Association Between Receipt of General Anesthesia During Childhood and Attention Deficit Hyperactive Disorder and Neurodevelopment.

BACKGROUND: There are inconsistent reports regarding the association between general anesthesia and adverse neurodevelopmental and behavioral disorders in children. METHODS: This nationwide administrative cohort study included children born in Korea between 2008 and 2009, and followed until December 31, 2017. The cohort included 93,717 participants who received general anesthesia with endotracheal intubation (ETI) who were matched to unexposed subjects in a 1:1 ratio. General anesthesia was defined by National Health Insurance Service treatment codes with intratracheal anesthesia, and the index date was the first event of general anesthesia. The primary outcome was attention deficit hyperactive disorder (ADHD), which was defined as at least a principal diagnosis of 10th revision of the International Classification of Diseases code F90.X after the age of 72 months. Neurodevelopment, which was assessed using a developmental screening test (Korean-Ages and Stages Questionnaire [K-ASQ]), was a secondary outcome. The K-ASQ is performed annually from 1 to 6 years of age and consists of 5 domains. The association between general anesthesia and ADHD was estimated using a Cox hazard model, and its association with neurodevelopment was estimated using a generalized estimation equation, with control for multiple risk factors beyond 1 year after the index date. RESULTS: The median age at the index date was 3.8 (95% confidence interval [CI], 1.7-5.8) years, and there were 57,625 (61.5%) men. During a mean follow-up period of 5 years, the incidence rate of ADHD was 42.6 and 27.7 per 10,000 person-years (PY) in the exposed and unexposed groups, respectively (absolute rate difference 14.9 [95% CI, 12.5-17.3] per 10,000 PY). Compared to the unexposed group, the exposed group had an increased risk of ADHD (adjusted hazard ratio, 1.41 [95% CI, 1.30-1.52]). In addition, a longer duration of anesthesia with ETI and more general anesthesia procedures with ETI were associated with greater risk of ADHD. General anesthesia with ETI was also associated with poorer results in the K-ASQ. CONCLUSION: Administration of general anesthesia with ETI to children is associated with an increased risk of ADHD and poor results in a neurodevelopmental screening test.

Neurodevelopmental Outcomes in Infants Fed with Soy Formula: A Retrospective, National Population-Based Observational Cohort Study.

BACKGROUND: Soy-based infant formulas are increasingly popular, but data regarding their effects on neurodevelopmental outcomes during early childhood is scanty. OBJECTIVE: This study investigated the effect of consuming soy-based infant formula at 9-12 mo after birth on the subsequent development of epilepsy, neurodevelopmental disorders, and developmental status. METHODS: This nationwide retrospective administrative study used health screening examinations and linked insurance claims data of children born in Korea during 2008 and 2009. Infants who received soy formula were compared with those who received cow's milk formula using propensity score matching that considered birth history, economic status, clinical conditions, and drug prescription records. Exposure was defined as soy formula feeding determined from questionnaires completed by the parents when children were 9-12 mo old. Outcomes were epilepsy, attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and developmental status. Children were followed until 31 December, 2017. RESULTS: A total of 153,841 eligible participants were enrolled; 11,535 (7.5%) children received soy formula, while 142,864 (92.5%) received cow's milk formula. The incidence rate of epilepsy during the follow-up period was 29.8 per 100,000 person-years (95% CI: 19.48, 41.65) in the soy formula group and 22.6 per 100,000 person-years (95% CI: 31.97, 59.07) in the cow's milk formula group, with no significant difference (aHR: 1.318; 95% CI: 0.825, 2.106). The 2 groups also had no difference based on prespecified analysis using different definitions of epilepsy. Likewise, no significant associations of soy formula with ADHD (aHR: 1.26; 95% CI: 1.00, 1.60) or ASD (aHR: 0.99; 95% CI: 0.54, 1.83), or delays of developmental stages were observed. CONCLUSIONS: Feeding with soy formula rather than cow's milk formula had no apparent association with increased risks of epilepsy, ADHD, ASD, and developmental status, according to this cohort composed of a general pediatric population.

Fecal calprotectin level in healthy children aged less than 4 years in South Korea.

BACKGROUND: Fecal calprotectin (FC) is non-invasive inflammatory marker indicating various bowel diseases. However, the median-specific cut-off values and the standard deviations (SD) of the FC levels in each age group <4 years were not elucidated. METHODS: Healthy volunteers were enrolled from four kindergartens. A questionnaire was used to confirm that the children met the inclusion criteria, and several demographics and history of bowel symptoms were collected. The FC level was measured. RESULTS: A total of 234 healthy children aged between 6 months and 4 years were recruited. The median FC concentration of all participants was 245 µg/g (range 12-1033 µg/g, mean 68.5 µg/g, SD 123.12 µg/g). The children were divided into six age groups. The upper limit of 95% CI of median FC values was 135 µg/g in 7-12 months group, 65 µg/g in 13-18 months group, 55 µg/g in 19-24 months group, 40 µg/g in 25-30 months group, 21 µg/g in 31-36 months group, and 12 µg/g in 37-48 months group. A negative correlation trend was found between the age and the FC concentration. CONCLUSION: This is the first study to present the FC median levels in the specific age groups <4 years in Korea. We found a FC level reduction with age, indicating a bowel maturation process and decreased intestinal permeability of the intestinal mucosa. In our study, FC levels reached the values of 50 µg/g around the age of 2 years.

Atypical Neonatal Marfan Syndrome with p.Glu1073Lys Mutation of FBN1: the First Case in Korea.

Neonatal Marfan syndrome (nMFS) is considered to be on the most severe end of the spectrum of type I fibrillinopathies. The common features of nMFS include ascending aortic dilatation, severe mitral and/or tricuspid valve insufficiency, ectopia lentis, arachnodactyly, joint contractures, crumpled ear, loose skin, and pulmonary emphysema.We describe a newborn male diagnosed with nMFS. He presented several atypical features, such as diaphragmatic eventration, severe hydronephrosis with hydroureter, and dilated cisterna magna. Molecular analysis revealed a missense mutation at nucleotide 3217 (c.3217G>A) in exon 26 of the fibrillin-1 (FBN1) gene, resulting in the substitution of a glutamate for a lysine at codon 1073 (E1073K) in the 12th calcium binding epidermal growth factor-like domain of the FBN1 protein. Here we report a rare case of Nmfs with several combined atypical features, such as diaphragmatic eventration, severe hydronephrosis with hydroureter, and dilated cisterna magna. Our report is the first atypical nMFS case with p.Glu1073Lys mutation of FBN1 in Korea and may help clinicians with the diagnosis and follow-up of atypical nMFS.

Successful weaning from mechanical ventilation in a patient with SMA type 1 treated with nusinersen.

SMA type 1 is the most severe type, characterized by early onset at <6 months of age, and rapid progression resulting in permanent assisted ventilation before 2 years of life. Supportive care was the only treatment until the approval of nusinersen, an antisense oligonucleotide drug that increases functional SMN protein levels. We present a case of successful weaning from permanent ventilation via tracheostomy with nusinersen in an infant who had been diagnosed with SMA type 1 at the age of one month and had become ventilator-dependent from the age of 3 months.

The association of nasal patency with small airway resistance in children with allergic and nonallergic rhinitis.

INTRODUCTION: Allergic rhinitis (AR) is immunologically and morphologically related to disorders in the lower airway. We investigated the relationship between the anatomy of the intranasal cavity and small airway resistance in subjects with nonallergic rhinitis (NAR). METHODS: We enrolled 226 children who were 7 years old and participated in the Seongnam Atopy Project 2016. We evaluated nasal patency using acoustic rhinometry to measure the volume of the nasal cavity at 0-5 cm, and measured lung function of the lower airway using an impulse oscillometry system (IOS) and spirometry. We also performed skin prick tests for 18 aero-allergens, and measured blood total eosinophil counts (TEC) and rhinitis symptom scores for the previous month using a visual analog scale (VAS, range: 0-10). RESULTS: We examined 226 children, 71 (31.7%) with AR, and 62 (27.7%) with NAR. Nasal patency in children with AR (median: 8.28 mm3 , IQR: 7.07-9.83) was lower than that of healthy children (median: 9.3 mm3 , IQR: 7.69-10.64, P = 0.011). Multivariate regression analysis showed that nasal patency was inversely associated with IOS resistance at 5 Hz after adjustment for compounding factors (B = -0.005, SE = 0.0032, P = 0.041). Analysis of NAR subjects, according to quartiles of nasal patency and quartiles of small airway resistance (Rrs5), indicated that nasal patency decreased as Rrs5 increased (linear trend: P = 0.020). CONCLUSION: Nasal symptoms and TEC negatively correlated with nasal patency. Children with AR and NAR who had poor nasal patency had increased small airway resistance.

Characteristics and prognosis of hepatic cytomegalovirus infection in children: 10 years of experience at a university hospital in Korea.

PURPOSE: Studies on cytomegalovirus (CMV) infections in immunocompetent children are lacking, and minimal information is available in the medical literature on hepatic manifestations and complications of CMV. The aims of this study were to evaluate the clinical characteristics, laboratory data, and prognosis of children with CMV hepatitis, and to investigate its prevalence at a single medical center in Korea over a 10-year period. METHODS: One hundred thirty-two children diagnosed with CMV infection based on specific markers (anti-CMV IgM, CMV polymerase chain reaction in blood and urine, or CMV culture of urine) were included in the study. Clinical and biochemical characteristics, immunological markers, and outcomes of hepatic CMV infection were determined. RESULTS: The median age of patients (n=132) was 8.5 months (range, 14 days-11.3 years). Peak total bilirubin and alanine aminotransferase levels in serum ranged from 0.11-21.97 mg/dL, and 5-1,517 IU/L, respectively. Alanine aminotransferase remained elevated from 2-48 weeks. Jaundice was the most common clinical feature of hepatic CMV infection during infancy. The hematologic findings revealed anemia, leukocytosis, and monocytosis in CMV-infected patients. All participants recovered without administration of ganciclovir. CONCLUSION: In children with CMV hepatitis, fever was the most common symptom at presentation, and jaundice was the most common clinical feature of hepatic CMV infection in infants younger than 3 months of age. Hepatic CMV infection in immunocompetent children is often a self-limited illness that does not require antiviral therapy, as most patients in this study had favorable outcomes.

Association of ALDH2 polymorphism with sensitivity to acetaldehyde-induced micronuclei and facial flushing after alcohol intake.

To investigate whether sensitivity to the induction of micronuclei by acetaldehyde is associated with genetic polymorphisms of the aldehyde dehydrogenase-2 (ALDH2) gene, cytokinesis-block micronucleus (CBMN) assays were performed on peripheral lymphocytes from 47 healthy human subjects exposed to acetaldehyde in vitro. Facial flushing following alcohol intake was analyzed to determine if it was correlated with ALDH2 gene polymorphisms. The frequencies of the ALDH2 genotypes ALDH2(1)/ALDH2(1), ALDH2(1)/ALDH2(2), and ALDH2(2)/ALDH2(2) were 66.0, 27.7, and 6.4%, respectively, in the 47 subjects. Therefore, 34% of the studied subjects carried the mutant allele ALDH2(2), which is associated with the lack of enzyme activity. The frequency of micronuclei induced by acetaldehyde increased in a dose-dependent manner with the largest increase seen in subjects that were homozygous for the ALDH2(2) allele. A significant association was observed between the ALDH2 genotype and alcohol-induced facial flushing. Average alcohol consumption of the study subjects was also associated with the ALDH2 genotype. The frequency of heavy drinking was significantly higher among subjects with the ALDH2(1)/ALDH2(1) genotype than among subjects with the ALDH2(2) allele (ALDH2(1)/ALDH2(2) and ALDH2(2)/ALDH2(2) genotypes). Alcohol-induced facial flushing was also associated with an increased frequency of micronuclei in lymphocytes treated with acetaldehyde. The results suggest that the ALDH2 genotype is significantly associated with acetaldehyde-induced micronuclei and alcohol-induced facial flushing.

Development of a rapid planning technique based on heuristic target shaping for stereotactic radiosurgery.

Stereotactic radiosurgery (SRS) is a technique to delivering a high dose to a target region and a low dose to a critical organ by using only one or a few irradiations. Traditionally, SRS is performed using a Gamma knife with using 201 cobalt 60 sources or a linear accelerator with equally spaced noncoplanar arcs. Finding a specific condition that includes the target in the prescription dose while sparing the critical organ is tedious, because there are many combinations of positions and collimator sizes for each isocenter. Many methods of identifying suitable planning condition automatically have been proposed. However, there are some limitations using these methods. These include a long calculation time to obtain the final plan, and difficulties finding a unique solution due to different tumor shapes. This study uses three steps to solve these problems. (1) The dose distribution of one isocenter is modeled as a sphere. This makes it possible to reduce the time needed to obtain the result due to the absence of a dose calculation. (2) The target was constructed by piling up cylinders along a virtual axis, which was the longest line in a given target. (3) Spheres were then packed in each cylinder according to the position and diameter of each cylinder in order to cover each target divided by the height of the cylinder. The results of applying three imaginary targets were found to be satisfactory in terms of: target coverage-more than 50%, the reproducibility of the result and the calculation time-several tens of seconds. The PITV ratio was less than 2.0. However, the dose applied to normal tissue around the target must be reduced slightly. Planner or conventional optimization algorithms might easily solve this limitation.

Intravascular large B-cell lymphoma presenting as interstitial lung disease.

Intravascular large B-cell lymphoma (IVLBL) is a rare subtype of diffuse large B-cell lymphoma that resides in the lumen of blood vessels. Patients typically present with nonspecific findings, particularly bizarre neurologic symptoms, fever, and skin lesions. A woman presented with shortness of breath and a chest CT scan showed diffuse interstitial thickening and ground glass opacities suggestive of an interstitial lung disease. On physical exam she was noted to have splenomegaly. The patient died and at autopsy was found to have an IVLBL in her lungs as well as nearly all her organs that were sampled. Although rare, IVLBL should be included in the differential diagnosis of interstitial lung disease and this case underscores the importance of the continuation of autopsies.

Microarray analysis of gene expression in lung cancer cell lines treated by fractionated irradiation.

BACKGROUND: To identify differentially expressed genes between parent and radioresistant lung cancer cell lines established by fractionated irradiation. MATERIALS AND METHODS: Lung cancer cell lines (A549, NCI-H1650) were irradiated with several fractionation schemes. Clonogenic assays were used to identify radioresistant cell lines. We compared the gene expression profiles on a cDNA microarray. RESULTS: Four established cell (A549-2G, A549-5G, H1650-2G and H1650-5G) were shown to be radioresistant (p≤0.05). Seventy-two genes were commonly altered in A549-G and 655 genes in H1650-G, compared to their parental cells. Genes in the wingless-type MMTV integration site family (WNT) signaling pathway were the ones most frequently altered in both A549-G and H1650-G cells. Those involved in inflammation; integrin, platelet-derived growth factor (PDGF), interleukin, transforming growth factor-beta (TGFB), epidermal growth factor receptor (EGFR) signaling, were commonly altered in radioresistant H1650 sublines. CONCLUSION: The major gene expression changes during irradiation are related to WNT signaling pathway.

Simple acupoints prescription flow chart based on meridian theory: a retrospective study in 102 dogs.

To help the clinicians prescribe acupoints easily and effectively, we developed one simple flow chart to select acupoints. This study aimed to evaluate the usefulness of flow chart to select acupoints in dogs. Total 102 dogs showing intervertebral disc disease (IVDD) (n = 12), vomiting (n = 11), diarrhea (n = 2), abdominal pain (n = 5), cough (n = 66), or epilepsy (n = 6) received acupuncture treatment according to the chart, and its outcomes were evaluated as regards clinical symptoms, duration, treatment numbers, and recovery time. Dogs (8/8) with IVDD from grades I to III recovered over periods of 5 days to 6 weeks after 1-12 treatments, while 1/4 dogs with grade IV recovered over 7 weeks after 15 treatments. Vomiting dogs with acute/subacute (n = 8) and chronic symptoms (n = 3) required about 1 and 7 treatments to recover fully, respectively. All dogs (n = 5) with abdominal pain showed fast relief within 24 hours after acupuncture. Two diarrhea cases recovered over 2-9 days after 1-2 treatments. Fifty-four of 66 coughing dogs were recovered by 1-2 treatments. And 5 of 6 epilepsy dogs under a regular acupuncture treatment had no epileptic episode during followup of 12 months. These results suggest that this flow chart can help the clinicians prescribe acupoints effectively.

A phase III concurrent chemoradiotherapy trial with cisplatin and paclitaxel or docetaxel or gemcitabine in unresectable non-small cell lung cancer: KASLC 0401.

PURPOSE: Concurrent chemoradiotherapy (CCRT) is recommended for the management of patients with unresectable non-small cell lung cancer (NSCLC). This prospective study aimed to compare the efficacy of concurrently delivered cisplatin doublets with paclitaxel, or docetaxel, or gemcitabine. METHODS: The main eligibility criteria consisted of previously untreated stage IIIB NSCLC. The subjects were randomized into three arms: paclitaxel 45 mg/m(2)/week (TP), docetaxel 20 mg/m(2)/week (DP), and gemcitabine 350 mg/m(2)/week (GP) in addition to cisplatin 20 mg/m(2)/week. Three-dimensional conformal radiotherapy was given once daily, weekly 5 fractions and the total prescription dose was 60-66 Gy. The primary endpoint was response rate, and the secondary endpoints were survival and toxicity. RESULTS: A total of 101 patients were recruited into this trial of whom 93 (TP: 33, DP: 29, GP: 31) patients were treated with CCRT from March 2005 to July 2007. Similar response rates were observed across arms: TP: 63.6 %, DP: 72.4 %, GP: 61.3 % (p = 0.679). There was no statistically significant difference of median survival (TP: 27.3, DP: 27.6, GP: 16.5 months, p = 0.771). In subgroup analysis, a survival benefit of consolidation chemotherapy was not seen, but leucopenia (63.2 %) and neutropenia (68.4 %) more than grade 3 were significantly high in DP arm. The grade ≥3 radiation esophagitis was more frequent in the GP arm (22.6 %, p = 0.163). CONCLUSIONS: Among the three arms, no statistically significant difference in response rate, survival, and toxicity was observed. However, clinically significant radiation toxicity was more frequent in the GP arm.