Relationship of Circadian Rhythm in Behavioral Characteristics and Lipid Peroxidation of Brain Tissues in Mice.

Objective: This study aimed to explore the relationship among several indices of circadian rhythms and lipid peroxidation of brain tissue in mice. Methods: After entrainment of 4-week-old mice, one group was disrupted their circadian rhythms for three days and the other group for seven days (n = 10, respectively). After a recovery period, the Y-maze test, the elevated plus maze test, the tail suspension test, and the forced swimming test were conducted. To assess lipid peroxidation in brain tissue, thiobarbituric acid reactive substances were measured in the cortex, hippocampus, and cerebellum. Results: When circadian rhythms were disrupted and adapted back to their original rhythm, the recovery time of the 7-day disruption group (median 3.35 days) was significiantly faster than one of the 3-day disruption group (median 4.87 days). In the group with a 7-day disruption, mice that had recovered their rhythms early had higher malondialdehyde levels in their hippocampus compared to those with delayed recovery. The entrainment of circadian rhythms was negatively correlated with the malondialdehyde level of brain tissue. The behavioral test results showed no differences depending on the disruption durations or recovery patterns of circadian rhythms. Conclusion: These results suggest that disruption types, recovery patterns, and the entrainment of circadian rhythms are likely to affect oxidative stress in adolescents or young adult mice. Future study is needed to confirm and specify these results on the effects of circadian rhythms on oxidative stress and age-dependent effects.

A Novel Frameshift CASK Variant in a 6-Month-Old Korean Female Infant with Global Developmental Delay, Progressive Microcephaly, and Pontocerebellar Hypoplasia: A Case Report.

Pontocerebellar hypoplasia is a heterogeneous group of rare genetic neurodevelopmental disorders marked by early degeneration of the cerebellum and brainstem. Intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH; MIM#300749) is a disorder caused by pathogenic loss-of-function variants in CASK CASK gene plays a critical role in brain development by controlling neuronal development and synapse formation. This report describes a 6-month-old Korean female infant with global developmental delay, sensorineural hearing loss, axial hypotonia with hypertonia of extremities, progressive microcephaly, and pontocerebellar hypoplasia. On whole exome sequencing, the patient had a novel heterozygous frameshift CASK variant, NM_003688.3:c.535del (NP_003679.2:p. Arg179Valfs*22). This report highlights the importance of considering CASK pathogenic variants in patients with global developmental delay, progressive microcephaly, and pontocerebellar hypoplasia and the genotype-phenotype relationships.

Evaluating medical students' ability to identify and report errors: finding gaps in patient safety education.

BACKGROUND: Although there are frequent complaints of medical students' incompetence in reporting errors, few studies have examined their error-reporting abilities in the real world. OBJECTIVES: Three sub-functions of self-regulation theory were used to evaluate medical students' ability to identify errors (self-monitoring), analyse root causes (self-judgment), and devise improvement plans (self-reactions). In addition, whether students reacted differently to their errors and those of others (three sub-functions) was also examined. METHODS: A total of 952 patient safety reports were reviewed retrospectively, submitted by third-year medical students between 2016 and 2018. Data were quantitatively and qualitatively analysed to investigate who committed the error, to identify the type of error and its root causes, and to find suggested improvement plans. Chi-square and Fisher's exact tests were used to compare students' responses to error origins. RESULTS: Students reported other errors more frequently than their own (67.6% vs. 32.4%). They reported common critical medical errors, including errors related to engaging with patients (34.5%), invasive procedures (20.2%), and infection (18.5%). The root causes identified were more precise than the improvement plans by the students (75.5% vs. 18.4%, respectively). The students' improvement plans were not practical, especially at the patient level (25.8%). When students committed errors, they considered human factors such as fatigue, scheduling, and training as the most common root cause, focussing on improvement plans at the individual level. CONCLUSIONS: The results suggest that students were good at self-judgment, but not at self-monitoring and self-reactions. They reacted differently, based on who committed the error. To enhance self-regulated learning, Educators should encourage students to confront their errors, reflect on their self-reactions towards errors, develop well-being with time management, and think about the meaning of patient-centredness. Finally, active participation in clinical clerkship longitudinally may provide students with opportunities to learn from their errors.

Clinical Characteristics and Treatment Outcomes of Childhood Acute Promyelocytic Leukemia in Korea: A Nationwide Multicenter Retrospective Study by Korean Pediatric Oncology Study Group.

PURPOSE: Acute promyelocytic leukemia (APL) is a rare disease in children and there are some different characteristics between children and adult. We aimed to evaluate incidence, clinical characteristics and treatment outcomes of pediatric APL in Korea. MATERIALS AND METHODS: Seventy-nine pediatric APL patients diagnosed from January 2009 to December 2016 in 16 tertiary medical centers in Korea were reviewed retrospectively. RESULTS: Of 801 acute myeloid leukemia children, 79 (9.9%) were diagnosed with APL. The median age at diagnosis was 10.6 years (range, 1.3 to 18.0). Male and female ratio was 1:0.93. Thirty patients (38.0%) had white blood cell (WBC) count greater than 10×109/L at diagnosis. All patients received induction therapy consisting of all-trans retinoic acid and chemotherapy. Five patients (6.6%) died during induction chemotherapy and 66 patients (86.8%) achieved complete remission (CR) after induction chemotherapy. The causes of death were three intracranial hemorrhage, one cerebral infarction, and one sepsis. Five patients (7.1%) suffered a relapse during or after maintenance chemotherapy. The estimated 4-year event-free survival and overall survival (OS) rates were 82.1%±4.4%, 89.7%±5.1%, respectively. The 4-year OS was significantly higher in patients with initial WBC < 10×109/L than in those with initial WBC ≥ 10×109/L (p=0.020). CONCLUSION: This study showed that the CR rates and survival outcomes in Korean pediatric APL patients were relatively good. The initial WBC count was the most important prognostic factor and most causes of death were related to serious bleeding in the early stage of treatment.

Treatment Outcomes of Pediatric Acute Myeloid Leukemia in the Yeungnam Region: A Multicenter Retrospective Study of the Study Alliance of Yeungnam Pediatric Hematology-Oncology (SAYPH).

Acute myeloid leukemia (AML) is the second most common pediatric leukemia, with a survival rate of 70%. In this retrospective study, we evaluated the treatment outcomes of pediatric AML among 144 patients diagnosed between 2000 and 2013. After induction, 80.6% of patients achieved complete remission (CR). The 5-year overall survival (OS) and event-free survival (EFS) rates were 58.8 ± 4.2% and 49.8 ± 4.2%, respectively. Based on the response to induction therapy, the 5-year OS was 66.9 ± 5.7% in patients with CR (p < 0.001). Ninety-nine patients with CR after induction therapy were examined, and their 5-year OS and EFS were 66.4 ± 4.9% and 56.3 ± 5.1%, respectively. The 5-year OS rates according to treatment were 59.9 ± 7.4% in the chemotherapy group and 72.3 ± 6.3% in the hematopoietic stem cell transplantation (HSCT) group (p = 0.089). The EFS was 50.1 ± 7.4% in the chemotherapy group and 61.7 ± 6.9% in the HSCT group (p = 0.098). OS and EFS according to cytogenetics were insignificant. Our findings confirmed that the response to induction treatment was important for survival and HSCT had no significant survival benefits compared with those of chemotherapy. Moreover, many early induction deaths under the age of 2 years were observed.

Epidemiological Study of Hereditary Hemolytic Anemia in the Korean Pediatric Population during 1997-2016: a Nationwide Retrospective Cohort Study.

BACKGROUND: Hereditary hemolytic anemia (HHA) is a rare disease characterized by premature red blood cell (RBC) destruction due to intrinsic RBC defects. The RBC Disorder Working Party of the Korean Society of Hematology established and updated the standard operating procedure for making an accurate diagnosis of HHA since 2007. The aim of this study was to investigate a nationwide epidemiology of Korean HHA. METHODS: We collected the data of a newly diagnosed pediatric HHA cohort (2007-2016) and compared this cohort's characteristics with those of a previously surveyed pediatric HHA cohort (1997-2006) in Korea. Each participant's information was retrospectively collected by a questionnaire survey. RESULTS: A total of 369 children with HHA from 38 hospitals distributed in 16 of 17 districts of Korea were investigated. RBC membranopathies, hemoglobinopathies, RBC enzymopathies, and unknown etiologies accounted for 263 (71.3%), 59 (16.0%), 23 (6.2%), and 24 (6.5%) of the cases, respectively. Compared to the cohort from the previous decade, the proportions of hemoglobinopathies and RBC enzymopathies significantly increased (P < 0.001 and P = 0.008, respectively). Twenty-three of the 59 hemoglobinopathy patients had immigrant mothers, mostly from South-East Asia. CONCLUSION: In Korea, thalassemia traits have increased over the past 10 years, reflecting both increased awareness of this disease and increased international marriages. The enhanced recognition of RBC enzymopathies is due to advances in diagnostic technique; however, 6.5% of HHA patients still do not have a clear diagnosis. It is necessary to improve accessibility of diagnosing HHA.

Korean parents' perceptions of the challenges and needs on school re-entry during or after childhood and adolescent cancer: a multi-institutional survey by Korean Society of Pediatric Hematology and Oncology.

BACKGROUND: For children and adolescents with cancer, going back to school is a key milestone in returning to "normal life." PURPOSE: To identify the support vital for a successful transition, we evaluated the parents' needs and the challenges they face when their children return to school. METHODS: This multi-institutional study was conducted by the Korean Society of Pediatric Hematology and Oncology. The written survey comprised 24 questions and was completed by 210 parents without an interviewer. RESULTS: Most parents (165 of 206) reported that their children experienced difficulties with physical status (n=60), peer relationships (n=30), academic performance (n=27), emotional/behavioral issues (n=11), and relationships with teachers (n=4) on reentering school. Parents wanted to be kept informed about and remain involved in their children's school lives and reported good parent-teacher communication (88 of 209, 42.1%). Parents reported that 83.1% and 44.9% of teachers and peers, respectively, displayed an adequate understanding of their children's condition. Most parents (197 of 208) answered that a special program is necessary to facilitate return to school after cancer therapy that offers emotional support (n=85), facilitates social adaptation (n=61), and provides tutoring to accelerate catch up (n=56), and continued health care by hospital outreach and school personnel (n=50). CONCLUSION: In addition to scholastic aptitude-oriented programs, emotional and psychosocial support is necessary for a successful return to school. Pediatric oncologists should actively improve oncology practices to better integrate individualized school plans and educate peers and teachers to improve health literacy to aid them in understanding the needs of children with cancer.

Molecular diagnosis of hereditary spherocytosis by multi-gene target sequencing in Korea: matching with osmotic fragility test and presence of spherocyte.

BACKGROUND: Current diagnostic tests for hereditary spherocytosis (HS) focus on the detection of hemolysis or indirectly assessing defects of membrane protein, whereas direct methods to detect protein defects are complicated and difficult to implement. In the present study, we investigated the patterns of genetic variation associated with HS among patients clinically diagnosed with HS. METHODS: Multi-gene targeted sequencing of 43 genes (17 RBC membrane protein-encoding genes, 20 RBC enzyme-encoding genes, and six additional genes for the differential diagnosis) was performed using the Illumina HiSeq platform. RESULTS: Among 59 patients with HS, 50 (84.7%) had one or more significant variants in a RBC membrane protein-encoding genes. A total of 54 significant variants including 46 novel mutations were detected in six RBC membrane protein-encoding genes, with the highest number of variants found in SPTB (n = 28), and followed by ANK1 (n = 19), SLC4A1 (n = 3), SPTA1 (n = 2), EPB41 (n = 1), and EPB42 (n = 1). Concurrent mutations of genes encoding RBC enzymes (ALDOB, GAPDH, and GSR) were detected in three patients. UGT1A1 mutations were present in 24 patients (40.7%). Positive rate of osmotic fragility test was 86.8% among patients harboring HS-related gene mutations. CONCLUSIONS: This constitutes the first large-scaled genetic study of Korean patients with HS. We demonstrated that multi-gene target sequencing is sensitive and feasible that can be used as a powerful tool for diagnosing HS. Considering the discrepancies of clinical and molecular diagnoses of HS, our findings suggest that molecular genetic analysis is required for accurate diagnosis of HS.

School performance of childhood cancer survivors in Korea: A multi-institutional study on behalf of the Korean Society of Pediatric Hematology and Oncology.

OBJECTIVE: To investigate school performance of childhood cancer survivors focusing on the child's functioning, including peer relationships, school attendance, and academic achievement. METHODS: We studied 241 children from 15 institutions in Korea between 2015 and 2016. The self-reported paper-and-pencil questionnaires were used. RESULTS: Approximately 22% of the survivors suffered from lack of friends. Bullying was reported by 30% of survivors. Survivors who returned to primary school reported a higher incidence of bullying compared with survivors who returned to middle or high school (P = 0.03). The percentage of children who missed classes more than 4 days in a month was higher in survivors with brain tumors than those with other tumors (P = 0.04). Approximately 41% of children reported learning difficulty. After returning to school, 53% of the patients reported that they had lower overall mark averages than they had before. Patients who returned to high school showed the highest rate of repeating a grade and the lowest rate of achieving high academic marks. The school marks in the Korean (P = 0.03), English (P = 0.04), and physical education (P = 0.04) were worse for the children with brain tumors than for the children with other tumors. CONCLUSION: We found that 20% to 25% of survivors experienced peer-related difficulties upon returning to school. Patients who return to school, especially high school, should be provided more educational support to overcome low academic achievement. Particular concern is needed to the patients with brain tumors, who are at risk for significant academic and social difficulties and therefore may require more intensive support in school.

Comparison of survival outcome between donor types or stem cell sources for childhood acute myeloid leukemia after allogenic hematopoietic stem cell transplantation: A multicenter retrospective study of Study Alliance of Yeungnam Pediatric Hematology-oncology.

We compared transplant outcomes between donor types and stem cell sources for childhood acute myeloid leukemia (AML). The medical records of children with AML in the Yeungnam region of Korea from January 2000 to June 2017 were reviewed. In all, 76 children with AML (male-to-female ratio = 46:30) received allogenic hematopoietic stem cell transplantation (allo-HSCT). In total, 29 patients received HSCT from either a matched-related donor or a mismatched-related donor, 32 patients received an unrelated donor, and 15 patients received umbilical cord blood. In term of stem cell sources, bone marrow was used in 15 patients and peripheral blood in 46 patients. For all HSCT cases, the 5-year overall survival (OS) was 73.1% (95% CI: 62.7-83.5) and the 5-year event-free survival (EFS) was 66.1% (95% CI: 54.5-77.7). There was no statistical difference in 5-year OS according to the donor types or stem cell sources (P = .869 and P = .911). There was no statistical difference in 5-year EFS between donor types or stem cell sources (P = .526 and P = .478). For all HSCT cases, the 5-year relapse rate was 16.1% (95% CI: 7.3-24.9) and the 5-year non-relapse mortality (NRM) was 13.3% (95% CI: 5.1-21.5). There was no statistical difference in the 5-year relapse rate according to the donor types or stem cell sources (P = .971 and P = .965). There was no statistical difference in the 5-year NRM between donor types or stem cell sources (P = .461 and P = .470).

G-CSF-treated donor CD4+ T cells attenuate acute GVHD through a reduction in Th17 cell differentiation.

The immunoregulatory effects of granulocyte colony-stimulating factor (G-CSF) on allogeneic peripheral blood cell transplantation (PBCT) have been demonstrated to reduce acute graft-versus-host disease (GVHD). However, the underlying mechanism is still not clear. In this study, we focused on the direct effects of G-CSF on donor CD4(+) T cell responses after transplantation. We observed that lethally irradiated B6D2F1 recipient mice that are transplanted with CD4(+) T cells from G-CSF-treated B6 donors showed mild attenuations in severity and mortality compared with recipients transplanted with PBS-treated CD4(+) T cells. Notably, skin GVHD was significantly reduced, but no such reduction was observed in other organs. Although there was no difference with respect to alloreactive expansion or Foxp3(+) Treg induction, the use of G-CSF-treated CD4(+) T cells significantly reduced the numbers of IL-17-producing and RORγt-expressing cells in the secondary lymphoid organs of allogeneic recipients after transplantation compared with the use of the control cells. Finally, we found that the suppressor of cytokine signaling-3 (SOCS3) expression in G-CSF-treated donor CD4(+) T cells was much higher than that in control CD4(+) T cells. Our results demonstrate that the inhibition of Th17 cell differentiation by SOCS3 induction is associated with the immunoregulatory role of G-CSF in CD4(+) T cell-mediated acute GVHD.

May-Thurner syndrome found incidentally after left femoral catheterization in a pediatric patient.

In May-Thurner syndrome, the left common iliac vein is compressed between the overlying right common iliac artery and the underlying vertebral body. Chronic and/or repetitive compressions at this site cause fibrosis of the vein and thus stenosis, potentially occluding the lumen. This report describes a case of May-Thurner syndrome discovered incidentally after femoral catheterization for chemotherapy in a 25-month-old child with juvenile myelomonocytic leukemia (JMML). The patient had no symptoms associated with compression. The syndrome was diagnosed by computed tomography, and there was no evidence of thrombosis. The patient died secondary to sepsis.

Two childhood cases of acute leukemia with t(16;21)(p11.2;q22): second case report of infantile acute lymphoblastic leukemia with unusual type of FUS-ERG chimeric transcript.

We report two childhood cases of acute leukemia with t(16;21)(p11.2;q22) and FUS-ERG rearrangements. Patient 1 (14 years old) was initially diagnosed with acute myeloid leukemia. Chromosome study showed a t(16;21)(p11.2;q22) clone in more than one third of the cells analyzed, and further investigation with reverse-transcriptase polymerase chain reaction, cloning, and sequencing confirmed FUS-ERG rearrangement (type B). Patient 2 (8 months old) was diagnosed with acute lymphoblastic leukemia (ALL) on the basis of bone marrow morphology and immunophenotyping. Chromosome study revealed a 45,XY,-16,der(21)t(16;21)(p11.2;q22) in 50% of the cells analyzed. Further studies for the detection of a FUS-ERG chimeric transcript were conducted, and an unusual type of FUS-ERG rearrangement was discovered, which has been reported in only three patients including a 1-year-old infant with ALL. Although more clinical studies are necessary, we believe that a possible association between ALL and a specific type of FUS-ERG fusion transcript might be considered, especially in childhood cases with t(16;21).

Granulocyte colony-stimulating factor-induced immature myeloid cells inhibit acute graft-versus-host disease lethality through an indoleamine dioxygenase-independent mechanism.

Granulocyte colony-stimulating factor (G-CSF)-mobilized donor graft tissue used for peripheral blood stem cell transplantation contains a large number of immature myeloid cells that suppress alloreactive donor T cells, resulting in an inhibition of acute graft-versus-host disease (GVHD). However, the molecular mechanism underlying the suppressive function of immature myeloid cells is not fully understood. Here, we investigated whether indoleamine 2,3-dioxygenase (IDO) is related to the suppressive mechanism of G-CSF-induced immature myeloid cells (gMCs). We found that Gr-1(+) CD11b(+) cells were highly induced in G-CSF-injected donor graft tissue, which is a phenotype of immature myeloid cells, resulting in an inhibition of acute GVHD lethality by suppressing alloreactive donor T-cell expansion. IDO was not detected in primary isolated gMCs; however, this enzyme was markedly induced after treatment with interferon-gamma (IFN-gamma). This level was significantly higher in IFN-gamma-treated gMCs than in bone marrow myeloid cells, which promote alloreactive T-cell responses. We next investigated the functional role of IDO in gMC-mediated inhibition of acute GVHD lethality. We found no changes in gMC-mediated survival or alloreactive donor T-cell suppression when IDO activity was blocked using 1-methyl tryptophan. In addition, there was no difference in gMC-mediated survival rates between recipients transferred with either wild-type gMCs or IDO(-/-) gMCs. Taken together, our data suggest that gMC-mediated inhibition of lethal acute GVHD is through an IDO-independent mechanism.