Host-derived protein profiles of human neonatal meconium across gestational ages.

Meconium, a non-invasive biomaterial reflecting prenatal substance accumulation, could provide valuable insights into neonatal health. However, the comprehensive protein profile of meconium across gestational ages remains unclear. Here, we conducted an extensive proteomic analysis of first meconium from 259 newborns across varied gestational ages to delineate protein composition and elucidate its relevance to neonatal diseases. The first meconium samples were collected, with the majority obtained before feeding, and the mean time for the first meconium passage from the anus was 11.9 ± 9.47 h. Our analysis revealed 5370 host-derived meconium proteins, which varied depending on sex and gestational age. Specifically, meconium from preterm infants exhibited elevated concentrations of proteins associated with the extracellular matrix. Additionally, the protein profiles of meconium also exhibited unique variations depending on both specific diseases, including gastrointestinal diseases, congenital heart diseases, and maternal conditions. Furthermore, we developed a machine learning model to predict gestational ages using meconium proteins. Our model suggests that newborns with gastrointestinal diseases and congenital heart diseases may have immature gastrointestinal systems. These findings highlight the intricate relationship between clinical parameters and meconium protein composition, offering potential for a novel approach to assess neonatal gastrointestinal health.

A Novel De Novo Variant in KCNH5 in a Patient with Refractory Epileptic Encephalopathy.

We herein report a novel de novo KCNH5 variant in a patient with refractory epileptic encephalopathy. The patient exhibited seizures at 1 year and 7 months old, which gradually worsened, leading to a bedridden status. Brain magnetic resonance imaging (MRI) showed cerebral atrophy and cerebellar hypoplasia. A trio whole-exome sequence analysis identified a de novo heterozygous c.640A>C, p.Lys214Gln variant in KCNH5 that was predicted to be deleterious. Recent studies have linked KCNH5 to various epileptic encephalopathies, with many patients showing normal MRI findings. The present case expands the clinical spectrum of the disease, as it is characterized by severe neurological prognosis, cerebral atrophy, and cerebellar hypoplasia.

Impact of Portal Flow on the Prognosis of Children With Congenital Portosystemic Shunt: A Multicentric Observation Study in Japan.

BACKGROUND: Although congenital portosystemic shunts (CPSSs) are increasingly being recognized, the optimal treatment strategies and natural prognosis remain unclear, as individual CPSSs show different phenotypes. METHODS: The medical records of 122 patients who were diagnosed with CPSSs at 15 participating hospitals in Japan between 2000 and 2019 were collected for a retrospective analysis based on the state of portal vein (PV) visualization on imaging. RESULTS: Among the 122 patients, 75 (61.5%) showed PV on imaging. The median age at the diagnosis was 5 months. The main complications related to CPSS were hyperammonemia (85.2%), liver masses (25.4%), hepatopulmonary shunts (13.9%), and pulmonary hypertension (11.5%). The prevalence of complications was significantly higher in patients without PV visualization than in those with PV visualization (P < 0.001). Overall, 91 patients (74.6%) received treatment, including shunt closure by surgery or interventional radiology (n = 82) and liver transplantation (LT) or liver resection (n = 9). Over the past 20 years, there has been a decrease in the number of patients undergoing LT. Although most patients showed improvement or reduced progression of symptoms, liver masses and pulmonary hypertension were less likely to improve after shunt closure. Complications related to shunt closure were more likely to occur in patients without PV visualization (P = 0.001). In 25 patients (20.5%) without treatment, those without PV visualization were significantly more likely to develop complications related to CPSS than those with PV visualization (P = 0.011). CONCLUSION: Patients without PV visualization develop CPSS-related complications and, early treatment using prophylactic approaches should be considered, even if they are asymptomatic. LEVEL OF EVIDENCE: Level III.

Impact of gallbladder hypoplasia on hilar hepatic ducts in biliary atresia.

BACKGROUND: Biliary atresia (BA) is an intractable disease of unknown cause that develops in the neonatal period. It causes jaundice and liver damage due to the destruction of extrahepatic biliary tracts,. We have found that heterozygous knockout mice of the SRY related HMG-box 17 (Sox17) gene, a master regulator of stem/progenitor cells in the gallbladder wall, exhibit a condition like BA. However, the precise contribution of hypoplastic gallbladder wall to the pathogenesis of hepatobiliary disease in Sox17 heterozygous embryos and human BA remains unclear. METHODS: We employed cholangiography and histological analyses in the mouse BA model. Furthermore, we conducted a retrospective analysis of human BA. RESULTS: We show that gallbladder wall hypoplasia causes abnormal multiple connections between the hilar hepatic bile ducts and the gallbladder-cystic duct in Sox17 heterozygous embryos. These multiple hilar extrahepatic ducts fuse with the developing intrahepatic duct walls and pull them out of the liver parenchyma, resulting in abnormal intrahepatic duct network and severe cholestasis. In human BA with gallbladder wall hypoplasia (i.e., abnormally reduced expression of SOX17), we also identify a strong association between reduced gallbladder width (a morphometric parameter indicating gallbladder wall hypoplasia) and severe liver injury at the time of the Kasai surgery, like the Sox17-mutant mouse model. CONCLUSIONS: Together with the close correlation between gallbladder wall hypoplasia and liver damage in both mouse and human cases, these findings provide an insight into the critical role of SOX17-positive gallbladder walls in establishing functional bile duct networks in the hepatic hilus of neonates.

Biliary atresia (BA) is a disease in newborns that causes a serious liver condition due to damage to the bile ducts (the pathways that carry bile juice). Although reduced function of a key gene called Sox17, which is essential for forming the gallbladder wall, has been observed in some BA cases, the link between gallbladder issues and liver damage is unknown. This study has shown how damage spreads through the bile ducts in the liver around the time of birth when there are problems in the gallbladder wall due to reduced SOX17 function. The findings indicate that proper growth of the gallbladder wall during this critical period is essential for forming a normal network of bile ducts in the developing liver. This discovery is promising for early diagnosis and better treatment of BA in newborns.

Treatment and Outcomes of 844 Cases of Pneumothorax in Heritable Connective Tissue Disorders.

BACKGROUND: Characteristics, practice patterns, and clinical outcomes of secondary spontaneous pneumothorax (SSP) with heritable connective tissue disorders (Marfan, Ehlers-Danlos, and Birt-Hogg-Dubé syndromes) are unclear. METHODS: A nationwide Japanese inpatient database that included data of 524 patients with SSP (884 hospitalizations) and 137,821 with primary spontaneous pneumothorax between July 2010 and March 2020 was used in this study. Hospitalization for SSP (n = 884) was categorized into surgical (n = 459) and nonsurgical (n = 425) groups, and the patient characteristics, treatment, and outcomes were compared between the groups. Multivariable analyses were performed to evaluate risk factors for pneumothorax recurrence. We also compared the characteristics of patients with different underlying heritable connective tissue disorders. RESULTS: Compared with the nonsurgical group, the surgical group had less frequent readmission for pneumothorax (26% vs 44%; hazard ratio, 0.47; 95% CI, 0.38-0.58). Young patients (2.46; 1.83-3.32) or those with Birt-Hogg-Dubé syndrome (2.53; 1.77-3.63) had a high risk of recurrence. Pneumothorax occurred frequently in teenagers with Marfan syndrome, in those aged 20 to 39 years with Ehlers-Danlos syndrome, and in those aged ≥40 years with Birt-Hogg-Dubé syndrome. CONCLUSIONS: Detailed information on the characteristics and clinical course of SSP in heritable connective tissue disorders will aid in the clinical decision-making process.

Postoperative pulmonary vascular growth in patients with congenital diaphragmatic hernia.

BACKGROUND: Postoperative pulmonary growth in congenital diaphragmatic hernias (CDH) remains unclear. We investigated postoperative pulmonary vascular growth using serial lung perfusion scintigraphy in patients with CDH. METHODS: Neonates with left CDH who underwent surgery and postoperative lung perfusion scintigraphy at our institution between 2001 and 2020 were included. Patient demographics, clinical courses, and lung scintigraphy data were retrospectively analyzed by reviewing medical records. RESULTS: Twenty-one patients with CDH were included. Of these, 10 underwent serial lung scintigraphy. The ipsilateral perfusion rate and median age on the 1st and serial lung scintigraphy were 32% (34 days) and 33% (3.6 years), respectively. Gestational age at prenatal diagnosis (p = 0.02), alveolar-arterial oxygen difference (A-aDO2) at birth (p = 0.007), and preoperative nitric oxide (NO) use (p = 0.014) significantly correlated with the 1st lung scintigraphy. No other variables, including operative approach, were significantly correlated with the 1st or serial scintigraphy findings. All patients improved lung perfusion with serial studies [Difference: + 7.0 (4.3-13.25) %, p = 0.001, paired t-test]. This improvement was not significantly correlated with preoperative A-aDO2 (p = 0.96), NO use (p = 0.28), or liver up (p = 0.90). The difference was significantly larger in patients who underwent thoracoscopic repair than in those who underwent open abdominal repair [+ 10.6 (5.0-17.1) % vs. + 4.25 (1.2-7.9) %, p = 0.042]. CONCLUSION: Our study indicated a postoperative improvement in ipsilateral lung vascular growth, which is possibly enhanced by a minimally invasive approach, in patients with CDH.

Case Series of Endoscopic Papillary Balloon Dilation for Children with Common Bile Duct Stones and a Review of the Literature.

Background: Endoscopic sphincterotomy (EST) has been employed for the endoscopic treatment of common bile duct stones (CBDSs) and has been reported to have a high success rate for stone removal. However, EST is associated with a risk of bleeding, perforation, and sphincter of Oddi function disruption. To avoid these risks, endoscopic papillary balloon dilation (EPBD) is an option for CBDS. Sphincter of Oddi function preservation decreases long-term biliary infection and gallstone recurrence. EPBD may have advantages in children who require a long follow up. However, there have been few reports on pediatric cases, particularly in infants. Methods: From September 2017 to December 2023, we performed EPBD for four pediatric CBDSs. The patients were aged from 5 months to 8 years, including two infants aged 5 and 6 months. Furthermore, we reviewed the stone removal rate and complications of 545 ESTs performed at high-volume centers and 13 EPBD-reported cases in children with CBDSs. Results: CBDSs of all patients who underwent EPBD in our institution were successfully removed. No bleeding or perforation was noted; pancreatitis was observed in three patients. In an analysis of 545 ESTs in children, the stone removal rate was high, ranging from 83% to 100% (mean 96%). The incidence of pancreatitis was 0-9.6% (mean 4.4%), and the grade of pancreatitis was almost mild. The bleeding frequency was 1.3-5.4% (mean 2.7%). With regards to the grade of bleeding, seven cases were mild (64%) and four were moderate (36%). Compared with adults who underwent EST, the frequencies of pancreatitis and bleeding were almost equal in children; however, in children, once bleeding occurs, it has a higher risk of leading to blood transfusion. Stone removal via EPBD in children has a 100% success rate. Pancreatitis was responsible for all complications were related; its frequency was 46% (6/13 patients, including five mild cases and one moderate case), which is higher than that of EST and adult cases who underwent EPBD. In most children with pancreatitis, pancreatic enzyme levels returned to normal within 2-3 days following EPBD, and no severe cases caused by EPBD were reported. Conclusions: CBDS removal via EPBD in children has a high success rate with very low risk of bleeding and perforation. Although pancreatitis frequently occurs, most cases are mild. Sphincter of Oddi function preservation via EPBD is expected to prevent long-term stone recurrence and biliary tract infection, and EPBD is considered to be an effective method for CBDS removal in children.

Impact of the novel coronavirus infection on pediatric surgery: an analysis of data from the National Clinical Database.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic limited the delivery of medical resources. Although surgeries are triaged according to disease severity and urgency, a delay in diagnosis and surgery can be detrimental. We conducted this study to analyze data on the impact of the COVID-19 pandemic on pediatric surgery for different diseases or disorders. METHODS: We compiled and compared data on pediatric surgical cases from 2018 to 2020, using the National Clinical Database. The number of diseases, severity, complication rates, mortality rates by disease/disorder, and the COVID-19 pandemic areas were analyzed. RESULTS: The total number of cases of pediatric surgery in 2018, 2019, and 2020 was 50,026, 49,794, and 45,621, respectively, reflecting an 8.8% decrease in 2020 from 2018 and an 8.4% decrease in 2020 from 2019. A decrease was observed when the number of patients with COVID-19 was high and was greater in areas with a low infection rate. There was a marked decrease in the number of inguinal hernia cases. The number of emergency room visits and emergency surgeries decreased, but their relative proportions increased. CONCLUSIONS: The COVID-19 pandemic decreased the number of pediatric surgeries, reflecting the limitations of scheduled surgeries and infection control measures.

Non-classical Monocytes Enhance the Efficacy of Immune Checkpoint Inhibitors on Colon Cancer in a Syngeneic Mouse Model.

BACKGROUND/AIM: The response rate to immune checkpoint inhibitors (ICIs) is approximately 10%-30% and only in a few cancer types. In the present study, we determined whether non-classical monocytes (NCMs) could enhance ICI efficacy in colon cancer using a syngeneic mouse model. MATERIALS AND METHODS: The MC38 C57BL/6 mouse colon cancer model was used. Cells collected from the bone marrow of C57BL/6 mice were cultured, and NCMs were fractionated by cell sorting and administered via the tail veins to the mice implanted with MC38 cells. The anti-mouse PD-L1 antibody was administered three times, and tumor volume and overall survival were observed. RESULTS: More tumors were eradicated and more complete response occurred, after cotreatment with ICIs and NCMs than after treatment with ICIs alone. Moreover, no efficacy was observed when NCMs were administered alone. CONCLUSION: NCMs enhance ICI efficacy. The underlying mechanisms and clinical applications will be studied in the future.

Intake levels and main sources of nutrients for Japanese children with motor or intellectual disabilities.

Proper nutritional management is important for the growth and development of children with motor or intellectual disabilities; however, few studies have investigated the nutrient intake of children with disabilities. This study aimed to investigate the nutrient intake and food groups that are the main sources of nutrients for children with disabilities. This cross-sectional observational study included twenty-five children (mean age, 11⋅8 years) from five hospitals in Japan. Using a 3-d weighed dietary record, we estimated the daily nutrient intake and food and beverage sources that contributed to nutrient intake. The mean values of calcium, magnesium, iron, vitamin A, thiamine, riboflavin, and vitamin C intake were below the recommended dietary allowance, and those of dietary fiber and potassium were below the levels recommended by the Tentative Dietary Goal for Preventing Lifestyle-related Diseases (DG). In contrast, the mean intake values of fat, saturated fatty acids, and sodium were above the DG levels. Dairy products, meat, vegetables, and cereals were found to be the major contributors of nutrients. Increased intake of vegetables may help alleviate insufficient micronutrient intake in children with disabilities.

Perioperative outcomes of thyroid cancer surgery in children and adults: a nationwide inpatient database study in Japan.

BACKGROUND: Little is known about perioperative outcomes after pediatric thyroidectomy. This study was performed to compare perioperative outcomes between children and adults undergoing thyroid cancer surgery using a nationwide inpatient database in Japan. METHODS: Using the Japanese Diagnosis Procedure Combination database, we identified patients aged 0 to 40 years with thyroid cancer who underwent thyroidectomy from July 2010 to March 2020. To compare the occurrence of in-hospital morbidities including local complications (e.g., recurrent laryngeal nerve paralysis, postoperative bleeding), duration of anesthesia, postoperative length of stay, and total hospitalization costs between children (0-18 years) and adults (19-40 years), we used multivariable logistic regression analysis for the occurrence of in-hospital morbidities and linear regression for other outcomes. RESULTS: For 16,016 eligible patients (666 children vs. 15,350 adults), no significant differences between the two groups were found in any in-hospital morbidity (5.4% vs. 5.9%; adjusted odds ratio [OR], 0.80; 95% confidence interval [CI], 0.57-1.14; P = 0.23), local complications (5.0% vs. 5.5%; OR, 0.80; 95% CI, 0.55-1.15; P = 0.22), recurrent laryngeal nerve paralysis (2.1% vs. 2.4%; OR, 0.78; 95% CI, 0.45-1.35; P = 0.37), or postoperative bleeding (1.7% vs. 1.4%; OR, 0.99; 95% CI, 0.53-1.87; P = 0.98). Children showed a longer duration of anesthesia (difference, 20 minutes; 95% CI, 13-27; P < 0.001) and higher total costs (difference, 445 US dollars; 95% CI, 239-651; P < 0.001) than adults. CONCLUSION: This large nationwide cohort study showed no significant difference in perioperative complications between children and adults undergoing thyroid cancer surgery.