All-Cause and Cause-Specific Mortality in Parents After the Death of a Child in Taiwan: A Population-Based Cohort Study.

OBJECTIVE: Research from Western countries suggests that there is an increase in mortality in parents bereaved by the death of a child. Few studies have investigated this issue in a non-Western context. We explored the impact of the death of a child on parental mortality in Taiwan. METHOD: By linking population-based national registers, we followed the 2004-2014 birth cohort ( N = 2,083,972) up until 2016. A total of 11,755 child deaths were identified. For each deceased child, four living children matched on age and sex were randomly selected; their parents were the comparison group. We used Cox proportional hazards regression models to compare the mortality risk of bereaved parents with the comparison group up until 2017. RESULTS: Overall mortality risk was increased in parents who experienced the death of a child; the risk was higher in bereaved mothers (adjusted hazard ratio = 4.91, 95% confidence interval = 3.96-6.09) than fathers (adjusted hazard ratio = 1.82, 95% confidence interval = 1.55-2.13). The risk did not differ according to the sex of the child, but parents whose children died of unexpected causes (i.e., suicide/accidents/violence) were at greater risk than those dying of other causes. Risk was higher when the child was older than 1 year at the time of death than for deaths before age 1 year. CONCLUSIONS: Parents who lost a child were at increased mortality risk in this East Asian population. Special attention should be paid to the health of bereaved parents and explore the pathways leading to their risk.

Maternal anemia and the risk of childhood cancer: A population-based cohort study in Taiwan.

BACKGROUND: Childhood cancer may be related to maternal health in pregnancy. Maternal anemia is a common condition in pregnancy, especially in low-income countries, but the association between maternal anemia and childhood cancer has not been widely studied. OBJECTIVE: To examine the potential relation between maternal anemia during pregnancy and childhood cancers in a population-based cohort study in Taiwan. METHODS: We examined the relationship between maternal anemia and childhood cancer in Taiwan (N = 2160 cancer cases, 2,076,877 noncases). Cases were taken from the National Cancer Registry, and noncases were selected from birth records. Using national health registries, we obtained maternal anemia diagnoses. We estimated the risks for childhood cancers using Cox proportional hazard analysis. RESULTS: There was an increased risk of cancers in children born to mothers with nutritional anemia (hazard ratio (HR): 1.32, 95% CI 0.99, 1.76). Iron deficiency anemia (HR: 1.30, 95% CI 0.97-1.75) carried an increased risk, while non-nutritional anemias were not associated with childhood cancer risk. CONCLUSION: Our results provide additional support for screening for anemia during pregnancy. Adequate nutrition and vitamin supplementation may help to prevent some childhood cancer.

Maternal diabetes and childhood cancer risks in offspring: two population-based studies.

BACKGROUND: The effect of maternal diabetes on childhood cancer has not been widely studied. METHODS: We examined this in two population-based studies in Denmark (N = 6420 cancer cases, 160,484 controls) and Taiwan (N = 2160 cancer cases, 2,076,877 non-cases) using logistic regression and Cox proportional hazard regression adjusted for birth year, child's sex, maternal age and birth order. RESULTS: Gestational diabetes in Denmark [odds ratio (OR) = 0.98, 95% confidence interval (CI): 0.71-1.35] or type II and gestational diabetes in Taiwan (type II: hazard ratio (HR) = 0.81, 95% CI: 0.63-1.05; gestational diabetes: HR = 1.06, 95% CI: 0.92-1.22) were not associated with cancer (all types combined). In Denmark, maternal type I diabetes was associated with the risk of glioma (OR = 2.33, 95% CI: 1.04-5.22), while in Taiwan, the risks of glioma (HR = 1.59, 95% CI: 1.01-2.50) were elevated among children whose mothers had gestational diabetes. There was a twofold increased risk for hepatoblastoma with maternal type II diabetes (HR = 2.02, 95% CI: 1.02-4.00). CONCLUSIONS: Our results suggest that maternal diabetes is an important risk factor for certain types of childhood cancers, emphasising the need for effective interventions targeting maternal diabetes to prevent serious health effects in offspring.

Cohort study of familial viral hepatitis and risks of paediatric cancers.

BACKGROUND: Although viral hepatitis causes paediatric hepatocellular carcinoma and hepatic and extrahepatic cancers in adults, there are few epidemiologic studies on paediatric-cancer risks from parental viral hepatitis. In a nationwide study in a viral hepatitis endemic region and with confirmation in another population-based sample, we examined associations between parental hepatitis B (HBV) and C (HCV) infections and risks of cancers in offspring. METHODS: We included all children born in Taiwan in 2004-2014 (N = 2 079 037) with 2160 cancer cases ascertained from the Cancer Registry. We estimated risks for paediatric cancers using Cox proportional-hazard regressions. We checked these associations in a nationwide case-control study in Denmark (6422 cases, 160 522 controls). RESULTS: In Taiwan, paternal HBV was related to child's hepatoblastoma [hazard ratio (HR) = 1.77, 95% confidence interval (CI) = 1.05, 2.97] when identified at any time in the medical record, and when analyses were limited to hepatitis diagnoses occurring before the child's birth, risks increased (HR = 2.08, 95% CI = 1.13-3.80). Paternal HCV was related to child's non-Hodgkin lymphoma (HR = 2.06, 95% CI = 1.13-3.74). Maternal HCV was weakly related to increased risks of all childhood cancers [all types combined; HR = 1.45, 95% CI = 0.95-2.22]. The population-attributable fraction of hepatoblastoma for maternal, paternal and child HBV was 2.6%, 6.8% and 2.8%, respectively. CONCLUSIONS: Parental HBV and HCV may be risk factors for hepatic and non-hepatic cancers in children. If associations are causal, then parental screening and treatment with antivirals may prevent some paediatric cancers.

Residential greenness and birth outcomes: Evaluating the mediation and interaction effects of particulate air pollution.

BACKGROUND: The few studies that examined the association between residential greenness and birth outcomes have produced inconsistent results, and the underlying mechanisms of these associations remain unclear. OBJECTIVES: We examined the mediation and interaction effects of particulate matter (PM) air pollution on the relationship between greenness exposure during the first and third trimesters of pregnancy and birth outcomes, including preterm birth (PTB), term low birth weight (TLBW), small for gestational age (SGA), birth weight (BW), and head circumference (HC). METHODS: We conducted a retrospective cohort study on 16,184 singleton live births between 2010 and 2012 in Taiwan. Residential greenness was estimated based on the normalized difference vegetation index (NDVI), and the PM information during the first and third trimesters was estimated through hybrid kriging land use regression and ordinary kriging interpolation methods. Multiple regression analyses were performed to evaluate the associations between greenness exposure and birth outcomes. We estimated the mediating effects of PM associated with greenness exposure on birth outcomes through causal mediation analyses. We also examined the potential multiplicative and additive interactions between greenness exposure and PM and their effects on birth outcomes. RESULTS: The first trimester NDVI exposure was associated with reduced risks for PTB, TLBW, and SGA, which had an adjusted OR (aOR) of 0.93 (95% CI: 0.89-0.97), 0.91 (95% CI: 0.83-0.99), and 0.95 (95% CI: 0.91-1.00), respectively, per 0.1 unit increase in multi-pollutant models. The causal mediation analysis showed that PM mediated approximately 5-19% of the association between first and third trimester greenness and PTB and mediated approximately 15-37% of the association between greenness and SGA. We identified multiplicative interactions in log scale between first trimester PM10 and NDVI exposure for SGA (aORinteraction = 0.92, p = 0.03) and HC (estimateinteraction = 1.47, p = 0.04). CONCLUSIONS: This study revealed beneficial associations between residential greenness and birth outcomes, including PTB, TLBW, and SGA. The associations were partly mediated by a reduction in exposure to PM air pollution. SUMMARY: The beneficial effects of greenness on PTB and SGA are partly mediated by a reduction in exposure to PM air pollution.

Spina bifida and pediatric cancers.

Spina bifida has been reported to co-occur with pediatric cancer, but comprehensive evaluations remained elusive. We investigated this co-occurrence in two large, population-based studies in Taiwan (N = 1900 cancer cases, 2,077,137 controls) and Denmark (N = 5508 cases, 137,700 controls). Analyses in Denmark were restricted to the period before prenatal diagnostics became available (2004) and pregnancy terminations of fetuses with birth defects became more common. Using national patient and cancer registries, we linked spina bifida and cancer diagnoses among cases and non-cases. The risk of spina bifida among all cancer cases was increased and similar in Denmark [odds ratio (OR)=8.4, 95% confidence interval (CI) 5.1-13.8] and Taiwan (OR = 8.5, 95% CI 4.0-17.8), particularly for central nervous system (CNS) tumors (Denmark: OR = 16.3, 95% CI 8.1-33.0; Taiwan: OR = 26.6, 95% CI 8.5, 83.1), including benign CNS tumors (Denmark: OR = 41.5, 95% CI 21.2, 81.4). These findings suggest the need for comprehensive investigation of shared risk factors in the link between spina bifida and pediatric cancer.

Gestational risk factors and childhood cancers: A cohort study in Taiwan.

Gestational risk factors such as birth weight, gestational age and parity have been repeatedly found to be related to pediatric cancers, but few reports have emerged from Asian countries. Here we report on demographic and gestational factors in a Taiwanese cohort. Our study included all children born in Taiwan 2004-2014 for whom there was a birth record (n = 2,079,037), of which 1900 children had been diagnosed with cancer prior to age 12. We conducted multivariable hazard regression to examine associations between demographic and gestational factors with cancer. Greater parity (family with 2+ older children) was related to acute myeloid leukemia [Hazard ratio (HR) = 2.15, 95% confidence interval (CI): 1.31, 3.55), central nervous system tumors (HR = 1.67, CI: 1.13, 2.48) and neuroblastoma (HR = 1.67, CI: 1.07, 2.63). Hepatoblastoma cases had a higher risk of low birth weight (<2,500 g; HR = 3.01, CI: 1.85, 4.91), very preterm birth (<33 weeks gestation; HR = 13.71, CI: 7.45, 25.23), plural pregnancies (HR = 2.37, CI: 1.10, 5.14) and both small (HR = 2.13, CI: 1.23, 3.67) and large (HR = 1.83, CI: 1.01, 3.32) for gestational age. Germ cell tumors were more common among children born in rural areas (HR = 1.63, CI: 1.02, 2.60). Despite that Taiwan has lower rates of both high and low birthweight compared to other developed nations, we observed several similar associations to those reported in Western Countries. Further research should examine unique exposures in Taiwan that may be contributing to higher incidence of certain cancer types.

Parent-child discrepancies in the report of adolescent emotional and behavioral problems in Taiwan.

The majority of studies on parent-child discrepancies in the assessment of adolescent emotional and behavioral problems have been conducted in Western countries. It is believed that parent-adolescent agreement would be higher in societies with a strong culture of familism. We examined whether parent-adolescent discrepancies in the rating of adolescent emotional and behavioral problems are related to parental and family factors in Taiwan. Participants included 1,421 child-parent pairs of 7th-grade students from 12 middle schools in Northern Taiwan and their parents. We calculated Pearson's correlation coefficients to assess the relationship between parental (Child Behavior Checklist, CBCL) and adolescent (Youth Self Report, YSR) report of emotional/behavioral problem syndromes. Regression models were used to assess parent-adolescent differences in relation to parental psychopathology and family factors. We found that parent-adolescent agreement was moderate (r = 0.37). Adolescents reported higher symptom scores than their parents (Mean Total Problem Score: CBCL: 20.79, YSR: 33.14). Parental psychopathology was related to higher parental ratings and better informant agreement. Parents with higher socioeconomic status (SES) tended to report lower scores for adolescent problem syndromes, resulting in higher levels of disagreement. Greater maternal care was related to higher parent-adolescent agreement. Based on our study findings, we conclude that familism values do not seem to improve parent-child agreement in the assessment of adolescent problem syndromes. The finding that higher SES was related to increased discrepancies speaks to the need to explore the culture-specific mechanisms giving rise to informant discrepancies.

The Immunodominance Change and Protection of CD4+ T-Cell Responses Elicited by an Envelope Protein Domain III-Based Tetravalent Dengue Vaccine in Mice.

Dengue is the leading cause of mosquito-borne viral infections and no vaccine is available now. Envelope protein domain III (ED3) is the major target for the binding of dengue virus neutralizing antibodies; however, the ED3-specifc T-cell response is less well understood. To investigate the T-cell responses to four serotypes of dengue virus (DENV-1 to 4), we immunized mice using either a tetravalent ED3-based DNA or protein vaccine, or combined both as a DNA prime-protein boost strategy (prime-boost). A significant serotype-dependent IFN-γ or IL-4 response was observed in mice immunized with either the DNA or protein vaccine. The IFN-γ response was dominant to DENV-1 to 3, whereas the IL-4 response was dominant to DENV-4. Although the similar IgG titers for the four serotypes were observed in mice immunized with the tetravalent vaccines, the neutralizing antibody titers varied and followed the order of 2 = 3>1>4. Interestingly, the lower IFN-γ response to DENV-4 is attributable to the immunodominance change between two CD4+ T-cell epitopes; one T-cell epitope located at E349-363 of DENV-1 to 3 was more immunogenic than the DENV-4 epitope E313-327. Despite DENV-4 specific IFN-γ responses were suppressed by immunodominance change, either DENV-4-specific IFN-γ or neutralizing antibody responses were still recalled after DENV-4 challenge and contributed to virus clearance. Immunization with the prime-boost elicited both IFN-γ and neutralizing antibody responses and provided better protection than either DNA or protein immunization. Our findings shed light on how ED3-based tetravalent dengue vaccines sharpen host CD4 T-cell responses and contribute to protection against dengue virus.

Tyrosine phosphorylation of c-Maf enhances the expression of IL-4 gene.

Maf proteins are involved in a variety of biological processes, such as oncogenesis, lens development, and differentiation. In immune system, c-Maf transactivates IL-4 promoter, and ectopic expression of c-Maf skews primary T cell response toward the Th2 pathway. Numerous transcription factors are subjected to posttranslational modification. In this study, to our knowledge, we show for the first time that c-Maf is subjective to tyrosine phosphorylation in Th cells and that the level of its tyrosine phosphorylation positively correlates with IL-4 expression by peripheral Th cells, but is negatively associated with the severity of disease in NOD mice. c-Maf undergoes tyrosine phosphorylation at Tyr(21), Tyr(92), and Tyr(131) residues in Th2 cells. Furthermore, tyrosine phosphorylation at these three residues is critical for the recruitment of c-Maf to IL-4 promoter and IL-4 production in Th cells. Taken together, this study sheds new light on the role of posttranslational modification of c-Maf in IL-4 production and Th cell-mediated autoimmune diseases.