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Ichiro Morioka, Sota Iwatani, Tsubasa Koda, Miwako Nagasaka, Keiji Yamana, Daisuke Kurokawa, Kaori Fujita, Kosuke Nishida, Kazumoto Iijima Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanAbstract: Neonatal sepsis is a significant cause of morbidity and mortality in newborns, particularly in the preterm or low birth weight infant. In this epidemiologic review regarding neonatal sepsis, the recent epidemiology and causative pathogens in Japan are described and compared with data from international organizations. Recent Japanese multicenter studies report the incidence of neonatal sepsis at 0.74%. Although the incidence of early-onset sepsis has been low (0.13%), approximately 5% of very or extremely low birth weight infants develop late-onset sepsis with a high mortality rate. In Japan for such cases, the most predominant causative pathogen is methicillin-resistant Staphylococcus aureus; internationally, the most commonly reported pathogen is coagulase-negative staphylococci. It is our contention that the incorporation of the strategies to control and to prevent health care-associated MRSA transmission has contributed to the reduction in the incidence of late-onset sepsis.Keywords: coagulase-negative staphylococci, incidence, methicillin-resistant Staphylococcus aureus, mortality, neonatal intensive care, nosocomial infections

This study investigates the long-term outcomes of palliative and definitive surgeries for esophageal atresia (EA) in patients with trisomy 18 syndrome. A retrospective study included 25 cases undergoing EA surgery at our center between 2008 and 2022. The Palliative group (n = 16) comprised 13 cases with esophageal banding and 3 with tracheoesophageal fistula (TEF) division. The Definitive group (n = 9) included 5 cases with primary repair and 4 with staged repair following TEF division. The patient characteristics exhibited no significant differences between the groups. In the Definitive group, 56% (5/9) were successfully weaned off mechanical ventilation, compared with none in the Palliative group (p = 0.002). Survival-to-discharge rates were 31% (5/16) in the Palliative group and 67% (6/9) in the Definitive group. Home ventilator management was required for all 5 cases that required ventilation in the Palliative group, whereas only 17% (1/6) in the Definitive group needed it. The Palliative group also required continuous oral suction for persistent saliva removal, with two cases undergoing laryngotracheal separation. Overall, definitive surgery for EA in patients with trisomy 18 syndrome may provide enhanced respiratory stability, thereby improving the survival-to-discharge rate and overall quality of life for patients and their families., (© 2024 Wiley Periodicals LLC.)

Objectives: In this study, we investigated the clinical feasibility of using umbilical cord blood as an alternative to neonatal blood for measuring serum albumin and immunoglobulin G (IgG) levels in newborns, including preterm newborns., Methods: Serum levels of albumin and IgG were measured in cord and neonatal blood from singleton newborns. We analyzed correlations and systematic errors between cord and neonatal blood measurements, stratifying the results for very preterm newborns (VPNs) born at a gestational age of less than 32 weeks and non-VPNs born at a gestational age of 32 weeks or later., Results: Among all 494 newborns (78 VPNs and 416 non-VPNs), serum albumin and IgG levels were determined for 95.7% and 88.7% of them, respectively. Strong correlations between cord and neonatal blood were observed for the serum albumin and IgG levels (rs = 0.864 and 0.966, respectively). Moreover, the measurement errors between cord and neonatal blood were small for all newborns (0.2 g/dL and 65 mg/dL, respectively). These findings were consistent with both VPNs and non-VPNs., Conclusions: Umbilical cord blood is a suitable substitute for neonatal blood in measuring serum albumin and IgG levels in newborns, even in premature newborns., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Muse cells, identified as cells positive for the pluripotent surface marker SSEA-3, are pluripotent-like endogenous stem cells located in the bone marrow (BM), peripheral blood, and organ connective tissues. The detailed characteristics of SSEA-3(+) cells in extraembryonic tissue, however, are unknown. Here, we demonstrated that similar to human-adult tissue-Muse cells collected from the BM, adipose tissue, and dermis as SSEA-3(+), human-umbilical cord (UC)-SSEA-3(+) cells express pluripotency markers, differentiate into triploblastic-lineage cells at a single cell level, migrate to damaged tissue, and exhibit low telomerase activity and non-tumorigenicity. Notably, ~ 20% of human-UC-SSEA-3(+) cells were negative for X-inactive specific transcript (XIST), a naïve pluripotent stem cell characteristic, whereas all human adult tissue-Muse cells are XIST-positive. Single-cell RNA sequencing revealed that the gene expression profile of human-UC-SSEA-3(+) cells was more similar to that of human post-implantation blastocysts than human-adult tissue-Muse cells. The DNA methylation level showed the same trend, and notably, the methylation levels in genes particularly related to differentiation were lower in human-UC-SSEA-3(+) cells than in human-adult tissue-Muse cells. Furthermore, human-UC-SSEA-3(+) cells newly express markers specific to extraembryonic-, germline-, and hematopoietic-lineages after differentiation induction in vitro whereas human-adult tissue-Muse cells respond only partially to the induction. Among various stem/progenitor cells in living bodies, those that exhibit properties similar to post-implantation blastocysts in a naïve state have not yet been found in humans. Easily accessible human-UC-SSEA-3(+) cells may be a valuable tool for studying early-stage human development and human reproductive medicine., (© 2024. The Author(s).)

Background: To accurately assess hypogammaglobulinemia at birth, it is essential to determine the reference intervals of serum immunoglobulin (IgG) levels in newborns. In the present study, we determined the gestational age (GA)-/birth weight (BW)-dependent percentile-based reference intervals of serum IgG levels and converted them into simple formulas for practical use., Methods: Serum IgG levels were measured in cord blood from 2902 newborns delivered at 22 to 41 weeks of GA or 264 to 4642 g of BW after exclusion of those with congenital disorders. Linear regression analysis was used to correlate GA and UC-IgG levels and BW and UC-IgG levels. After calculation of the percentile values of UC-IgG levels for each GA or BW, the distributions were approximated by the least-squares method. Fitness was evaluated by the coefficient of determination ( R 2 )., Results: Significant positive correlations were found both between GA and UC-IgG levels ( r s = 0.790, P < 0.001) and BW and UC-IgG levels ( r s = 0.626, P < 0.001). The distribution of the 5%ile of UC-IgG levels (Y) by GA or BW (X) was approximated as a straight line (Y = 37.5 *X - 775.8; Y = 0.161 *X + 95.34, respectively). The fitness was stronger in the GA-derived formula than the BW-derived formula ( R 2 = 0.973 vs 0.913)., Conclusions: We established GA-/BW-dependent reference percentile-based intervals for serum IgG levels using cord blood from 2902 newborns without congenital disorders. Using GA-dependent reference intervals may be useful for assessing hypogammaglobulinemia at birth., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Bleomycin (BLM)-induced lung injury is characterized by mixed histopathologic changes with inflammation and fibrosis, such as observed in human patients with bronchopulmonary dysplasia, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. Although no curative therapies for these lung diseases exist, stem cell therapy has emerged as a potential therapeutic option. Multilineage-differentiating stress-enduring (Muse) cells are endogenous pluripotent- and macrophage-like stem cells distributed in various adult and fetal tissues as stage-specific embryonic antigen-3-positive cells. They selectively home to damaged tissue by sensing sphingosine-1-phosphate and replace the damaged/apoptotic cells by in vivo differentiation. Clinical trials for some human diseases suggest the safety and therapeutic efficacy of intravenously injected human leukocyte antigen-mismatched allogenic Muse cells from adult bone marrow (BM) without immunosuppressant. Here, we evaluated the therapeutic effects of human Muse cells from preterm and term umbilical cord (UC), and adult BM in a rat BLM-induced lung injury model., Methods: Rats were endotracheally administered BLM to induce lung injury on day 0. On day 3, human preterm UC-Muse, term UC-Muse, or adult BM-Muse cells were administered intravenously without immunosuppressants, and rats were subjected to histopathologic analysis on day 21. Body weight, serum surfactant protein D (SP-D) levels, and oxygen saturation (SpO 2 ) were monitored. Histopathologic lung injury scoring by the Ashcroft and modified American Thoracic Society document scales, quantitative characterization of engrafted Muse cells, RNA sequencing analysis, and in vitro migration assay of infused Muse cells were performed., Results: Rats administered preterm- and term-UC-Muse cells exhibited a significantly better recovery based on weight loss, serum SP-D levels, SpO 2 , and histopathologic lung injury scores, and a significantly higher rate of both Muse cell homing to the lung and alveolar marker expression (podoplanin and prosurfactant protein-C) than rats administered BM-Muse cells. Rats receiving preterm-UC-Muse cells showed statistically superior results to those receiving term-UC-Muse cells in many of the measures. These findings are thought to be due to higher expression of genes related to cell migration, lung differentiation, and cell adhesion., Conclusion: Preterm UC-Muse cells deliver more efficient therapeutic effects than term UC- and BM-Muse cells for treating BLM-induced lung injury in a rat model., (© 2024. The Author(s).)

Contrary to previous studies on the antecedent factors of social media addiction, we focused on the social environmental factor of relational mobility (i.e., the ease of constructing new interpersonal relationships) and investigated its relationship with social media addiction. People in low relational mobility societies have fewer opportunities to select new relationship partners and consequently feel a stronger need to maintain their reputation. We hypothesized that (1) people in low relational mobility societies are more strongly addicted to social media because they estimate that greater reputational damage will be caused by ignoring messages and (2) people in low relational mobility societies estimate greater reputational damage than actual damage. We conducted two online experiments with 715 and 1,826 participants. Our results demonstrated that (1) there is no relationship between relational mobility and social media addiction and (2) people in both high and low relational mobility societies overestimate reputational damage. Furthermore, we demonstrated that the social media addiction mechanism differs between societies: (3) people in low relational mobility societies estimate greater reputational damage, whereas (4) people in high relational mobility societies are more motivated to expand their social networks; both mechanisms strengthen their social media addiction. Based on these results, we propose interventions for moderating social media addiction in both high and low relational mobility societies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Iwatani, Watamura. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Fetal inflammatory response syndrome (FIRS) is defined by elevated levels of inflammatory cytokines circulating in fetal blood, which may result in preterm morbidities. Serum interleukin-6 (IL-6) level has been reported to be a good indicator of FIRS; however, changes in IL-6 levels after birth remain to be elucidated. Herein, we characterized early changes in serum IL-6 levels in extremely premature newborns (EPNs, < 28 wks gestation), and then determined the cut-off values for detecting fetal inflammation at each postnatal epoch., Methods: In this single-center study, 49 EPNs were retrospectively studied. Serum IL-6 measurements are routinely performed at delivery, 1-3, 6-12, and 24-36 h of life. Receiver operating characteristic (ROC) curve analyses were performed for detecting the presence of funisitis, the histologic counterpart of FIRS., Results: Overall, serum IL-6 levels were significantly elevated at 1-3 (298 [31-4719] pg/mL) and 6-12 (29 [2-12,635] pg/mL) hours of life, then returned to at-delivery levels at 24-36 h of life. When comparing serum IL-6 levels at each postnatal epoch, the levels at delivery, 1-3, and 6-12 h of life were significantly higher in the EPNs with funisitis. Serum IL-6 cut-off values at delivery, 1-3, 6-12, and 24-36 h of life for the presence of funisitis were 20, 572, 290, and 13 pg/mL with area under ROCs of 0.75, 0.71, 0.68, and 0.53, respectively., Conclusions: Serum IL-6 levels in EPNs significantly increase early after birth, then decrease to at-delivery levels by 24-36 h of life. Therefore, postnatal age-dependent cut-off values of serum IL-6 might be considered for detecting fetal inflammation with confirmed funisitis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Inhaled nitric oxide (iNO) use is recommended for persistent pulmonary hypertension of the newborn in term and late preterm infants. Recently, iNO therapy to prevent bronchopulmonary dysplasia (BPD) or rescue for hypoxic respiratory failure and pulmonary hypertension secondary to BPD has increasingly been used in preterm infants after 7 days of postnatal age (in the postacute phase), despite its off-label use. However, the initiation criteria of iNO therapy for preterm infants in the postacute phase are varied. The aim of this scoping review is to identify the clinical and/or echo findings at the initiation of iNO therapy in preterm infants in the postacute phase., Methods and Analysis: We will search PubMed, Embase and the Japanese database 'Ichushi.' The following studies will be included in the review: randomised controlled trials, prospective/retrospective cohort studies, case-control studies and case series on iNO therapy for preterm infants in the postacute phase; studies published between January 2003 and August 2023; studies conducted in developed countries and studies written in English or Japanese. We will independently screen, extract and chart data using the population-concept-context framework following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. We will summarise the characteristics and findings of the included studies., Ethics and Dissemination: Obtaining an institutional review board approval is not required because of the nature of this review. A final report of review findings will be published and disseminated through a peer-reviewed journal and presentation at relevant conferences., Trial Registration Number: UMIN000051498., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To determine the clinical features of bilirubin encephalopathy in preterm infants (pBE) in Japan., Methods: We performed a retrospective, nationwide questionnaire-based survey. The initial survey determined the number of children with pBE who were born after 2000. Using a structured questionnaire, the second survey clarified the clinical manifestations and characteristics of children with pBE, including demographic data, neurological symptoms, and MRI and auditory brainstem response (ABR) findings., Results: The initial survey identified 41 pBE infants from 18 institutions. After exclusion of patients included in previous studies, clinical information was collected from 30 patients (21 boys and 9 girls) during the secondary survey. The median gestational age was 26 weeks and the median birthweight was 846 g. Chronic lung disease and symptomatic patent ductus arteriosus were common neonatal complications. Head control was observed in 63% and functional gait in 17% of patients. Purposeful hand use was seen in 57% and verbal communication in 50% of patients. MRI showed T2 hyperintensities in the globus pallidus of 29 of 30 patients. ABR abnormalities were present in 11 of 15 patients. None of the variables were significantly different between the 2017 and 2021 surveys., Conclusions: The pBE infants had severely impaired gross motor function and relatively preserved manual function and verbal communication. MRI and ABR findings aid in the diagnosis of pBE., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Conflict of interest The author have no conflicts of interest to declare.

Some people overestimate the benefits of certain kinds of foods, such as organic foods, while others underestimate it. Previous studies have found that reducing people's self-assessed knowledge successfully moderated these extreme attitudes. In this study, we investigated interventions to reduce people's self-assessed knowledge and to moderate attitude extremity. We examined extreme attitudes toward organic foods and investigated the effects of implementing two intervention methods to moderate their attitude: (1) providing knowledge on organic food after asking them some questions and (2) simply providing them with knowledge. We conducted a two-factor mixed-design experiment with 653 college-educated Japanese women. In the first condition, before knowledge provision, participants were asked to answer questions about organic foods and were then informed of the correct answer and whether their answer was correct (Q&A Intervention). This step was based on an intervention conducted in a previous study to reduce their self-assessed factual knowledge. In the second condition, participants were simply provided with knowledge without being asked to answer any questions (Simple Intervention). The results showed that both intervention methods, on average, decreased the participants' self-assessed knowledge and attitude extremity. Therefore, simply providing knowledge may be effective in reducing their self-assessed factual knowledge and moderating their extreme attitudes toward organic foods., 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 © 2023 Iwatani, Honda, Otaki and Ueda.)

In this retrospective cohort study, we investigated the impact of tracheostomies on the long-term survival of children with trisomy 13 syndrome at a Japanese tertiary pediatric center. We compared survival and survival to discharge rates between patients who underwent tracheostomies during their NICU stays (T group, n = 8) and those who did not (non-T group, n = 11). A total of 19 patients enrolled. Median survival in all patients was 673 (266-1535) days. Significant differences in the 1-, 2-, and 3-year survival rates were found between the T and the non-T groups (100% vs. 46%, p = 0.018; 88% vs. 18%, p = 0.006; 63% vs. 9%, p = 0.041, respectively). The survival to discharge rate was higher in the T versus non-T group (75% vs. 45%, p = 0.352). This study highlights a significantly higher long-term survival of patients with trisomy 13 syndrome who underwent tracheostomies during their NICU stays., (© 2023 Wiley Periodicals LLC.)

Background: Elevated albumin-free or unbound bilirubin (UB) levels beyond the first week of life have been associated with the development of bilirubin encephalopathy in preterm infants. However, the mechanism(s) that induces this prolonged unbound bilirubinemia has remained unknown. We hypothesized that it may due to a sustained lower bilirubin-binding affinity of albumin in extremely premature infants., Methods: Twenty-two very preterm infants born at 28-31 weeks' gestational age (GA) (VPT Group) and 21 extremely preterm infants born at 22-27 weeks' GA (EPT Group) were retrospectively studied. On days 14, 21, and 28, bilirubin-binding affinity of albumin was assessed by calculating of the UB/total bilirubin ratio, bilirubin-albumin molar ratio (BAMR), and binding affinity (Ka)., Results: On days 14, 21, and 28, significantly higher UB/total bilirubin ratios were found in the EPT than in the VPT Group. Although BAMRs were comparable, significantly lower Ka values on days 14, 21, and 28 were observed in the EPT than those in the VPT Group (56.1 vs. 70.9 L/μmol, p < 0.001; 55.2 vs. 74.7 L/μmol, p < 0.001; 53.0 vs. 86.5 L/μmol, p < 0.001, respectively)., Conclusions: EPT infants have a sustained lower bilirubin-binding affinity of albumin beyond the first week of life., Impact: Bilirubin encephalopathy is still reported in extremely preterm (EPT) infants. EPT infants often have prolonged unbound bilirubinemia beyond the first week of life. Sustained lower bilirubin-binding affinity of albumin, regardless of the bilirubin-albumin molar ratio (BAMR), is observed in EPT infants. BAMRs should not be used as a surrogate marker of unbound bilirubinemia, especially in EPT infants at a later postnatal period., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

This corrects the article in Kobe J Med Sci. 2023 May 31; 69(1): E25-E32.

Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare.

Orogastric (OG) and nasogastric (NG) tubes have been reported to delay breastfeeding initiation and affect respiratory function. However, the effects of feeding tubes on sucking pressure have not been well studied. Fourteen preterm infants were enrolled in this study, and their sucking pressures during bottle feeding with an OG tube, NG tube, and without any tube were measured. Sucking pressure significantly increased after changing the OG tube to an NG tube (p = 0.044). However, sucking pressure showed no significant differences after changing the feeding method from an NG tube to oral intake. Thus, NG tubes are superior to OG tubes in terms of sucking pressure.

Several probiotic lactic acid bacteria (LAB) exert immunomodulatory effects on the host. However, the reasons for the different effects of LAB have not been fully elucidated. To understand the different immunomodulatory effects of LAB, we evaluated the levels of critical molecules in differentiated monocytic THP-1 and dendritic cells (DCs) following the uptake of various LAB strains. Lactobacillus helveticus JCM 1120, Lactobacillus acidophilus JCM 1132, Levilactobacillus brevis JCM 1059, and Lentilactobacillus kefiri JCM 5818 showed significantly higher uptake among the 12 LAB species tested. The uptake of microbeads by THP-1 DC increased when coupled with the surface layer proteins (Slps) from the tested strains. SlpB was mainly observed in the L. brevis JCM 1059 Slps extract. The expected cell surface receptor for SlpB on THP-1 DC was purified using SlpB-coupled affinity resin and identified as adenylyl cyclase-associated protein 1 (CAP-1). SlpB binding to THP-1 DC decreased after the addition of anti-CAP-1 and anti-DC-SIGN antibodies but not after the addition of anti-macrophage-inducible C-type lectin (Mincle) antibody. These results suggest that SlpB on L. brevis JCM 1059 plays preferentially binds to CAP-1 on THP-1 DC and plays a crucial role in bacterial uptake by THP-1 cells as well as in subsequent interleukin-12 (IL-12) production.

Background: This nationwide survey aimed to determine the status of jaundice management in Japan., Methods: A questionnaire about bilirubin level measurements and neonatal jaundice treatment was sent to 330 institutions providing neonatal care. The responses were analyzed according to institution level., Results: Of 330 institutions, 172 responded (52.1% response rate). Total bilirubin levels were measured in the central laboratory using spectrophotometry at 134 institutions and a blood gas analyzer at 81 institutions. Unbound bilirubin (UB) levels were measured by 79 institutions, while transcutaneous bilirubin measurements were taken at 63 institutions. There was no association between institution level and UB or transcutaneous bilirubin measurement. For phototherapy criteria, the Murata-Imura criteria were adopted by 67 institutions, Nakamura criteria by 36, and Morioka criteria by 39. Light-emitting diodes (LED) were used by 160 institutions versus fluorescent lights by 31. When a blue LED was used, 119 institutions used the high mode. There is no standard for increasing light intensity. No association was found between institution level and phototherapy criteria. UB was measured in 14 of 63 institutions using the Murata-Imura criteria., Conclusions: There is a large variation in the management and treatment of neonatal jaundice among institutes in Japan., (© 2023 Japan Pediatric Society.)

Commensal intestinal microbiota interacts with gut epithelial cells in the host by binding to specific host receptors. Several pattern recognition receptors on the gut that sense conserved microbial-associated molecular patterns have been reported; however, many of the gut receptor molecules involved in bacterial binding have not yet been identified. In this study, commensal intestinal bacteria interacting with mouse gut surface proteins were screened from fecal bacterial samples, to identify novel receptors on the epithelial cells in the mouse gut. Among the screened intestinal lactic acid bacteria, the frequently isolated Lactobacillus johnsonii MG was used for the purification of gut receptor proteins. An approximately 30 kDa protein was purified using affinity resin coupled surface layer proteins isolated from L. johnsonii MG. The purified gut protein was identified as a member of the tight junction protein family, junctional adhesion molecule-2 (JAM-2). As expected, the tight junctions of Caco-2 cells damaged by H 2 O 2 were repaired by incubation with L. johnsonii MG. RNA sequence analysis showed significant upregulation of the expression of genes for tight junctions, anti-inflammatory effects, transcriptional regulation, and apoptosis in Caco-2 cells, following L. johnsonii MG treatment. In L. johnsonii MG, the surface layer 40 kDa protein was purified with gut protein-coupled affinity resin and identified as the moonlighting protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH). These results suggest that L. johnsonii MG promotes the barrier function integrity in Caco-2 cells via GAPDH-JAM-2 binding. Here, we propose a promising approach to identify novel gut receptor molecules based on commensal bacterial interactions and understand host-bacterial communication in a mouse model.

Food protein-derived peptides with agonistic effects on receptors have great potential for treating anxiety, hypertension, and stress. In the present study, opioid peptides with agonistic activities for δ-receptor-expressing HEK293 cells were screened from casein hydrolysates prepared with five types of food grade proteolytic enzymes, among which casein hydrolysate with Aspergillus oryzae protease ASD showed the highest opioid activity. Eluted fractions showing potent opioid activity were further purified for active peptides by reverse phase-HPLC. The peptide in the active fraction was identified as YPFPGPIPNS, a member of β-casomorphin (CM-10) (β-casein 60-69). Various CM-10 derivative peptides were synthesized and their characteristic features for specificities towards δ- and μ-receptors were determined. Peptides 5 to 12 amino acids long showed relatively higher opioid activities for δ- and μ-receptors. CM-10 was docked into the optimized δ-receptor model. The CDOCKER energies of the CM-10 derivatives were consistent with their opioid activities. In the elevated plus-maze study, CM-10 showed a significant anti-anxiety effect in BALB/c mice at a dose of 10 mg per kg body weight when administered orally, but not via intravenous injection. Furthermore, intravital imaging revealed that Ca 2+ signaling was induced in the small intestinal villi of a Yellow Cameleon 3.60 (YC3.60)-expressing mouse upon injection with CM-10. However, this decreased in the presence of δ- or μ-receptor antagonists. These results suggest that the opioid peptide CM-10 prepared from casein with ASD has an anti-anxiety effect through interaction with gut δ- and/or μ-opioid receptors in the mouse gut.

Background and Aim: Non-steroidal anti-inflammatory drugs (NSAIDs) induce intestinal enteropathy and the pathophysiology is related to immune-mediated mechanisms. We aimed to investigate the role of C-C chemokine receptor type 7 (CCR7) which regulates immune cell migration in NSAID-induced enteropathy., Methods: Injury of the small intestine was evaluated 24 h after the subcutaneous injection of indomethacin in CCR7-deficient (Ccr7 -/- ) and wild-type (WT) mice. The cellular profile and cytokine production in intestinal cells were analyzed. Indomethacin-induced enteropathy was evaluated in mice adoptively transferred with CD103 + dendritic cells (DCs) from Ccr7 -/- or WT mice., Results: Indomethacin induced more severe intestinal injury in Ccr7 -/- mice than in WT mice. The major inflammatory cytokines were not increased and the proportion of regulatory T cells following indomethacin injection was not decreased in Ccr7 -/- mice compared with WT mice. The expression of interleukin (IL)-22 binding protein (IL-22BP), which inhibits IL-22 activity, was significantly higher in CD103 + DCs from Ccr7 -/- mice than those from WT mice. Mice adoptively transferred with CD103 + DCs isolated from Ccr7 -/- mice exhibited more severe intestinal injury following indomethacin injection compared with those adoptively transferred with CD103 + DCs of WT mice. Ccr7 -/- mice injected with indomethacin showed a significant reduction in regenerating islet-derived 1 (Reg1) mRNA expression, which is regulated by IL-22, in intestinal epithelial cells., Conclusions: C-C chemokine receptor type 7 deficiency exacerbated NSAID-induced enteropathy in association with an altered phenotype of CD103 + DCs that produces IL-22BP. CCR7 contributes to protect the small intestine from NSAID-induced mucosal injury., (© 2022 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objective: The fetal inflammatory response syndrome (FIRS) is characterized by elevated concentrations of inflammatory cytokines in fetal blood, with preterm delivery and morbidity. Umbilical cord serum interleukin-6 (UC-s-IL-6) is an ideal marker for detecting FIRS. However, the effect of gestational age (GA) on UC-s-IL-6 levels has not been reported. This study aimed to determine the relationship between GA and UC-s-IL-6 levels, and GA-dependent cutoff values of UC-s-IL-6 levels for detecting fetal inflammation., Study Design: UC-s-IL-6 concentrations were measured in 194 newborns (44 extremely preterm newborns (EPNs) at 22-27 weeks' GA, 68 very preterm newborns (VPNs) at 28-31 weeks' GA, and 82 preterm newborns (PNs) at 32-34 weeks' GA). Linear regression analyses were used to correlate GA and UC-s-IL-6 levels. Receiver operating characteristic (ROC) curves analyses were performed for detecting the presence of funisitis, as the histopathological counterpart of FIRS., Results: A significant negative correlation between GA and UC-s-IL-6 levels was found in newborns with severe funisitis ( r s  =  - 0.427, p  = 0.004) and those with mild funisitis ( r  = 0.025). ROC curve analyses revealed the area under the curve for detecting funisitis were 0.856, 0.837, and 0.622 in EPNs, VPNs, and PNs, respectively. The UC-s-IL-6 cutoff value in EPNs (28.1 pg/mL) exceeded those in VPNs and PNs (3.7 and 3.0 pg/mL, respectively).s  =  - 0.396, p  = 0.025). ROC curve analyses revealed the area under the curve for detecting funisitis were 0.856, 0.837, and 0.622 in EPNs, VPNs, and PNs, respectively. The UC-s-IL-6 cutoff value in EPNs (28.1 pg/mL) exceeded those in VPNs and PNs (3.7 and 3.0 pg/mL, respectively)., Conclusion: UC-s-IL-6 levels were inversely correlated with GA especially in newborns with funisitis. Such GA dependency of UC-s-IL-6 should be considered for detecting fetal inflammation., Key Points: · IL-6 levels inversely correlate with GA.. · Higher IL-6 levels strongly indicate funisitis.. · Detecting cutoff values differ depending on GA.., Competing Interests: None declared., (Thieme. All rights reserved.)

The effects of medical and surgical interventions on the survival of patients with trisomy 18 have been reported, leading to changes in perinatal management and decision-making. However, few studies have fully reported the recent changes in survival and treatment of trisomy 18. We examined how treatment and survival of patients with trisomy 18 have changed over a decade in a Japanese pediatric tertiary referral center. This retrospective cohort study included patients with trisomy 18 who were admitted within the first 7 days of life at the Hyogo Prefectural Kobe Children's Hospital between 2008 and 2017. The patients were divided into early period (EP) and late period (LP) groups based on the birth year of 2008-2012 and 2013-2017, respectively. Changes in treatment and survival rates were compared between the two groups. A total of 56 patients were studied (29 in the EP group and 27 in the LP group). One-year survival rates were 34.5% and 59.3% in the EP and LP groups, respectively. The survival to discharge rate significantly increased from 27.6% in the EP group to 81.5% in the LP group (p < 0.001). The proportion of patients receiving surgery, especially for congenital heart defects, significantly increased from 59% in the EP group to 96% in the LP group (p = 0.001). In our single-center study, survival and survival to discharge were significantly improved in patients with trisomy 18, probably because of increased rate of surgical interventions. These findings may facilitate better decision-making by patients' families and healthcare providers., (© 2021 Wiley Periodicals LLC.)

The outcomes of patients with elderly onset (EO) inflammatory bowel disease (IBD) treated with anti-tumor necrosis factor (TNF) remains uncertain. The present study evaluated the efficacy and safety of anti-TNF treatment for bio-naïve EO-IBD. Elderly patients were defined as those 60 years and older, and further divided into those with EO (Elderly-EO) and those with non-elderly onset (Elderly-NEO). A total of 432 bio-naïve patients were enrolled in this multicenter observational study, comprising 55 with Elderly-EO (12.7%), 25 with Elderly-NEO (5.8%), and 352 under age 60 (Non-elderly, 81.5%). After 52 weeks of anti-TNF treatment, clinical and steroid-free remission rates were significantly lower in Elderly-EO than in Non-elderly (37.7% and 60.8%; P = 0.001, and 35.9% and 57.8%; P = 0.003, respectively), and comparable between Elderly-NEO and Non-elderly. Multivariate analysis revealed that elderly onset was a significant factor for both clinical remission (OR, 0.49, 95% CI 0.25-0.96) and steroid-free remission (OR, 0.51, 95% CI 0.26-0.99) after 52 weeks of anti-TNF treatment. The rate of cumulative severe adverse events was significantly higher in Elderly-EO than in Non-elderly (P = 0.007), and comparable between Elderly-NEO and Non-elderly. In conclusion, anti-TNF treatment for bio-naïve EO-IBD may be less effective and raise safety concerns., (© 2022. The Author(s).)

Background: In the original glucose oxidase-peroxidase (GOD-POD) protocol, the time required to decrease the initial total bilirubin (TB) level by 20% is used for unbound bilirubin (UB) calculation. However, it needs to continuously monitor the TB levels by spectrometry., Methods: Here, we hypothesized that the TB decrease during fixed time periods can also be used to extrapolate UB values (fixed-time protocol). Serum UB levels measured by the different protocols were compared using 10 newborn serum samples., Results: Serum UB levels determined using the fixed-time protocol, especially using periods of 10 - 40 seconds, were strongly correlated with those determined using the original protocol (coefficient of determination > 0.9). The fixed-time protocol, using periods of 20 - 60 seconds, showed the high measurement precision (coefficient of variation < 5%)., Conclusions: The fixed-time protocol, using periods of 20 - 40 seconds, can help determine serum UB levels as effectively as the original protocol.

Background: Admission temperature is inversely correlated with mortality and morbidity risk in extremely preterm newborns (EPNs). As almost all EPNs require advanced resuscitation at birth, we improved a simple and comprehensive management protocol to reduce admission hypothermia. This study reports the changes over the past 15 years in the rate of admission hypothermia in all EPNs. It clarified the distribution of admission temperature and the risk factors for developing admission hypothermia in recent EPNs., Methods: This single-center study retrospectively analyzed the EPNs delivered at our institution between January 2006 and December 2020. The comprehensive management protocol, including warming equipment, plastic wrapping, aluminum-polyethylene sheet, and room temperature, was applied to avoid heat loss during resuscitation. On admission, the rectal temperature was measured and defined as moderate (32.0-35.9 °C) or mild (36.0-36.4 °C) hypothermia., Results: Overall (n = 432), the rate of admission with moderate hypothermia decreased from 48% in 2006 to 8% in 2020. In the recent evaluation of 80 EPNs delivered in 2017-2020, 10 (13%) and 26 (33%) had moderate and mild hypothermia on admission, respectively. Extremely preterm newborns with moderate-to-mild hypothermia had a significantly smaller gestational age and lower birthweight than those without hypothermia. No significant differences in the other perinatal and environmental risk factors were observed between EPNs with and without hypothermia., Conclusions: Our comprehensive management protocol reduced the rate of moderate hypothermia on admission in EPNs to only 13%. However, eliminating mild hypothermia remains a challenge and requires continuous improvement, especially in smaller EPNs., (© 2022 Japan Pediatric Society.)

Background: To diagnose hypoalbuminemia in newborns, it is essential to establish a definition applicable to those with a different gestational age (GA) and clinical conditions. A positive correlation between serum albumin levels and GA has been reported, but the study was limited to small numbers of newborns. We therefore investigated the GA-dependent reference ranges for serum albumin levels using cord venous blood (UC-Alb levels) from a large number of newborns delivered at a tertiary perinatal center., Methods: Albumin levels were assessed in 2,917 newborns at 22-41 weeks of GA after exclusion of those with congenital disorders. Linear regression analysis was used to correlate GA and UC-Alb levels. After calculation of the percentile values of UC-Alb levels for each week of GA, the distributions were approximated by the least-squares method. To validate the determined linear approximation of the 5%ile value, the UC-Alb levels in newborns with hydrops fetalis and gastroschisis were used., Results: A significant positive correlation between GA and UC-Alb levels was found (rs = 0.701, p < 0.001, respectively). The distribution of the 5%ile of UC-Alb levels (Y) by GA (X) was approximated as a straight line (Y = 0.062 × X + 0.326, R2 = 0.951). Among the 59 and 18 newborns with hydrops fetalis and gastroschisis, 51 (86.4%) and 15 (83.3%), respectively, were below the line., Conclusions: We established GA-dependent reference ranges for serum albumin levels, which may be useful to accurately diagnose hypoalbuminemia in newborns., (© 2022 S. Karger AG, Basel.)