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Patients with asplenia are at high risks of severe infections caused by encapsulated bacteria, particularly Streptococcus pneumoniae . Thirteen-valent pneumococcal conjugate vaccine (PCV13) and 23-valent pneumococcal polysaccharide vaccine (PPSV23) are recommended for invasive pneumococcal disease prevention; however, little is known about the immunity to pneumococci in young patients with asplenia. We measured pneumococcal serotype-specific IgG (Pn-IgG) levels and pneumococcal opsonophagocytic activity (Pn-OPA) against some PCV13-contained serotypes (1, 3, 5, 6A, 7 F, 19A) in 23 young patients with asplenia using surplus serum samples. In this study, 5 and 13 patients had received PCV13 during routine immunizations and PPSV23, respectively; however, >5 years had passed since the last dose in most cases. The geometric mean concentrations (GMCs) of Pn-IgG in all study patients were not under the cutoff level against six serotypes, but they were lower than the those of age-matched healthy controls, as we have previously published. The patients who had received only PPSV23 had significantly lower GMCs against four serotypes (serotypes 1, 6A, 7 F, and 19A) than that of the patients who had received at least one PCV13 vaccination. The patients who had received only PPSV23 also had significantly lower geometric mean titers (GMTs) of Pn-OPA against all three serotypes we measured (serotypes 3, 5, and 19A) than that of the patients who had received at least one PCV13 vaccination. Our findings are useful data that can indicate insufficient immunity in young patients with asplenia against some PCV13 pneumococci serotypes and suggest the need for appropriate vaccinations in the post-PCV13 era.

Atopic dermatitis (AD) mostly develops in early childhood and tends to resolve with age. However, its time course in severity before and after adolescence varies widely among patients. To investigate the course of disease severity from birth to 19 years old of adult patients with AD, we conducted a nationwide Web-based survey of 3090 Japanese adult subjects diagnosed with AD, using a questionnaire to choose a pattern that most resembled their own out of 10 courses of AD severity. Patients in the 20s and 30s age groups tended to choose the option "gradually improved" or "improved by the age of 12", but patients in the 40s or older age group tended to choose the option "aggravation between the age of 12 and 19". Those who chose "AD development at age 20 or older" increased as the generation was older. This survey revealed that the time course of AD severity from birth to 19 years old varies depending on the generation targeted in this study. It is presumed that the acquired factors affecting the natural history of AD have changed over the past 50 years in Japan., (© 2021 Japanese Dermatological Association.)

Background: Previous studies have demonstrated that delayed antibiotic administration increases the risk of mortality in patients with sepsis., Local Problem: In the emergency department, the antibiotic administration rate within 1 and 3 hours for patients with suspected sepsis was low., Methods/interventions: We implemented an educational intervention with the nursing staff, which included training sessions and feedback, to ensure early detection and management of patients with suspected sepsis. Antibiotic administration rates were compared before and after education., Results: A total of 503 patients were included. The antibiotic administration rate improved as the phases continued (1 hour: from 5.2% to 15.6%, P = .004; 3 hours: from 35.6% to 49.7%, P = .04; 6 hours: from 74.1% to 89.1%, P = .002). The time to initial antibiotic administration also improved from 229 to 185 minutes (P < .001)., Conclusions: Nurse-initiated quality improvement improved the early administration of antibiotics for patients with suspected sepsis., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Maternal tobacco smoke exposure during pregnancy impairs fetal body size, including head circumference (HC) at birth; however, the mechanism still remains unclear. This analysis using a large prospective cohort study evaluated the impact of maternal tobacco exposure on their offspring's HC and the relationship with placental weight ratio (PWR) and placental abnormalities. Parents-children pairs (n = 84,856) were included from the 104,065 records of the Japan Environmental and Children's Study. Maternal perinatal clinical and social information by self-administered questionnaires, offspring's body size, and placental information were collected. Data were analyzed with binominal logistic regression analysis and path analysis. Logistic regression showed significantly elevated adjusted odds ratio (aOR) (1.653, 95% CI 1.387-1.969) for the impact of maternal smoking during pregnancy on their offspring's smaller HC at birth. Maternal exposure to environmental tobacco smoke in the non-smoking group did not increase aOR for the smaller HC. Path analysis showed that maternal smoking during pregnancy decreased the offspring's HC directly, but not indirectly via PWR or placental abnormalities. The quitting smoking during pregnancy group did not increase aOR for the smaller HC than the non-smoking group, suggesting that quitting smoking may reduce their offspring's neurological impairment even after pregnancy., (© 2021. The Author(s).)

Chemokine (C-C motif) ligand 17 (CCL17) is a pro-allergic factor: high CCL17 levels in cord blood (CB) precede later allergic predisposition. Short-chain fatty acid (SCFA) treatment during pregnancy has been shown to protect mouse pups against allergic diseases. The maternal microbial metabolome during pregnancy may affect fetal allergic immune responses. We therefore examined the associations between CB CCL17 and gut SCFA levels in healthy pregnant Japanese women. CB CCL17 serum levels at birth, and maternal non-specific IgE levels in maternal sera at 32 weeks of gestation were measured. Maternal stool samples were collected at 12 ( n = 59) and 32 ( n = 58) weeks of gestation for gut microbiota analysis, based on barcoded 16S rRNA sequencing and metabolite levels. The CB CCL17 levels correlated negatively with butyrate concentrations and positively with isobutyrate at 12 weeks; CB CCL17 correlated positively with valerate and lactate at 32 weeks. Similarly, butyrate levels correlated negatively with maternal non-specific IgE levels, whereas the lactate concentration correlated positively with IgE levels. At 32 weeks, the Shannon diversity index (SDI) of Firmicutes and Proteobacteria correlated negatively with CB CCL17 levels, while those of the total microbiota correlated positively with the CB CCL17 levels. These metabolites may alter fetal immune responses. This study provides the first link between maternal metabolites during pregnancy and the risk of allergic diseases in human offspring.

In the present study, we report a human-inherited, impaired, adaptive immunity disorder, which predominantly manifested as a B cell differentiation defect, caused by a heterozygous IKZF3 missense variant, resulting in a glycine-to-arginine replacement within the DNA-binding domain of the encoded AIOLOS protein. Using mice that bear the corresponding variant and recapitulate the B and T cell phenotypes, we show that the mutant AIOLOS homodimers and AIOLOS-IKAROS heterodimers did not bind the canonical AIOLOS-IKAROS DNA sequence. In addition, homodimers and heterodimers containing one mutant AIOLOS bound to genomic regions lacking both canonical motifs. However, the removal of the dimerization capacity from mutant AIOLOS restored B cell development. Hence, the adaptive immunity defect is caused by the AIOLOS variant hijacking IKAROS function. Heterodimeric interference is a new mechanism of autosomal dominance that causes inborn errors of immunity by impairing protein function via the mutation of its heterodimeric partner.

Breastfeeding influences the immune system development in infants and may even affect various immunological responses later in life. Breast milk provides a rich source of early nutrition for infant growth and development. However, the presence of certain compounds in breast milk, related to an unhealthy lifestyle or the diet of lactating mothers, may negatively impact infants. Based on a cohort study of atopic dermatitis (AD), we find the presence of damage-associated molecular patterns (DAMPs) activity in the mother's milk. By non-targeted metabolomic analysis, we identify the long-chain saturated fatty acids (LCSFA) as a biomarker DAMPs (+) breast milk samples. Similarly, a mouse model in which breastfed offspring are fed milk high in LCSFA show AD onset later in life. We prove that LCSFA are a type of damage-associated molecular patterns, which initiate a series of inflammatory events in the gut involving type 3 innate lymphoid cells (ILC3s). A remarkable increase in inflammatory ILC3s is observed in the gut, and the migration of these ILC3s to the skin may be potential triggers of AD. Gene expression analysis of ILC3s isolated from the gut reveal upregulation of genes that increase ILC3s and chemokines/chemokine receptors, which may play a role in ILC migration to the skin. Even in the absence of adaptive immunity, Rag1 knockout mice fed a high-LCSFA milk diet develop eczema, accompanied by increased gut ILC3s. We also present that gut microbiota of AD-prone PA milk-fed mice is different from non-AD OA/ND milk-fed mice. Here, we propose that early exposure to LCSFAs in infants may affect the balance of intestinal innate immunity, inducing a highly inflammatory environment with the proliferation of ILC3s and production of interleukin-17 and interleukin-22, these factors may be potential triggers or worsening factors of AD.

Aim: During chest compressions (CCs), the hand position at the lower half of the sternum is not strictly maintained, unlike depth or rate. This study was conducted to determine whether medical staff could adequately push at a marked location on the lower half of the sternum, identify where the inappropriate hand position was shifted to, and correct the inappropriate hand position., Methods: This simulation-based, prospective single-center study enrolled 44 medical personnel. Pressure and hand position during CC were ascertained using a flexible pressure sensor. The participants were divided into four groups by standing position and the hand in contact with the sternum: right-left (R- l ), right-right (R- r ), left-right (L- r ), and left-left (L- l ). We compared the groups and the methods: the manual method (MM), the thenar method, and the hypothenar method (HM)., Results: Among participants using the MM, 80% did not push adequately at the marked location on the lower half of the sternum; 60%-90% of the inadequate positions were shifted to the hypothenar side. CCs with the HM facilitated stronger pressure, and the position was minimally shifted to the hypothenar side., Conclusion: Medical staff could not push at an appropriate position during CCs. Resuscitation courses should be designed to educate personnel on the appropriate position for application of maximal pressure while also evaluating the position during CCs., Competing Interests: Approval of Research Protocol: The Ethics Committee of the University of Tsukuba Hospital, Japan (H30‐355). Informed consent: All participants provided written informed consent. Registry and the registration no. of the study/trial: N/A. Animal studies: N/A. Conflict of interest: None declared., (© 2021 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

Suvorexant is a novel hypnotic that acts as an orexin-1 receptor and orexin-2 receptor antagonist. Owing to its safety and tolerability, suvorexant has recently become widely used. However, little is known about the presentation of suvorexant poisoning. Here, we describe an 83-year-old man with cirrhosis and renal failure, who had taken 270 mg of suvorexant at the same time. After the overdose, he did not develop any symptoms other than prolonged drowsiness. He was successfully treated with supportive therapy alone. This is the first report describing suvorexant poisoning. Further reports should be accumulated to determine whether patients with suvorexant poisoning present with mild symptoms without intensive treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Ito et al.)

The effects of beta-hydroxy-beta-methylbutyrate (HMB) complex administration and the significance of titin, a biomarker of muscle injury, in elderly minor trauma patients in acute phase has not been established. In this single-center, randomized controlled study, trauma patients aged ≥ 70 years with an injury severity score < 16 were included. Titin values on days 1 and 3 were measured and the intervention group received HMB complex (2.4 g of HMB + 14 g of glutamine + 14 g of arginine) and the control group received glutamine complex (7.2 g of protein including 6 g of glutamine). The cross-sectional area of the rectus femoris (RFCSA) on ultrasound, grip strength, and the Barthel Index were assessed on the first day of rehabilitation and after 2 weeks. We analyzed 24 HMB and 25 control participants. Titin values on day 3 correlated with grip strength ( r = -0.34, p = 0.03) and the Barthel Index ( r = -0.39, p = 0.01) at follow-up. HMB complex supplementation had no effect on the RFCSA (2.41 vs. 2.45 cm 2 , p = 0.887), grip strength (13.3 vs. 13.1 kg, p = 0.946), or the Barthel Index (20.0 vs. 50.0, p = 0.404) at follow-up. Titin values might associate with subsequent physical function. Short-term HMB complex supplementation from acute phase did not ameliorate muscle injury.

Since December 2019, the SARS-CoV-2 (COVID-19) pandemic has transfixed the medical world. COVID-19 symptoms vary from mild to severe and underlying chronic conditions such as pulmonary/cardiovascular disease and diabetes induce excessive inflammatory responses to COVID-19 and these underlying chronic diseases are mediated by endothelial dysfunction. Acute respiratory distress syndrome (ARDS) is the most common cause of death in COVID-19 patients, but coagulation induced by excessive inflammation, thrombosis, and disseminated intravascular coagulation (DIC) also induce death by multiple-organ dysfunction syndrome. These associations imply that maintaining endothelial integrity is crucial for favorable prognoses with COVID-19 and therapeutic intervention to support this may be beneficial. Here, we summarize the extent of heart injuries, ischemic stroke and hemorrhage, acute kidney injury, and liver injury caused by immune-mediated endothelial dysfunction that result in the phenomenon of multi-organ dysfunction seen in COVID-19 patients. Moreover, the potential therapeutic effect of angiotensin receptor blockers and angiotensin-converting enzyme inhibitors that improve endothelial dysfunction as well as the bradykinin storm are discussed.

Objective: Eczema and food allergy start in infancy and have shared genetic risk factors that affect skin barrier. We aimed to evaluate whether skincare interventions can prevent eczema or food allergy., Design: A prospectively planned individual participant data meta-analysis was carried out within a Cochrane systematic review to determine whether skincare interventions in term infants prevent eczema or food allergy., Data Sources: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries to July 2020., Eligibility Criteria for Selected Studies: Included studies were randomized controlled trials of infants <1 year with healthy skin comparing a skin intervention with a control, for prevention of eczema and food allergy outcomes between 1 and 3 years., Results: Of the 33 identified trials, 17 trials (5823 participants) had relevant outcome data and 10 (5154 participants) contributed to IPD meta-analysis. Three of seven trials contributing to primary eczema analysis were at low risk of bias, and the single trial contributing to primary food allergy analysis was at high risk of bias. Interventions were mainly emollients, applied for the first 3-12 months. Skincare interventions probably do not change risk of eczema by age 1-3 years (RR 1.03, 95% CI 0.81, 1.31; I 2 =41%; moderate certainty; 3075 participants, 7 trials). Sensitivity analysis found heterogeneity was explained by increased eczema in a trial of daily bathing as part of the intervention. It is unclear whether skincare interventions increase risk of food allergy by age 1-3 years (RR 2.53, 95% CI 0.99 to 6.47; very low certainty; 996 participants, 1 trial), but they probably increase risk of local skin infections (RR 1.34, 95% CI 1.02, 1.77; I 2 =0%; moderate certainty; 2728 participants, 6 trials)., Conclusion: Regular emollients during infancy probably do not prevent eczema and probably increase local skin infections., (© 2021 John Wiley & Sons Ltd.)

Background: Eczema and food allergy are common health conditions that usually begin in early childhood and often occur together in the same people. They can be associated with an impaired skin barrier in early infancy. It is unclear whether trying to prevent or reverse an impaired skin barrier soon after birth is effective in preventing eczema or food allergy., Objectives: Primary objective To assess effects of skin care interventions, such as emollients, for primary prevention of eczema and food allergy in infants Secondary objective To identify features of study populations such as age, hereditary risk, and adherence to interventions that are associated with the greatest treatment benefit or harm for both eczema and food allergy., Search Methods: We searched the following databases up to July 2020: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. We searched two trials registers and checked reference lists of included studies and relevant systematic reviews for further references to relevant randomised controlled trials (RCTs). We contacted field experts to identify planned trials and to seek information about unpublished or incomplete trials., Selection Criteria: RCTs of skin care interventions that could potentially enhance skin barrier function, reduce dryness, or reduce subclinical inflammation in healthy term (> 37 weeks) infants (0 to 12 months) without pre-existing diagnosis of eczema, food allergy, or other skin condition were included. Comparison was standard care in the locality or no treatment. Types of skin care interventions included moisturisers/emollients; bathing products; advice regarding reducing soap exposure and bathing frequency; and use of water softeners. No minimum follow-up was required., Data Collection and Analysis: This is a prospective individual participant data (IPD) meta-analysis. We used standard Cochrane methodological procedures, and primary analyses used the IPD dataset. Primary outcomes were cumulative incidence of eczema and cumulative incidence of immunoglobulin (Ig)E-mediated food allergy by one to three years, both measured by the closest available time point to two years. Secondary outcomes included adverse events during the intervention period; eczema severity (clinician-assessed); parent report of eczema severity; time to onset of eczema; parent report of immediate food allergy; and allergic sensitisation to food or inhalant allergen., Main Results: This review identified 33 RCTs, comprising 25,827 participants. A total of 17 studies, randomising 5823 participants, reported information on one or more outcomes specified in this review. Eleven studies randomising 5217 participants, with 10 of these studies providing IPD, were included in one or more meta-analysis (range 2 to 9 studies per individual meta-analysis). Most studies were conducted at children's hospitals. All interventions were compared against no skin care intervention or local standard care. Of the 17 studies that reported our outcomes, 13 assessed emollients. Twenty-five studies, including all those contributing data to meta-analyses, randomised newborns up to age three weeks to receive a skin care intervention or standard infant skin care. Eight of the 11 studies contributing to meta-analyses recruited infants at high risk of developing eczema or food allergy, although definition of high risk varied between studies. Durations of intervention and follow-up ranged from 24 hours to two years. We assessed most of this review's evidence as low certainty or had some concerns of risk of bias. A rating of some concerns was most often due to lack of blinding of outcome assessors or significant missing data, which could have impacted outcome measurement but was judged unlikely to have done so. Evidence for the primary food allergy outcome was rated as high risk of bias due to inclusion of only one trial where findings varied when different assumptions were made about missing data. Skin care interventions during infancy probably do not change risk of eczema by one to two years of age (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.81 to 1.31; moderate-certainty evidence; 3075 participants, 7 trials) nor time to onset of eczema (hazard ratio 0.86, 95% CI 0.65 to 1.14; moderate-certainty evidence; 3349 participants, 9 trials). It is unclear whether skin care interventions during infancy change risk of IgE-mediated food allergy by one to two years of age (RR 2.53, 95% CI 0.99 to 6.47; 996 participants, 1 trial) or allergic sensitisation to a food allergen at age one to two years (RR 0.86, 95% CI 0.28 to 2.69; 1055 participants, 2 trials) due to very low-certainty evidence for these outcomes. Skin care interventions during infancy may slightly increase risk of parent report of immediate reaction to a common food allergen at two years (RR 1.27, 95% CI 1.00 to 1.61; low-certainty evidence; 1171 participants, 1 trial). However, this was only seen for cow's milk, and may be unreliable due to significant over-reporting of cow's milk allergy in infants. Skin care interventions during infancy probably increase risk of skin infection over the intervention period (RR 1.34, 95% CI 1.02 to 1.77; moderate-certainty evidence; 2728 participants, 6 trials) and may increase risk of infant slippage over the intervention period (RR 1.42, 95% CI 0.67 to 2.99; low-certainty evidence; 2538 participants, 4 trials) or stinging/allergic reactions to moisturisers (RR 2.24, 95% 0.67 to 7.43; low-certainty evidence; 343 participants, 4 trials), although confidence intervals for slippages and stinging/allergic reactions are wide and include the possibility of no effect or reduced risk. Preplanned subgroup analyses show that effects of interventions were not influenced by age, duration of intervention, hereditary risk, FLG mutation,  or classification of intervention type for risk of developing eczema. We could not evaluate these effects on risk of food allergy. Evidence was insufficient to show whether adherence to interventions influenced the relationship between skin care interventions and risk of developing eczema or food allergy., Authors' Conclusions: Skin care interventions such as emollients during the first year of life in healthy infants are probably not effective for preventing eczema, and probably increase risk of skin infection. Effects of skin care interventions on risk of food allergy are uncertain. Further work is needed to understand whether different approaches to infant skin care might promote or prevent eczema and to evaluate effects on food allergy based on robust outcome assessments., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Introduction: The functional role of milk for the developing neonate is an area of great interest, and a significant amount of research has been done. However, a lot of work remains to fully understand the complexities of milk, and the variations imposed through genetics. It has previously been shown that both secretor (Se) and Lewis blood type (Le) status impacts the human milk oligosaccharide (HMO) content of human milk. While some studies have compared the non-HMO milk metabolome of Se+ and Se- women, none have reported on the non-HMO milk metabolome of Se- and Le- mothers. Method and Results: To determine the differences in the non-HMO milk metabolome between Se-Le- mothers and other HMO phenotypes (Se+Le+, Se+Le-, and Se-Le+), 10 milk samples from 10 lactating mothers were analyzed using nuclear magnetic resonance (NMR) spectroscopy. Se or Le HMO phenotypes were assigned based on the presence and absence of 6 HMOs generated by the Se and Le genes. After classification, 58 milk metabolites were compared among the HMO phenotypes. Principal component analysis (PCA) identified clear separation between Se-Le- milk and the other milks. Fold change analysis demonstrated that the Se-Le- milk had major differences in free fatty acids, free amino acids, and metabolites related to energy metabolism. Conclusion: The results of this brief research report suggest that the milk metabolome of mothers with the Se-Le- phenotype differs in its non-HMO metabolite composition from mothers with other HMO phenotypes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Koleva, du Toit, Geddes, Munblit, Prescott, Eggesbø, Johnson, Wegienka, Shimojo, Campbell, Kozyrskyj and Slupsky.)

Background: Nevoid basal cell carcinoma syndrome (NBCCS) is a neurocutaneous disease, characterized by tumorigenesis and developmental anomalies due to aberrant sonic hedgehog (Shh) signaling. Patients with NBCCS typically appear calm and carefree, suggesting that a specific personality in these patients may be associated with an enhanced hedgehog pathway. Our study aimed to determine the personality type in these patients., Methods: We enrolled 14 mentally normal patients with genetically confirmed NBCCS (seven males and seven females; mean age = 25.2 years) and 20 controls (10 males and 10 females; mean age = 27.9 years). The patients were assessed with the Japanese version of the Temperament and Character Inventory, based on the seven-dimensional model of temperament and character, and their clinical symptoms were evaluated. The amygdala volumes of six patients with NBCCS were measured using magnetic resonance imaging with image-processing software., Results: Patients with NBCCS scored significantly lower on harm avoidance (0.89) than controls (1.00; P = 0.0084). Moreover, patients with NBCCS and developmental malformations such as rib anomalies, who may have experienced Shh signaling enhancement from the prenatal period, scored significantly lower on harm avoidance (0.80 [P = 0.0031]). The left amygdala volume was also significantly reduced in patients with NBCCS (P = 0.0426)., Conclusions: Patients with NBCCS who experienced increased Shh signaling from the prenatal period showed significantly lower harm avoidance related to serotonin. The left amygdala volume was significantly reduced in these patients. Our results indicate that Shh signaling may influence the human personality., (© 2020 Japan Pediatric Society.)

Chronic pancreatitis is a pancreatic inflammation that can result in endocrine pancreatic insufficiency. We present a case of starvation ketoacidosis in a 44-year-old Japanese man with chronic alcoholic pancreatitis. On admission, he exhibited hypoglycemia and severe acidosis. Intravenous glucose and vitamin B1 were administered in the emergency department, and nutritional management for presumed starvation ketoacidosis was begun. Because the patient did not have diabetes mellitus, his insulin secretion and insulin resistance were examined. A diagnosis of pancreatic diabetes caused by chronic pancreatitis was made based on decreased insulin secretion, normal insulin resistance, and negative anti-glutamic acid decarboxylase antibody. Intensive insulin therapy was initiated, and he was discharged 15 days after hospitalization. Although starvation rarely causes hypoglycemia and severe ketoacidosis, they can be induced by short-term fasting in patients with decreased pancreatic function., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Kakurai et al.)

Biotin is a water-soluble B complex vitamin and coenzyme of five types of carboxylase and plays crucial roles in fatty acid, glucose, and amino acid metabolism. Nutritional biotin deficiency and defective enzymes essential for biotin metabolism cause inflammatory diseases such as eczema-like dermatitis and Crohn's disease; however, little is known about the pathophysiological roles of biotin. This study investigated the relationship between biotin metabolism and human allergic sensitization and diseases by measuring serum levels of biotin, total immunoglobulin E (IgE) and allergen-specific IgEs in more than 400 Japanese schoolchildren aged 6 to 12. The prevalence of allergic diseases, and environmental and life-style factors were also examined by a questionnaire. Like total IgE, serum biotin levels of children showed a log-normal distribution. Meanwhile, Spearman's rank correlation analysis showed weak but significant positive associations between serum biotin levels and total IgE (rho=0.147, p=0.0029) as well as allergen-specific IgEs against egg whites (rho=0.215, p=0.00013), cedar pollen (rho=0.176, p=0.00036), and cat dander (rho=0.130, p=0.0085). Furthermore, mean serum biotin levels in children with cedar pollinosis, but not with other allergic diseases such as asthma and allergic rhinitis, were significantly higher than in those without (p=0.0015). These results suggest a correlation between serum biotin levels and the development of cedar pollinosis. Further prospective studies are needed to evaluate the causal relationship between biotin metabolism and cedar pollen sensitization and pollinosis development.

Bifidobacterium bifidum OLB6378 (OLB6378) was selected as a strain that enhances the production of secretory immunoglobulin A (IgA) in vitro . This ability of non-live OLB6378 has been shown by a clinical trial in preterm infants. In the present study, we examined whether non-live OLB6378 also enhances the production of secretory IgA, even in full-term infants. One hundred full-term infants were allocated to receive formula with (BbF group, 49 infants) or without non-live OLB6378 (PF group, 51 infants). Breastfeeding was prioritised, so infant formula was used for infants with breastfeeding difficulties. The intervention was initiated by five days of age. The faecal IgA concentration and OLB6378 level were determined at one, two, four, and eight weeks of age. Faecal IgA in the BbF group (1.04 ± 0.47 mg/g of faeces, n=45) was significantly higher than that in the PF group (0.85 ± 0.42 mg/g of faeces, n=49) at four weeks of age (p=0.047). OLB6378 was not detected in faeces at any age. This indicated that production of secretory IgA in full-term infants may also be enhanced by non-live OLB6378 intake., (©2021 BMFH Press.)

SOX11 is a transcription factor in the SOX family of genes that regulate multiple cellular events by influencing the expression of key genes in developmental, physiological, and tumorigenic cells. To elucidate the role of SOX11 in prostate cancer cells, PC-3 prostate cancer cells were cloned (S6 and S9 cells) to highly express SOX11. We demonstrated that both S6 and S9 lose vimentin expression, acquiring epithelial marker proteins, which indicates the Epithelial state phenotype. S6 and S9 cells have cancer-promoting characteristics that include higher migratory properties compared with control cells. The mechanisms that are responsible for the enhanced migration are cofilin activity and keratin 18 expression. TCGA (The Cancer Genome Atlas) dataset analysis revealed that metastatic prostate cancer tumors tend to have more SOX11 gene amplification compared with primary tumors. These results suggest the tumor promotive role and epithelial protein induction of SOX11 in prostate cancer cell., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Staphylococcus schleiferi is a coagulase-negative staphylococcus known to cause canine external otitis but has rarely been reported in human infections. However, unlike other coagulase-negative staphylococci, S. schleiferi can cause disseminated infection in immunocompetent patients. Here, we present a case of S. schleiferi bacteremia, accompanied by infective endocarditis, brain abscesses, acute focal bacterial nephritis, and possible epididymitis, in which an S. aureus bacteremia treatment strategy was useful for resolution. Further reports should be accumulated to determine if S. schleiferi is a virulent pathogen that frequently causes the disseminated infection type seen in our patient., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Ezaki et al.)

Fish collagen is one of the major allergens involved in fish allergies; however, it has not been well-established whether fish collagen can cause anaphylaxis among individuals with fish allergies, especially children. A 9-year-old girl experienced anaphylaxis after consuming 2 fruit-flavored gummy tablets. Contacting the manufacturing company revealed that fish-derived collagen was used in the gummy tablets, and an oral fish collagen challenge test confirmed that the anaphylaxis was induced by fish collagen. Immunoblot analysis showed a 120-kDa band in a sample of the fish collagen in the gummy tablets, and no reactive band of the pork gelatin was observed. Additionally, salmon collagen and other fish samples that provoked symptoms were detected as a 120-kDa band in the immunoblot analysis. The 120-kDa band was identified as fish collagen by mass spectrometry confirming that it was the causative antigen of our patient's allergy. This case study confirms that fish collagen can cause anaphylaxis in children with fish allergies. Physicians and allergic individuals need to be aware that processed foods may contain fish collagen to avoid allergic reactions., Competing Interests: Conflict of interest: The authors have no financial conflicts of interest., (Copyright © 2020. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.)

Acute hyperammonemic encephalopathy (AHE) is a rare but life-threatening condition. We present a case of an 81-year-old woman with cirrhotic AHE who presented with prolonged disorientation. Her magnetic resonance (MR) images were normal on the third hospital day, which showed bilateral abnormalities in the insular and cingulate cortices on day 13. The imaging abnormalities were slightly improved but remained on day 24. The imaging abnormalities seemed correlated with her persistent disorientation. AHE can present as delayed cerebral abnormalities, and follow-up imaging tests are useful in detecting such conditions. Further reports are needed to investigate the correlation between imaging abnormalities and clinical outcomes in patients with AHE., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Ito et al.)

JPH203 is a novel anti-cancer drug targeting L-type amino acid transporter 1 (LAT1), which plays a primary role in the uptake of essential amino acids in tumor cells. Although a co-incubation inhibitory effect of JPH203 has been shown in a conventional uptake assay, its preincubation inhibitory effects have remained undetermined. Therefore, we aimed to characterize the preincubation inhibitory effects of JPH203 on LAT1 function using leucine uptake assays in LAT1-positive human colon cancer HT-29 cells. Preincubation of the cells with JPH203 (0.3 μM for 120 min) decreased the activity level to 30% of that in dimethylsulfoxide-treated cells. Similarly, in time-dependency analysis, preincubation of HT-29 cells with 10 μM JPH203 for 30, 60, and 120 min decreased the leucine uptake activity (42%, 32%, and 28% of that in control cells, respectively). Furthermore, the IC 50 value of the combination of preincubation and co-incubation effects was lower than that of co-incubation inhibition alone (34.2 ± 3.6 nM vs. 99.2 ± 11.0 nM). In conclusion, we revealed that JPH203 has the capability to inhibit LAT1 function through preincubation effects. Moreover, preincubation synergistically enhances the co-incubation inhibitory effects. These findings provide a novel insight into the anti-cancer effects of JPH203 in cancer therapy., Competing Interests: Declaration of Competing Interest The authors indicated no potential conflicts of interest., (Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Individuals with immunosuppressive condition have a high risk of invasive Haemophilus influenzae type b (Hib) infection. In Japan, routine Hib vaccination program for children under 5 years old was introduced in December 2008. However, the national policy does not make provision for individuals aged ≥5 years who have medical conditions associated with a high risk of invasive Hib disease to receive Hib vaccine. We measured serum anti-polyribosylribitol phosphate specific (anti-PRP) antibodies to Hib in patients aged ≥5 years with hematological malignancies and asplenia and evaluated their levels of anti-PRP antibodies in post administration of Hib vaccine era. A total of 65 patients (48 with hematological malignancies, and 17 with asplenia) were included in this study, of which 84% had not received Hib vaccine. In addition, 95.4% had short-term protective levels of anti-PRP antibodies (defined as ≥0.15 μg/mL) and 41.5% had long-term protective levels of anti-PRP antibodies (defined as ≥1.0 μg/mL). Five patients had low anti-PRP antibody levels despite a history of Hib vaccination. Our results suggest that young patients with underlying diseases such as hematological malignancies and asplenia may be at risk of invasive Hib disease. Hence, we recommend they should receive Hib vaccines even if they are over the age limit for routine Hib vaccination program., Competing Interests: Declaration of Competing Interest All authors reported no potential conflicts of interest., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Pathogenic germline variants in the gap junction protein alpha 1 (GJA1) gene have been identified in several congenital disorders affecting cutaneous, skeletal, and cardiac tissues. Here, we describe a 12-year-old patient with a GJA1 c.113G>A, p.(Gly38Glu) variant, who presented with fulminant myocarditis following recurrent generalized erythrokeratoderma. His mother and younger sister had the same clinical manifestations with the same GJA1 variant, but did not have cardiac dysfunction. GJA1 variants have been reported in patients with congenital cardiac malformations, while acute myocarditis in GJA1-related disorders has not been reported so far., (© 2020 Wiley Periodicals, Inc.)

Background: Manual rib cage compression is a chest physiotherapy technique routinely used in clinical practice. However, scientific evidence remains scarce on the effects of manual rib cage compression on airway clearance and oxygenation in mechanically ventilated patients., Methods: Anesthetized pigs were intubated via the trachea and mechanically ventilated. To create atelectasis, artificial mucus was infused into the airway. Each pig was randomly assigned to 1 of 2 groups: closed suctioning alone (control group, 7 pigs), or manual rib cage compression combined with closed suctioning (manual rib cage compression group, 8 pigs). Hard and brief rib cage compression synchronized with early expiratory phase was tested. Mucus clearance and oxygenation were assessed after the intervention. Sequential changes of hemodynamics were assessed after the intervention., Results: During hard manual rib cage compression, the mean ± SD peak expiratory flow increased to 44 ± 7 L/min compared with 31 ± 7 L/min without treatment ( P < .001). Manual rib cage compression combined with endotracheal suctioning increased mucus clearance compared with closed suctioning alone (mucus amounts, 5.5 [3.4-9.4] g vs 0.7 [0.5-2.0] g; P = .004); however, it did not improve gas exchange and radiologic findings. There were no significant differences in hemodynamic variables between the 2 groups., Conclusions: Our findings indicated that hard and brief manual rib cage compression combined with closed suctioning was safe and led to improvement of mucus clearance; however, no effectiveness was confirmed with regard to oxygenation and ventilation., (Copyright © 2020 by Daedalus Enterprises.)

Short chain fatty acids (SFCAs) are microbial metabolites produced in the gut upon fermentation of dietary fiber. These metabolites interact with the host immune system and can elicit epigenetic effects. There is evidence to suggest that SCFAs may play a role in the developmental programming of immune disorders and obesity, though evidence in humans remains sparse. Here we have quantified human milk (HM) SCFA levels in an international cohort of atopic and non-atopic mothers ( n = 109). Our results demonstrate that human milk contains detectable levels of the SCFAs acetate, butyrate, and formate. Samples from atopic mothers had significantly lower concentrations of acetate and butyrate than those of non-atopic mothers. HM SCFA levels in atopic and non-atopic women also varied based on maternal country of residence (Australia, Japan, Norway, South Africa, USA). Reduced exposure to HM SCFA in early life may program atopy or overweight risk in breastfed infants., (Copyright © 2020 Stinson, Gay, Koleva, Eggesbø, Johnson, Wegienka, du Toit, Shimojo, Munblit, Campbell, Prescott, Geddes and Kozyrskyj.)

Atopic dermatitis (AD) is commonly associated with colonization by Staphylococcus aureus in the affected skin. To understand the role of S. aureus in the development of AD, we performed whole-genome sequencing of S. aureus strains isolated from the cheek skin of 268 Japanese infants 1 and 6 months after birth. About 45% of infants were colonized with S. aureus at 1 month regardless of AD outcome. In contrast, skin colonization by S. aureus at 6 months of age increased the risk of developing AD. Acquisition of dysfunctional mutations in the S. aureus Agr quorum-sensing (QS) system was primarily observed in strains from 6-month-old infants who did not develop AD. Expression of a functional Agr system in S. aureus was required for epidermal colonization and the induction of AD-like inflammation in mice. Thus, retention of functional S. aureus agr virulence during infancy is associated with pathogen skin colonization and the development of AD., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Although some probiotic bacteria have been reported to prevent infections in children, there are few well-designed double-blind studies. Here we evaluated the effects of a probiotic strain of lactic acid bacteria (LAB), Pediococcus acidilactici K15, on viral respiratory tract infections in preschool children. A four-month, randomized, double-blind, placebo-controlled study was performed in 172 healthy children aged 3 to 6 years. Subjects were administered dextrin alone or dextrin including heat-killed K15 (5 × 10 10 bacteria). The number of febrile days was the primary outcome. The number of absent days from preschools and the influenza incidence were secondary outcomes. Secretory IgA (sIgA) concentrations in saliva were measured as an exploratory outcome. The primary and secondary outcomes were not significantly different between both groups. Analyses in children with little intake of fermented foods including LAB showed that the duration of a fever significantly decreased by K15 intake. The salivary sIgA level in the K15 group was maintained significantly higher than it was in the placebo group. The effects of K15 on preventing viral respiratory tract infections were not observed without the restriction of fermented foods intake. However, K15 supported anti-infectious immune systems in children who took less fermented foods and the maintenance of salivary sIgA levels in all subjects.

Invariant natural killer T (iNKT) cells are innate-like CD1d-restricted T cells that express the invariant T cell receptor (TCR) composed of Vα24 and Vβ11 in humans. iNKT cells specifically recognize glycolipid antigens such as α-galactosylceramide (αGalCer) presented by CD1d. iNKT cells show direct cytotoxicity toward CD1d-positive tumor cells, especially when CD1d presents glycolipid antigens. However, iNKT cell recognition of CD1d-negative tumor cells is unknown, and direct cytotoxicity of iNKT cells toward CD1d-negative tumor cells remains controversial. Here, we demonstrate that activated iNKT cells recognize leukemia cells in a CD1d-independent manner, however still in a TCR-mediated way. iNKT cells degranulated and released Th1 cytokines toward CD1d-negative leukemia cells (K562, HL-60, REH) as well as αGalCer-loaded CD1d-positive Jurkat cells. The CD1d-independent cytotoxicity was enhanced by natural killer cell-activating receptors such as NKG2D, 2B4, DNAM-1, LFA-1 and CD2, but iNKT cells did not depend on these receptors for the recognition of CD1d-negative leukemia cells. In contrast, TCR was essential for CD1d-independent recognition and cytotoxicity. iNKT cells degranulated toward patient-derived leukemia cells independently of CD1d expression. iNKT cells targeted myeloid malignancies more than acute lymphoblastic leukemia. These findings reveal a novel anti-tumor mechanism of iNKT cells in targeting CD1d-negative tumor cells and indicate the potential of iNKT cells for clinical application to treat leukemia independently of CD1d., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion, which is frequently encountered in clinical practice. Skin barrier dysfunction leads to enhanced skin irritability to non-specific stimuli and epicutaneous sensitization. In the lesion site, a further inflammation-related reduction in skin barrier function, enhanced irritability and scratching-related stimuli deteriorate eczema, leading to vicious cycle of inflammation. The current strategies to treat AD in Japan from the perspective of evidence-based medicine consist of three primary measures: (i) the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) of ectopic fat in muscles are associated with arterial stiffness in normal-weight individuals. Furthermore, aerobic exercise training-induced changes in IMCL or EMCL content are related to a decrease in arterial stiffness in elderly people. Though arterial stiffness is strongly related with obesity, but the effects of aerobic exercise training on IMCL or EMCL content, with a particular focus on arterial stiffness, in obese individuals remains unclear. Here, we investigated the effects of aerobic exercise training on IMCL or EMCL content and arterial stiffness in obese individuals. First, in a cross-sectional study, we examined the relationship between arterial stiffness and IMCL or EMCL content in 24 overweight and obese men. Secondly, we investigated the effects of aerobic exercise intervention on arterial stiffness and IMCL or EMCL content in 21 overweight and obese men. In the cross-sectional study, EMCL content was positively correlated with baPWV and β-stiffness index, whereas IMCL content was negatively correlated with baPWV. In the intervention study, there were no significant changes in baPWV, β-stiffness index, and IMCL and EMCL contents after aerobic exercise training. However, exercise-induced change in baPWV and β-stiffness index were positively correlated with changes in EMCL content. Moreover, the group of improvements in baPWV was only correlated significantly with reduced EMCL content. These results suggest that IMCL and EMCL contents may affect arterial stiffness in overweight and obese men.

Objectives: To examine validity and reliability of the Japanese version of the Cornell Assessment of Pediatric Delirium., Design: Prospective double-blinded observational cohort study., Setting: Eight-bed mixed PICU (post-surgical and internal medicine) from May 2017 to June 2018., Patients: All children between the ages of 0-13 years who were admitted to the PICU for at least 24 hours were eligible for inclusion, as long as the child was arousable to verbal stimulation., Interventions: Two nurses simultaneously and independently assessed each patient for pediatric delirium with the Japanese version of the Cornell Assessment of Pediatric Delirium; this was compared to the gold standard of psychiatric diagnosis based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition standards., Measurements and Main Results: Forty-one children were enrolled and 92 assessments (ranging from one to four per subject) were completed. Congenital heart disease patients accounted for 73 enrollees (79%). Forty-three percent of observations were performed in children on invasive mechanical ventilation. Pediatric delirium prevalence (as determined by psychiatric diagnosis) was 53%. The Japanese version of the Cornell Assessment of Pediatric Delirium demonstrated an optimal scoring cutpoint of 9. Overall, area under the curve was 92%, sensitivity 90% (95% CI, 79-97%), specificity 88% (95% CI, 75-96%), positive predictive value of 90% (95% CI, 79-97%), negative predictive value of 91% (95% CI, 80-97%), and a Cohen's κ of 0.89 (95% CI, 0.8-0.98). In children on invasive mechanical ventilation, the Japanese version of the Cornell Assessment of Pediatric Delirium maintained an area under the curve 87%, sensitivity 97%, and specificity 64%., Conclusions: The Japanese version of the Cornell Assessment of Pediatric Delirium is a valid and reliable tool for use in Japanese PICUs. This will allow for detection of delirium in real-time and may lead to better identification of the population and risk factors for appropriate management and therapeutic and preventative interventions.

Background: Acute mitral regurgitation could occur without common symptoms like hemodynamic instability, but with dyspnea, hemoptysis, and right-sided infiltration on radiography. We report a case of severe alveolar hemorrhage caused by acute mitral regurgitation, which occurred in the absence of shock., Case Presentation: A 40-year-old man presented with dyspnea with bloody phlegm and hypoxia, despite being hemodynamically stable. Chest radiography revealed right-sided infiltration, and bronchoscopy showed fresh bloody phlegm in his tracheae. No specific findings were detected with any tests. After treatment with several medications and support with extracorporeal membrane oxygenation, his condition improved, although the etiology of the disease remained unknown. Transthoracic and transesophageal echocardiogram revealed severe mitral valve regurgitation with ruptured mitral chordae tendineae. These suggested that the sudden onset of mitral valve regurgitation had caused severe alveolar hemorrhage., Conclusion: Severe alveolar hemorrhage, especially with right-sided infiltration on chest radiography, should be considered a symptom of acute mitral regurgitation., Competing Interests: Approval of the research protocol: N/A. Informed consent: Informed consent was obtained from the patient. Registry and the registration no. of the study/trial: N/A. Animal studies: N/A. Conflict of interest: None., (© 2020 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

Aim: Several studies have shown an association between fluid overload (FO) and mortality or duration of mechanical ventilation in critically ill patients. However, the association between FO and delirium duration remains unclear., Methods: This retrospective observational cohort study was undertaken at University of Tsukuba Hospital (Tsukuba, Japan) from April 2015 to March 2017. Mechanically ventilated patients who stayed in the intensive care unit for more than 7 days were eligible for inclusion. Univariate analysis was carried out with the Mann-Whitney U -test for continuous variables and Fisher's exact test for categorical variables. A multivariate proportional odds logistic regression model was used to evaluate the association between FO and delirium/coma days (DCDs) during the 7-day study period., Results: A total of 118 patients were included and divided into FO and non-FO groups. Fluid overload occurred in 40% of patients. The FO group had a higher APACHE II score than the non-FO group (19 [16-26] versus 23 [20-29], P  = 0.017). Cumulative fluid balance at day 3 was higher in the FO group (3,238 [281-6,530] versus 7,886 [4,106-10,631], P  < 0.001). Delirium days within 7 days was longer in the FO group (1 [0-3] versus 2 [1-3], P  = 0.048) and DCDs was longer in the FO group (4 [1-5] versus 6 [3-7], P  = 0.002). After adjusting for covariates, there were significant associations between FO and DCDs (odds ratio, 2.16; 95% confidence interval, 1.05-4.47)., Conclusions: Our findings suggest that FO is associated with increased DCDs in mechanically ventilated patients., Competing Interests: Approval of the research protocol: This study was approved by the Ethics Committee of the University of Tsukuba Hospital, Tsukuba, Japan (H27‐087). Informed consent: N/A. Registry and the registration no. of the study/trial: N/A. Animal studies: N/A. Conflict of interest: None., (© 2020 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

Background: Landiolol hydrochloride, a highly cardio-selective beta-1 blocker with an ultra-short-acting half-life of 4 minutes, was originally approved by Japan for treatment of intraoperative tachyarrhythmias. This review aims to provide an integrated overview of the current state of knowledge of landiolol hydrochloride in the management of arrhythmia in critical settings., Methods: We searched MEDLINE, EMBASE, and the Cochrane Library to retrieve relevant articles with a total of 65 records identified., Results: The high β1 selectivity (β1/β2 ratio of 255:1) of landiolol causes a more rapid heart rate (HR) decrease compared to esmolol while avoiding decreases in mean arterial blood pressure. Recently, it has been found useful in left ventricular dysfunction patients and fatal arrhythmia requiring emergency treatment. Recent random clinical trials (RCT) have revealed therapeutic and prophylactic effects on arrhythmia, and very low-dose landiolol might be effective for preventing postoperative atrial fibrillation (POAF) and sinus tachycardia. Likewise, landiolol is an optimal choice for perioperative tachycardia treatment during cardiac surgery. The high β1 selectivity of landiolol is useful in heart failure patients as a first-line therapy for tachycardia and arrhythmia as it avoids the typical depression of cardiac function seen in other β-blockers. Application in cardiac injury after percutaneous coronary intervention (PCI), protection for vital organs (lung, kidney, etc.) during sepsis, and stabilizing hemodynamics in pediatric patients are becoming the new frontier of landiolol use., Conclusion: Landiolol is useful as a first-line therapy for the prevention of POAF after cardiac/non-cardiac surgery, fatal arrhythmias in heart failure patients and during PCI. Moreover, the potential therapeutic effect of landiolol for sepsis in pediatric patients is currently being explored. As positive RCT results continue to be published, new clinical uses and further clinical studies in various settings by cardiologists, intensivists and pediatric cardiologists are being conducted., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Matsuishi et al.)

The hedgehog signaling pathway is a vital factor for embryonic development and stem cell maintenance. Dysregulation of its function results in tumor initiation and progression. The aim of this research was to establish a disease model of hedgehog-related tumorigenesis with Gorlin syndrome-derived induced pluripotent stem cells (GS-iPSCs). Induced neural progenitor cells from GS-iPSCs (GS-NPCs) show constitutive high GLI1 expression and higher sensitivity to smoothened (SMO) inhibition compared with wild-type induced neural progenitor cells (WT-NPCs). The differentiation process from iPSCs to NPCs may have similarity in gene expression to Hedgehog signal-related carcinogenesis. Therefore, GS-NPCs may be useful for screening compounds to find effective drugs to control Hedgehog signaling activity.

Down syndrome (DS) is frequently comorbid with congenital heart disease and has recently been shown to reduce the sedative effect of benzodiazepine (BDZ)-class anesthesia but this effect in a clinical setting has not been studied. Therefore, this study compared midazolam sedation after heart surgery in DS and normal children. We retrospectively reviewed patient records in our pediatric intensive care unit (PICU) of pediatric cardiovascular operations between March 2015 and March 2018. We selected five days of continuous post-operative data just after termination of muscle relaxants. Midazolam sedation was estimated by Bayesian inference for generalized linear mixed models. We enrolled 104 patients (average age 26 weeks) of which 16 (15%) had DS. DS patients had a high probability of receiving a higher midazolam dosage and dexmedetomidine dosage over the study period (probability = 0.99, probability = 0.97) while depth of sedation was not different in DS patients (probability = 0.35). Multi regression modeling included severity scores and demographic data showed DS decreases midazolam sedation compared with controls (posterior OR = 1.32, 95% CrI = 1.01-1.75). In conclusion, midazolam dosages should be carefully adjusted as DS significantly decreases midazolam sedative effect in pediatric heart surgery patients.

Aim: Hospital selection for patients with drug overdose (DOD) is a critical issue. In Tokyo, the 50-tablet rule has been widely utilized by paramedics for triaging patients with DOD given that it shortens the triage time. However, studies have not investigated the utility of such a rule in local cities. The present study aimed to identify prognostic pre- and in-hospital factors among patients with DOD and determine whether the 50-tablet rule benefits local cities., Methods: Clinical records of patients with DOD admitted at the University of Tsukuba Hospital (Tsukuba, Japan) between 2013 and 2017 were retrospectively reviewed., Results: A total of 93 patients with DOD were enrolled in this study. Multivariate analysis showed that creatine kinase and C-reactive protein values and the total number of ingested pills were in-hospital risk factors that significantly prolonged intensive care unit (ICU) and hospital stay. Moreover, Glasgow Coma Scale score on admission and the total number of ingested pills were identified as significant pre-hospital risk factors for prolonged ICU and hospital stay. Setting the total number of ingested pills to 50 tablets did not significantly influence ICU and hospital stay., Conclusion: The total number of ingested pills and creatine kinase and C-reactive protein values were identified as predictive factors for prolonged ICU and hospital stay in patients with DOD after admission. Moreover, pre-hospital risk factors included Glasgow Coma Scale score and the total number of ingested pills. However, the 50-tablet rule was determined to be a poor cut-off value for patients with DOD. We presented a subset of our findings at the 46th annual meeting of the Japanese Society for Acute Medicine (Yokohama, Japan) on 20 November 2018., Competing Interests: Approval of the research protocol and informed consent: This study was approved by the research ethics committee of the University of Tsukuba Hospital. The need for informed consent was waived on account of the retrospective study design. Registry and the registration no. of the study/trial: No. H28‐172. Animal studies: N/A. Conflict of interest: None., (© 2020 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

Background: Pediatric atopic dermatitis (PAD) is a pluricausal disease and is frequently seen in dermatological and pediatric practice. Therefore, it is important to find common views in clinical practice and to promote consensus among practitioners. Aiming to obtain common views among dermatologists and pediatricians and to disseminate them widely in clinical practice, we held the PAD Consensus Forums described herein., Methods: Questionnaire surveys of treatment goals and drug therapy were conducted to prepare topics for discussion at the PAD Consensus Forums. Reaching consensus was defined as agreement among at least 70% of the participants., Results: As a result of discussion among 24 dermatologists and 25 pediatricians, consensus was obtained on 7 topics. These topics configure 3 consensus of treatment goals (Attainment targets were divided into the short/medium term and the long term. Attainment targets were associated with the primary evaluation domains of the Harmonising Outcome Measures for Eczema (HOME) roadmap, etc.) and 4 consensus of drug therapy (The number of applications of topical anti-inflammatory drugs in the acute phase and selection and ideal intervals between applications of topical anti-inflammatory drugs in proactive therapy, etc.)., Conclusions: The consensus is expected to help practitioners set appropriate treatment goals in clinical practice and facilitate the choice of drugs for treatment., (Copyright © 2019 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion. The current strategies to treat AD in Japan from the perspective of evidence-based medicine consist of three primary measures: (i) the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice., (© 2019 Japanese Dermatological Association.)

Background: The prenatal maternal microbiome, including the gut microbiota, has been suggested to influence the incidence of allergies in offspring. Moreover, epidermal barrier dysfunction in early infancy has been attributed to the development of subsequent allergies. We hypothesized that the prenatal microbiome may affect the gut microbiota, acting as an initial trigger to alter immune development in the foetus. The maternal microbial composition may be linked to the prevalence of dermatitis in early infancy (DEI) of the offspring, leading to subsequent allergic symptoms., Methods: This study was conducted as part of the Chiba Study of Mother and Child Health (C-MACH) birth cohort that was initiated in 2013; 434 healthy pregnant women at < 13 weeks of gestation were recruited. DEI was assessed for up to 4 months after birth, and allergic symptoms were determined in 10-month-old infants using questionnaires. Other information related to the maternal microbiome was obtained from questionnaires filled out during pregnancy. Stool samples were collected from pregnant women at 12 ( n  = 59) and 32 weeks ( n  = 58) of gestation, which were used for gut microbiota analysis using barcoded 16S rRNA gene sequencing., Results: Symptoms of allergy, especially of inherited allergies, show a higher prevalence at 10 months after birth in the DEI group. DEI occurrence was negatively correlated with family size and cat ownership. The diversity of Proteobacteria at 12 weeks of gestation and the relative abundance of Actinobacteria at 32 weeks of gestation in maternal feces were lower at both time points of gestation in the DEI group. In addition, the diversity of Proteobacteria in prenatal feces was negatively correlated with family size at 12 weeks, and with dog ownership at both gestational time points., Conclusions: The composition of the maternal microbiome may influence the risk of allergies in offspring, even before birth. Furthermore, the diversity of Proteobacteria and the relative abundance of Actinobacteria in maternal feces were negatively associated with DEI, which may be associated with the risk of allergy development in infancy. This early trigger may be a good predictor of allergy development during infancy and childhood., (© 2019 The Authors.)

Background: Delirium is the most common postoperative complication of the central nervous system (CNS) that can trigger long-term cognitive impairment. Its underlying mechanism is not fully understood, but the dysfunction of the blood-brain barrier (BBB) has been implicated. The serum levels of the axonal damage biomarker, phosphorylated neurofilament heavy subunit (pNF-H) increase in moderate to severe delirium patients, indicating that postoperative delirium can induce irreversible CNS damage. Here, we investigated the relationship among postoperative delirium, CNS damage and BBB dysfunction, using pNF-H as reference., Methods: Blood samples were collected from 117 patients within 3 postoperative days. These patients were clinically diagnosed with postoperative delirium using the Confusion Assessment Method for the Intensive Care Unit. We measured intercellular adhesion molecule-1, platelet and endothelial cell adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and P-selectin as biomarkers for BBB disruption, pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6), and pNF-H. We conducted logistic regression analysis including all participants to identify independent biomarkers contributing to serum pNF-H detection. Next, by multiple regression analysis with a stepwise method we sought to determine which biomarkers influence serum pNF-H levels, in pNF-H positive patients., Results: Of the 117 subjects, 41 were clinically diagnosed with postoperative delirium, and 30 were positive for serum pNF-H. Sensitivity and specificity of serum pNF-H detection in the patients with postoperative delirium were 56% and 90%, respectively. P-selectin was the only independent variable to associate with pNF-H detection (P < 0.0001) in all 117 patients. In pNF-H positive patients, only PECAM-1 was associated with serum pNF-H levels (P = 0.02)., Conclusions: Serum pNF-H could be an objective delirium biomarker, superior to conventional tools in clinical settings. In reference to pNF-H, P-selectin may be involved in the development of delirium-related CNS damage and PECAM-1 may contribute to the progression of delirium- related CNS damage., Competing Interests: The authors have declared that no competing interests exist.