA EXTRACTION: Study and patient characteristics and model performance measures. Two authors independently extracted data from the studies. RESULTS: The Kobayashi, Egami, Sano, Formosa, and Harada scores were the only prediction models with 3 or more external validation of the161 model analyses in 48 studies. The summary C-statistics were 0.65 (95% confidence interval [CI]: 0.57-0.73), 0.63 (95% CI: 0.55-0.71), 0.58 (95% CI: 0.55-0.60), 0.50 (95% CI: 0.36-0.63), and 0.63 (95% CI: 0.44-0.78) for the Kobayashi, Egami, Sano, Formosa, and Harada models, respectively. All 5 models showed low positive predictive values (0.14-0.39) and high negative predictive values (0.85-0.92). LIMITATIONS: Potential differences in the characteristics of the target population among studies and lack of assessment of calibrations. CONCLUSIONS: None of the 5 prediction models with external validation accurately distinguished between patients with and without IVIG resistance.

Beta-lactam allergy and drug challenge test in children: a systematic review and meta-analysis.

BACKGROUND: Most cases of beta-lactam allergy in children are likely to be mislabeled. This study aimed to assess the prevalence of true positives, as determined by drug challenge tests, and the rate of false negatives in children with suspected allergies and confirm the safety of the drug challenge test. METHODS: We conducted a systematic review and meta-analysis according to established procedures. Study participants were children with suspected beta-lactam allergy who underwent a drug challenge. PubMed MEDLINE, Dialog EMBASE, Cochrane Central Register of Controlled Trials, World Health Organization International Clinical Trials Registry Platform, and clinicaltrials.gov were searched from inception until March 5, 2021. RESULTS: The pooled prevalence of (a) positive results in the first challenge was 0.049 (95% CI, 0.041-0.057; I2 = 71%) from 78 studies; (b) serious adverse events was 0.00 (95% CI, 0.00-0.00; I2 = 0.0%) from 62 studies; and (c) positive results in the second challenge after the first negative result was 0.028 (95% CI, 0.016-0.043; I2 = 38%) from 18 studies. CONCLUSIONS: The prevalence of children with suspected beta-lactam allergy with true-positive results and false-negative results from the drug challenge test was very low. Serious adverse events resulting from drug challenge tests were also very rare. IMPACT: Most children with suspected beta-lactam allergy were likely to be mislabeled. Serious adverse events caused by the drug challenge test were rare. Few false-negative results were obtained from the drug challenge test.

Interspecies Regulation Between Staphylococcus caprae and Staphylococcus aureus Colonized on Healed Skin After Injury.

Staphylococcus spp. colonize commensally on the human skin. Some commensal coagulase-negative staphylococci and Staphylococcus aureus are also involved in nosocomial infections. Bacteria were collected from skin healed from pressure injury (PI). After the collection time points, some patients suffered from recurrent PI (RPI). This study analyzed the characteristics of Staphylococcus spp. on healed skin before recurrence between healed skin that suffered from RPI within 6 weeks (RPI group) and healed skin that did not suffer within the duration (non-RPI group) by Staphylococcus spp.-specific sequencing. Of the seven patients in the RPI group, two were dominated by S. aureus and four by Staphylococcus caprae, coagulase-negative human commensal staphylococci in the RPI group. Using mouse models, both S. caprae and S. aureus, but not Staphylococcus epidermidis, colonized on skin healed from injury at significantly higher rates than normal skin. Although subcutaneous injection of S. caprae did not induce lesion formation, the bacterium exhibited high hemolytic activity on human red blood cells. Lesion formation by subcutaneous injection of S. aureus was significantly suppressed in the presence of S. caprae. The hemolytic activity of rabbit blood cells of S. aureus was suppressed by S. caprae, whereas the hemolytic activity of S. caprae was dramatically suppressed by S. aureus. Data indicated that each of the two Staphylococcus spp. suppresses the pathogenicity of the other and that the imbalance between the two is associated with RPI.

Increased temperature at the healed area detected by thermography predicts recurrent pressure ulcers.

Preventing recurrent pressure ulcers is an important challenge in healthcare. One of the reasons for the high rate of recurrent pressure ulcers is the lack of assessment methods for their early detection. Therefore, this study aimed to determine the thermographic characteristics of the healed area and to consider the predictive validity of thermographic images for recurrent pressure ulcers within a 2-week period. This observational study was conducted at a long-term care facility in Japan between July 2017 and February 2019 among patients whose pressure ulcers had healed. Thermographic images of the healed area were recorded once a week until recurrence or until the end of the study. We enrolled 30 participants, among whom 8 developed recurrent pressure ulcers. The generalised estimation equation revealed that the thermographic finding of increased temperature at the healed area compared to that of the surrounding skin was significantly associated with recurrent pressure ulcers (odds ratio: 101.13, 95% confidence interval: 3.60-2840.77, p = .007); the sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio and negative likelihood ratio for recurrent pressure ulcers within 2 weeks were 0.80, 0.94, 0.62, 0.97, 12.9 and 0.2, respectively. Our thermographic findings revealed that the temperature of the healed area was higher than that of the surrounding skin; this could be a useful predictor of pressure ulcer recurrence within 2 weeks, even in the absence of macroscopic changes.

Regional variation in the development of neonatal hyperbilirubinemia and relation with sunshine duration in Japan: an ecological study.

BACKGROUND: Few studies have investigated the regional variations in the development of neonatal hyperbilirubinemia. This study aimed to investigate regional variations in medical costs for neonatal hyperbilirubinemia and the correlations between sunshine duration and medical care costs for neonatal hyperbilirubinemia in an ecological study, using the National Database of Japan. METHODS: We obtained data on the annual medical costs for neonatal hyperbilirubinemia, annual live births, and annual sunshine duration in each prefecture from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) Open Data, Vital Statistics in Japan, and System of Social and Demographic Statistics Prefectural Data Basic Data from 2014 to 2017. We created choropleth maps showing the regional variations (quartiles) in the annual medical costs for neonatal hyperbilirubinemia per 10 live births and the annual sunshine duration in each prefecture. We used Pearson's correlation coefficients to evaluate the associations between the annual sunshine duration and annual medical care costs for neonatal hyperbilirubinemia per 10 live births in each prefecture. RESULTS: The Tohoku region (on the Sea of Japan side) and the Hokuriku region were likely to have higher medical care costs for neonatal hyperbilirubinemia and shorter sunshine duration than the rest of the country. There were weak and negative correlations between the annual sunshine duration and the annual medical care costs for neonatal hyperbilirubinemia. The correlation coefficients ranged from -0.086 to -0.33. CONCLUSION: There could be regional variations in the medical care costs for neonatal hyperbilirubinemia in Japan. Short sunshine duration could be a prognostic factor for the development of neonatal hyperbilirubinemia.

Routine varicella vaccination program and hospitalization for herpes zoster in Japan.

Whether reducing exposure to varicella by the implementation of the routine varicella vaccination program for children leads to increased incidence of herpes zoster (HZ) remains controversial. The aim of the present study was to identify the trend in the hospitalization associated with HZ before and after the introduction of routine varicella vaccination by using nationally representative data from an inpatient database in Japan. Data were obtained on the number of inpatients hospitalized for HZ from the "Survey on the effect of the introduction of Diagnosis Procedure Combination (DPC) database" and the total population in Japan from the Population Estimates created by the former Statistics Bureau between fiscal years 2013 and 2018. The data from the DPC hospitals only and all hospitals in the survey were analyzed separately. The trends in the annual incidence of HZ hospitalization were identified. The trends in the annual hospitalization for HZ per 100,000 persons were then analyzed by age group (0-20, 21-40, 41-60, 61-79, and ≥80 years of age). The annual number of hospitalizations for HZ was approximately 20,000 in the DPC hospitals and 25,000 in all hospitals, showing no upward trend. The age-specific annual hospitalization rate for HZ did not increase in all the age groups. As age increased, the hospitalization rate also increased. This study presents no upward trend in the hospitalizations for HZ after the implementation of the routine varicella vaccination program in Japan.

Amplicon-based skin microbiome profiles collected by tape stripping with different adhesive film dressings: a comparative study.

BACKGROUND: Medical film dressings have been used to obtain skin microbiota for skin microbiome studies, although their adhesive force may be so strong that the skin could be injured when applied to those who have fragile skin, such as older people. Several products with less adhesive force are available, although their applicability for skin microbiome studies remains unknown. This study aimed to test whether the dressings with less adhesive force could be used for amplicon-based skin microbiome studies. A set of three different film dressings, with acrylic, urethane, or silicone adhesive, was applied to the back skin of nine healthy young participants. The copy number of the 16S ribosomal RNA (rRNA) gene, microbial compositions, and alpha and beta diversity indices were analyzed by amplicon analysis of the 16S rRNA gene using next-generation sequencing and were compared among the three film dressings. RESULTS: The dressing with acrylic adhesive yielded the highest copy number of 16S rRNA genes, followed by that with urethane adhesive. The silicone-adhesive dressing yielded a significantly lower copy number of the 16S rRNA gene. The microbial composition of skin microbiota was similar among the three film dressings, although significant differences in the relative abundance of Pseudomonas species and alpha diversity indices were found in the silicone-adhesive dressing. The Bray-Curtis dissimilarity was significantly higher between the acrylic- and silicone-adhesive dressings than between the acrylic- and urethane-adhesive dressings. No adverse effects related to tape stripping were observed for any of the film dressings. CONCLUSION: We recommend dressings with acrylic or urethane adhesive for amplicon-based skin microbiome studies. An acrylic adhesive has an advantage in the yield of skin microbiota, and a urethane adhesive should be chosen when applied to fragile skin. The adhesive force of the dressing with silicone adhesive was too weak to be used for collecting skin microbiota.

Skin Physiology and its Microbiome as Factors Associated with the Recurrence of Pressure Injuries.

BACKGROUND: Preventing recurrent pressure injuries (RPIs) is one of the important challenges faced in healthcare, but the risk factors of RPIs have not been fully revealed. This study aims to explore factors associated with RPIs, by focusing on skin physiology and its microbiome as local factors crucial for the health of healed tissue after pressure injury healing. METHODS: This prospective observational study was conducted in a long-term care facility in Japan with patients whose PIs had healed within 1 month. Skin physiology was evaluated by stratum corneum (SC) hydration, pH, and transepidermal water loss. Skin bacteria was collected by tape stripping, followed by 16S ribosomal RNA-based metagenomics analysis. These parameters were evaluated every two weeks over a period of six weeks. RESULTS: A total of 30 patients were included in this study, and 8 patients (26.7%) had an RPI within 6 weeks. In this study, significantly lower SC hydration and a higher rate of Staphylococcus species on the healed site were found in the RPI group. DISCUSSION: A high rate of RPIs (about one in four) points out the necessity of a further care strategy on the healed PIs. Lower skin hydration and/or the increase in Staphylococcus bacteria may have a potential to be used as a biomarker for the prediction of RPIs, or may be an intervention point for the prevention of RPIs by, for example, skin cleansing with moisturizing care.

Comparison of Machine Learning Models for Prediction of Initial Intravenous Immunoglobulin Resistance in Children With Kawasaki Disease.

We constructed an optimal machine learning (ML) method for predicting intravenous immunoglobulin (IVIG) resistance in children with Kawasaki disease (KD) using commonly available clinical and laboratory variables. We retrospectively collected 98 clinical records of hospitalized children with KD (2-109 months of age). We found that 20 (20%) children were resistant to initial IVIG therapy. We trained three ML techniques, including logistic regression, linear support vector machine, and eXtreme gradient boosting with 10 variables against IVIG resistance. Moreover, we estimated the predictive performance based on nested 5-fold cross-validation (CV). We also selected variables using the recursive feature elimination method and performed the nested 5-fold CV with selected variables in a similar manner. We compared ML models with the existing system regardless of their predictive performance. Results of the area under the receiver operator characteristic curve were in the range of 0.58-0.60 in the all-variable model and 0.60-0.75 in the select model. The specificities were more than 0.90 and higher than those in existing scoring systems, but the sensitivities were lower. Three ML models based on demographics and routine laboratory variables did not provide reliable performance. This is possibly the first study that has attempted to establish a better predictive model. Additional biomarkers are probably needed to generate an effective prediction model.

Seawater transfer down-regulates C-type natriuretic peptide-3 expression in prolactin-producing cells of Japanese eel: Negative correlation with plasma chloride concentration.

In euryhaline fishes, atrial and B-type natriuretic peptides are important hormones in hypo-osmoregulation, whereas osmoregulatory functions of C-type natriuretic peptides (CNPs) remain to be investigated. Although four CNP isoforms (CNP1-4) are mainly expressed in the brain, multiorgan expression of CNP3 was found in euryhaline Japanese eel, Anguilla japonica. Here we identified the CNP3-expressing cells and examined their response to osmotic stress in eel. CNP3 was expressed in several endocrine cells: prolactin-producing cells (pituitary), glucagon-producing cells (pancreas), and cardiomyocytes (heart). Pituitary CNP3 expression was the highest among organs and was decreased following seawater transfer, followed by a decrease in the freshwater-adaptating (hyper-osmoregulatory) hormone prolactin. We also showed the negative correlation between CNP3/prolactin expression in the pituitary and plasma Cl- concentration, but not for plasma Na+ concentration. These results suggest that CNP3 in the pituitary (and pancreas) plays a critical role in freshwater adaptation of euryhaline eel together with prolactin.

Half-life of Fructosyl-valine in the Plasma of Chicks.

Eighty 14-d-old single-comb White Leghorn male chicks were divided into 16 groups with five birds each. Fructosyl-valine, which is a valine-glucose-Amadori product, was intravenously (2,250 nmol/kg body weight) or orally (300 µmol/kg body weight) administered to chicks. Blood samples were collected 15, 30, 60, 120, 180, 360, 720 and 1440 min after administration. Plasma concentrations of fructosyl-valine were measured by using a liquid chromatography / mass spectrometry (LC/MS). The time course change in plasma fructosyl-valine concentration showed an exponential curve, as y=a+be-λt. The half-life of plasma fructosyl-valine was calculated by the following equation: (loge2)/λ. When fructosyl-valine was injected intravenously, the highest value for plasma fructosyl-valine concentration was observed 15 min after administration. When injected intravenously, the half-life of plasma fructosyl-valine was calculated to be 231 min. When fructosyl-valine was administered orally to chicks, the highest value for plasma fructosyl-valine concentration was observed 180 min after administration. When administered orally, the half-life of plasma fructosyl-valine was calculated to be 277 min. We conclude that the half-life of fructosyl-valine in plasma was approximately 4 h, which is longer than that of glycated tryptophan.

Analysis of Tertiary Structural Features of Branched DNA Nanostructures with Partially Common Sequences Using Small-Angle X-ray Scattering.

We demonstrated that polypod-like structured DNA, composed of 3-8 kinds of oligodeoxynucleotides (ODNs), exhibit accelerated cellular uptake depending on their structural properties. The biological activities, including immunostimulation and unwanted adverse effects of ODNs depend on their sequences. Therefore, as the number of different types of ODNs within a polypod-like structured DNA increases, the possible risks and concerns regarding its future clinical applications also increase. To minimize this risk and to explore the relationship between structural properties and cellular uptake, we designed Tet(id12), a tetrapod-like structured DNA with 12 identical palindrome sequences in the center of ODNs, and compared it with other tetrapod-like structures without palindrome sequences, symmetric Tet(sym) and asymmetric Tet(asym12). The thermal stability analysis of Tet(id12) revealed a two-step dissociation process. Polyacrylamide gel electrophoresis, small-angle X-ray scattering profile, and the Guinier plot also revealed that the conformation of Tet(id12) was close to that of Tet(sym). No significant differences were observed between Tet(id12) and others in terms of cellular uptake. These results indicate that ODNs with palindrome sequences can be used to design polypod-like structured DNAs without significant changes to their physicochemical and biological properties, although their thermal stability is somewhat different from the ones without palindrome sequences.

A Rapid Cytologic Double Staining of Epstein-Barr Virus-encoded Small RNA and Cell Surface Markers for Diagnosis of Epstein-Barr Virus-associated Hemophagocytic Lymphohistiocytosis.

A 3-year-old boy was clinically diagnosed with Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis. We identified EBV-infected CD8-positive T-lymphocytes by cytologic double staining of the peripheral blood for EBV-encoded small RNA and cell surface markers. The patient was subsequently administered immunosuppressive therapy with a reduced dose of etoposide because of previous organ damage. EBV clearance was confirmed by serial quantification of cell-fractionated EBV-DNA, whereas EBV-DNA persisted in the plasma for 18 weeks. Immunochemotherapy with low-dose etoposide combined with serial viral load monitoring is a potential therapeutic option for severe EBV-hemophagocytic lymphohistiocytosis cases with organ damage.

Effect of Intensive and Standard Pitavastatin Treatment With or Without Eicosapentaenoic Acid on Progression of Coronary Artery Calcification Over 12 Months　- Prospective Multicenter Study.

BACKGROUND: The effect of lipid-lowering agents on progression of coronary artery calcification (CAC) remains unclear. We evaluated the effects of pitavastatin 2 mg/day (PIT2), pitavastatin 4 mg/day (PIT4), and PIT2 combined with eicosapentaenoic acid (PIT2+EPA) on CAC progression.Methods and Results:This prospective multicenter study in Japan included patients with an Agatston score of 1-999, hypercholesterolemia, and no evidence of cardiovascular disease. Patients were allocated into PIT2, PIT4, or PIT2+EPA groups. The primary outcome was the annual percent change in Agatston score in all patients. In total, 156 patients who had multi-detector row computed tomography without any artifacts were included in the primary analysis. Pitavastatin did not significantly reduce the annual progression rate of the Agatston score (40%; 95% CI: 19-61%). The annual progression rate of Agatston score in the PIT2 group was not significantly different from that in the PIT4 group (34% vs. 42%, respectively; P=0.88) or the PIT2+EPA group (34% vs. 44%, respectively; P=0.80). On post-hoc analysis the baseline ratio of low- to high-density lipoprotein cholesterol was a significant predictor of non-progression of Agatston score by pitavastatin (OR, 2.17; 95% CI: 1.10-44.12; P=0.02). CONCLUSIONS: Pitavastatin does not attenuate progression of CAC. Intensive pitavastatin treatment and standard treatment with EPA does not reduce progression of CAC compared with standard treatment.

Simple Stokes polarimeter using a liquid crystal grating with ternary orientation domains.

We propose a liquid crystal (LC) grating with a ternary orientation domain for application to optical polarization measurements. The ternary orientation domain, which generates two-dimensional diffraction properties, is the key to simultaneous acquisition of multiple of polarization parameters. The LC molecular orientation state and the polarization dependence of the diffraction efficiency were investigated experimentally, focusing on the applicability to a practical Stokes polarimeter. An experiment was conducted using the proposed LC grating as a Stokes polarimeter, and the four Stokes parameters (S0, S1, S2, and S3) were determined for linearly and circularly polarized incident light. As a result, the feasibility of the proposed LC grating Stokes polarimeter has been demonstrated experimentally. Finally, the operational performance of the proposed LC grating Stokes polarimeter is discussed using a figure of merit that is numerically derived from the measured polarization dependence of the diffracted light intensity.

Optical properties of a dichroic dye-doped liquid-crystal grating and its application to optical rotation measurement.

The diffraction properties of a twisted nematic liquid-crystal (TN-LC) grating, in which a dichroic dye was doped, were investigated experimentally in terms of the applicability to an optical system for determining the polarization angle of incident linearly polarized light. The main reason to dope a nematic LC material with a dichroic dye was to enhance the polarization dependence of the diffracted light intensities for the positive and negative first orders. We found the best values of the applied voltage for application in polarization angle measurement. The TN-LC grating with a high polarization sensibility was applied to the optical system for measuring the concentration of an optically active component in a liquid specimen. As a result, the applicability of the proposed optical system was revealed experimentally. Furthermore, the cause of the random measurement error is discussed briefly.

Effect of remote ischemia or nicorandil on myocardial injury following percutaneous coronary intervention in patients with stable coronary artery disease: A randomized controlled trial.

BACKGROUND: The effect of remote ischemic preconditioning (RIPC) and nicorandil on periprocedural myocardial injury (pMI) in patients with planned percutaneous coronary intervention (PCI) remains controversial. The aim of this randomized trial was to evaluate the effect of RIPC or nicorandil on pMI following PCI in patients with stable coronary artery disease (CAD) compared with a control group. METHODS: Patients with stable CAD who planned to undergo PCI were assigned to a 1:1:1 ratio to control, RIPC, or intravenous nicorandil (6mg/h). Automated RIPC was performed by a device, which performs intermittent arm ischemia through three cycles of 5min of inflation and 5min of deflation of a pressure cuff. The primary outcome was the incidence of pMI, determined by an elevation in high-sensitive troponin T or creatine kinase myocardial band at 12 or 24h after PCI. The secondary outcomes were ischemic events during PCI and adverse clinical events at 8months after PCI. RESULTS: A total of 391 patients were enrolled. The incidence of pMI following PCI was not significantly different between the control group (48.9%) and RIPC group (39.5%; p=0.14), or between the control group and nicorandil group (40.3%; p=0.17). There were no significant differences in ischemic events during PCI or adverse clinical events within 8months after PCI among the three groups. CONCLUSIONS: This study demonstrated moderate reductions in biomarker release and pMI by RIPC or intravenous nicorandil prior to the PCI consistently, but may have failed to achieve statistical significance because the study was underpowered.