Generalizability of "GWAS Hits" in Clinical Populations: Lessons from Childhood Cancer Survivors.

With mounting interest in translating genome-wide association study (GWAS) hits from large meta-analyses (meta-GWAS) in diverse clinical settings, evaluating their generalizability in target populations is crucial. Here, we consider long-term survivors of childhood cancers from the St. Jude Lifetime Cohort Study, and we show the limited generalizability of 1,376 robust SNP associations reported in the general population across 12 complex anthropometric and cardiometabolic phenotypes (n = 2,231; observed-to-expected replication ratio = 0.70, p = 6.2 × 10-8). An examination of five comparable phenotypes in a second independent cohort of survivors from the Childhood Cancer Survivor Study corroborated the overall limited generalizability of meta-GWAS hits to survivors (n = 4,212; observed-to-expected replication ratio = 0.55, p = 5.6 × 10-15). Finally, in direct comparisons of survivor samples against independent equivalently powered general population samples from the UK Biobank, we consistently observed lower meta-GWAS hit replication rates and poorer polygenic risk score predictive performance in survivor samples for multiple phenotypes. As a possible explanation, we found that meta-GWAS hits were less likely to be replicated in survivors who had been exposed to cancer therapies that are associated with phenotype risk. Examination of complementary DNA methylation data in a subset of survivors revealed that treatment-related methylation patterns at genomic sites linked to meta-GWAS hits may disrupt established genetic signals in survivors.

Hierarchical MOF@AuNP/Hairpin Nanotheranostic for Enhanced Photodynamic Therapy via O2 Self-Supply and Cancer-Related MicroRNA Imaging In Vivo.

Developing a nanotheranostic with a high sensing performance and efficient therapy was significant in cancer diagnosis and treatment. Herein, a Au nanoparticle and hairpin-loaded photosensitive metal-organic framework (PMOF@AuNP/hairpin) nanotheranostic was constructed by growing AuNPs on PMOF in situ and then attaching hairpins. On the one hand, the PMOF@AuNP/hairpin nanotheranostic could effectively transfer O2 into ROS, facilitating efficient PDT. Additionally, the nanotheranostic possessed catalase-like activity, which could effectively catalyze H2O2 to generate O2, thus achieving O2-evolving PDT and significantly enhancing the antitumor effect of PDT in vivo. On the other hand, the nanotheranostic showed a high loading efficiency of hairpins and achieved the sensitive and selective detection of miR-21 both in living cells and in vivo. Moreover, the nanotheranostic could dynamically monitor the miR-21 level. Due to the excellent imaging performance, the nanotheranostic could recognize cancer cells and might provide important information on cancer progression for PDT. The developed PMOF@AuNP/hairpin nanotheranostic provided a useful tool for tumor diagnosis and antitumor therapy.

'I'm still young it doesn't matter' - A qualitative study on the neglect of prodromal myocardial infarction symptoms among young- and middle-aged adults.

AIM: To explore why young- and middle-aged adults ignore prodromal myocardial infarction symptoms from a life course and sociocultural perspective. DESIGN: A qualitative descriptive study. METHODS: We applied purposeful sampling to recruit participants from a tertiary hospital in Guangzhou from July to November 2021. Face-to-face interviews were performed. Interviews were audio-recorded, transcribed verbatim and analysed using thematic analysis methods. RESULTS: Twenty-four young- and middle-aged adults diagnosed with acute myocardial infarction participated in this study. Analysis revealed three main themes: I'm still young, it will not happen to me; to be somebody and different roles, multiple pressures. Age-related self-confidence led to inappropriate perceptions and responses to prodromal symptoms among young- and middle-aged adults. These individuals strived to align their behaviours and attention with social expectations and self-expectations, underestimating the importance of perceiving the warning signs of acute myocardial infarction and seeking medical treatment. Pressure from social roles also prevented them from paying enough attention to prodromal symptoms. CONCLUSION: Targeted social support, public education and technologies should be provided to these individuals since they are pillars of the family and society. We also highlight how nurses can function these strategies appropriately. IMPACTS: This study contributes to a better understanding of the neglect of prodromal symptoms among young- and middle-aged adults. Its results enhance our understanding of the perception of and coping with prodromal symptoms among this population, which will help avoid the burden caused by acute myocardial infarction. PATIENT OR PUBLIC CONTRIBUTION: The patients involved in our study shared their experiences and insights to provide new perspectives regarding the neglect of prodromal myocardial infarction symptoms among young- and middle-aged adults.

The analysis of the lipid levels in patients with coronary artery disease after percutaneous coronary intervention: a one-year follow-up observational study.

BACKGROUND: Coronary heart disease (CHD) is one of the leading causes of death worldwide. Percutaneous coronary intervention (PCI) has been an important technology for the treatment of CHD. Blood lipid management is critical for PCI patients because not only should local vascular pathological changes be considered but the whole atherosclerotic process should be considered as well. METHODS: A total of 522 patients diagnosed with CHD (including acute myocardial infarction and unstable angina) successfully underwent stent implantation in acute or elective PCI in the cardiology department of one general hospital in Guangzhou from June 2015 to December 2017. The 2016 Chinese Guideline for the Management of dyslipidaemia in Adults and the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report (NCEP-ATP III) were used to classify total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels. RESULTS: A total of 522 patients were recruited for the study. The mean values of TC, TG, LDL-C, and HDL-C at baseline were 4.76, 1.80, 2.93 and 1.03 mmol/L, respectively. After 1 year of follow-up, the mean values of TC, TG, LDL-C, and HDL-C were 3.94, 1.62, 2.26 and 1.01 mmol/L, respectively. The prevalence of high TC, high TG, high LDL-C and low HDL-C at baseline was 12.05, 21.80, 10.90 and 56.79%, respectively, and the prevalence at follow-up was 4.59, 15.68, 3.25 and 59.85%, respectively. Logistic regression revealed that gender was risk factor for high TC (≥ 6.22 mmol/L), low HDL-C (< 1.04 mmol/L) and high LDL-C (≥ 4.14 mmol/L) at follow-up. Age was the factor associated with high TG (≥ 2.26 mmol/L) and low HDL-C (< 1.04 mmol/L) at follow-up. Besides, smoking and diet control were risk factors for low HDL-C (< 1.04 mmol/L) and high LDL-C (≥ 4.14 mmol/L) at follow-up, respectively. CONCLUSION: The patients with PCI at follow-up experienced lower mean values of lipids and prevalence of dyslipidaemia than those at baseline. Gender, age, smoking and diet control were the risk factors associated with elevated lipids. Improvement in lipid management at follow up demonstrated that such intervention can be effective.

Comparative performance of the EQ-5D-5L and SF-6D index scores in adults with type 2 diabetes.

PURPOSE: To explore the comparative performance including discriminative and longitudinal validity of EQ-5D-5L and SF-6D index scores in adults with type 2 diabetes. METHODS: Data from an on-going cohort study of adults with type 2 diabetes in Alberta, Canada, were used. Known-groups approach was used to examine discriminative validity. Correlation and agreement indices and scatter and Bland-Altman plots were used to examine the relationship between the two measures. Longitudinal validity was explored using Wilcoxon signed-rank test, effect size, and standardized response mean. RESULTS: In 1832 participants at baseline (age 64.3, standard deviation 10.6 years; 45% female), median EQ-5D-5L score was 0.85 [interquartile range (IQR) 0.17], and floor and ceiling effects of 0.1 and 16.1%, respectively; median SF-6D score was 0.72 (IQR 0.24), and floor and ceiling effects of 0.1 and 3.2%, respectively. EQ-5D-5L and SF-6D index scores were significantly correlated with an overall Spearman correlation coefficient of 0.73, and an ICC of 0.62 (95% CI 0.42-0.74). Both EQ-5D-5L and SF-6D scores demonstrated statistically significant differences in self-reported chronic conditions, depressive symptoms, and diabetes-related distress, and were able to detect changes in depressive symptoms and diabetes distress across all change groups. CONCLUSIONS: Both EQ-5D-5L and SF-6D index scores provide valid measurement in this patient population. Considerable overlap between the measures means it is not necessary to include both in surveys, however, the advantages and disadvantages of each should be considered.

Dose-response relationship between sulfonylureas and major adverse cardiovascular events in elderly patients with type 2 diabetes.

PURPOSE: The objective of this study was to determine if there is a dose-response relationship between sulfonylureas and major adverse cardiovascular events (MACE). METHODS: We conducted a retrospective cohort study among elderly patients with no history of acute coronary syndrome or stroke who initiated gliclazide or glyburide therapy between 1998 and 2010. Gliclazide and glyburide users were evaluated separately, and a high-dimensional propensity score (HDPS) was used to match patients initiating therapy with a low or high dose. A time-dependent variable was used to further characterize exposure, which can change during follow-up. Cox proportional hazard regression models were used to compare the risk of MACE between low (reference) and high doses. RESULTS: We identified 14,213 new users of gliclazide or glyburide (mean age, 74.7 (standard deviation 6.4) years; males, 52.8%; and mean follow-up duration, 2.7 (standard deviation 2.9) years). Among gliclazide users, there was a higher risk of MACE with high compared with low dose (crude rates: 32.8 and 28.2 per 1000 person-years, respectively), but this did not reach statistical significance (HDPS-matched hazard ratio) 1.15; 95% confidence interval (0.96-1.38). For glyburide users, however, MACE occurred more frequently in the high compared with low dose (crude rates: 38.9 and 31.5 per 1000 person-years, respectively; HDPS-matched hazard ratio 1.24; 95% confidence interval 1.02-1.50). CONCLUSIONS: Among new users of sulfonylureas, there appears to be a dose-response relationship between glyburide and MACE, but not for gliclazide. Copyright © 2016 John Wiley & Sons, Ltd.

Health literacy and health-related quality of life in adults with type 2 diabetes: a longitudinal study.

PURPOSE: To examine the association of health literacy (HL) with changes in health-related quality of life (HRQL) among patients with type 2 diabetes. METHODS: Data from a cohort study of type 2 diabetes patients were used. HL was assessed using 3 previously validated screening questions and HRQL using the EQ-5D-5L and SF-12 [physical and mental composite summary scores (PCS, MCS)]. The associations of baseline HL with changes in EQ-5D, PCS, and MCS scores over 1 year and with directions of changes (no change; declined; improved) were examined. Missing data were handled with multiple imputation and sensitivity analyses. RESULTS: Average age of participants (N = 1948) was 64.6 ± 10.9 years, 45 % were female, and 12.6 % had inadequate HL. Participants had mean decrements of 0.01 in EQ-5D, 1.0 in PCS, and 1.2 in MCS over 1 year. In adjusted analysis, HL was not associated with changes in EQ-5D over 1 year (ß = 0.01, P = 0.146); however, patients with adequate HL had 2.1 points greater increase in PCS (P < 0.001) and 3.1 points in MCS (P < 0.001) compared to those with inadequate HL. Patients with adequate HL were less likely to have a decline in EQ-5D (RR 0.66; 95 % CI 0.44, 0.98), PCS (RR 0.51; 95 % CI 0.34, 0.76), and MCS (RR 0.49; 95 % CI 0.33, 0.72) compared to those with inadequate HL. Patients with adequate HL were more likely to have an improvement in MCS compared to those with inadequate HL (RR 1.78; 95 % CI 1.04, 3.04); such associations were not observed for PCS or EQ-5D. All results were robust in sensitivity analyses. CONCLUSIONS: Inadequate HL was independently associated with worsening HRQL in adults with type 2 diabetes, particularly in the mental health domain.

Age at stroke onset influences the clinical outcome and health-related quality of life in pediatric ischemic stroke survivors.

AIM: Stroke in children occurs across different phases of brain development. Age at onset may affect outcome and health-related quality of life (HRQL). We evaluated the influence of age at stroke onset on the long-term neurological outcomes and HRQL of pediatric stroke survivors. METHOD: Children with ischemic stroke were recruited into three groups according to their age at onset of stroke (presumed perinatal, neonatal, and childhood). Neurological outcomes were assessed using the Pediatric Stroke Recovery and Recurrence Questionnaire. HRQL was evaluated using proxy report versions (2-18y) of the Pediatric Quality of Life Inventory (PedsQL 4.0). A χ(2) /Fisher's exact test and multivariable logistic regression analysis was performed for the neurological outcomes. HRQL scores from the different age groups were compared using linear regression. RESULTS: Ninety participants (presumed perinatal stroke, n=31; neonatal stroke, n=36; childhood stroke, n=23) were enrolled. Median age at the onset of stroke was 0.5 days and 3.7 years in neonatal and childhood participants respectively. Of the three groups, participants with presumed perinatal stroke demonstrated the worst global (p<0.002) and motor (p<0.001) outcomes and the lowest level of independence in daily activities (p<0.001). Parents reported the best global outcome and overall HRQL (p=0.007) after neonatal stroke. INTERPRETATION: The age at stroke onset has important implications regarding long-term clinical outcomes and HRQL for survivors. Individuals with presumed perinatal stroke should be considered at high-risk for poor outcomes.

Psychosocial adjustment changes and related factors in young and middle-aged patients with first-episode acute myocardial infarction: a longitudinal study.

AIMS: This study aimed to explore the change trend and group heterogeneity of psychosocial adjustment level and to determine its influencing factors among young and middle-aged patients with first-episode acute myocardial infarction (AMI). METHODS AND RESULTS: The Psychosocial Adjustment Scale of Illness was used to assess the psychosocial adjustment level of the patients at 1, 3, and 6 months after discharge, respectively. Data were analyzed using Pearson correlation analysis, generalized estimating equations, and growth mixed models. A total of 233 patients were included, and their psychosocial adjustment scores at the three-time points were 57.18 ± 15.50, 36.17 ± 15.02, and 24.22 ± 12.98, respectively. The trajectories of changes in patients' psychosocial adjustment levels were divided into three latent categories: moderate adjustment improvement group (72.5%), low adjustment improvement group (16.3%), and persistent maladjustment group (11.2%). Among them, predictors of the persistent maladjustment group included no spouse, low monthly family income per capita, normal body mass index, never smoking, never exercising, combined with hyperlipidemia, low social support, submission coping, and high perceived stress. CONCLUSIONS: The psychosocial adjustment level of young and middle-aged patients with first-episode AMI showed an upward trend within 6 months after discharge, and there was group heterogeneity in the change trajectory of psychosocial adjustment level. It is suggested that a multi-center, large-sample longitudinal study should be carried out in the future, and the time of follow-up investigation should be extended to further clarify the change trajectory and influencing factors of psychosocial adjustment of patients with different subtypes, to provide the theoretical basis for formulating targeted intervention programs.

Financial hardship and neighborhood socioeconomic disadvantage in long-term childhood cancer survivors.

BACKGROUND: Long-term survivors of childhood cancer face elevated risk for financial hardship. We evaluate whether childhood cancer survivors live in areas of greater deprivation and the association with self-reported financial hardships. METHODS: We performed a cross-sectional analysis of data from the Childhood Cancer Survivor Study between 1970 and 1999 and self-reported financial information from 2017 to 2019. We measured neighborhood deprivation with the Area Deprivation Index (ADI) based on current zip code. Financial hardship was measured with validated surveys that captured behavioral, material and financial sacrifice, and psychological hardship. Bivariate analyses described neighborhood differences between survivors and siblings. Generalized linear models estimated effect sizes between ADI and financial hardship adjusting for clinical factors and personal socioeconomic status. RESULTS: Analysis was restricted to 3475 long-term childhood cancer survivors and 923 sibling controls. Median ages at time of evaluation was 39 years (interquartile range [IQR] = 33-46 years and 47 years (IQR = 39-59 years), respectively. Survivors resided in areas with greater deprivation (ADI ≥ 50: 38.7% survivors vs 31.8% siblings; P < .001). One quintile increases in deprivation were associated with small increases in behavioral (second quintile, P = .017) and psychological financial hardship (second quintile, P = .009; third quintile, P = .014). Lower psychological financial hardship was associated with individual factors including greater household income (≥$60 000 income, P < .001) and being single (P = .048). CONCLUSIONS: Childhood cancer survivors were more likely to live in areas with socioeconomic deprivation. Neighborhood-level disadvantage and personal socioeconomic circumstances should be evaluated when trying to assist childhood cancer survivors with financial hardships.

Hydrogen-Rich Water Treatment of Fresh-Cut Kiwifruit with Slightly Acidic Electrolytic Water: Influence on Antioxidant Metabolism and Cell Wall Stability.

The synergistic impact of hydrogen-rich water (HRW, 394 ppb) and slightly acidic electrolyzed water (SAEW, pH of 6.25 ± 0.19) on the antioxidant metabolism of fresh-cut kiwifruit during storage was investigated (temperature: (3 ± 1) °C, humidity: 80%-85%). Compared with control group, H+S treatment increased the contents of active oxygen-scavenging enzymes (SOD, CAT, POD, and APX) and inhibited the increase of O2•- and H2O2 contents during the storage of fresh-cut kiwifruit. Meanwhile, H+S treatment could reduce the activities of the cell wall-degrading enzymes PG, PME, PL, Cx, and ß-Gal, inhibit the formation of soluble pectin, delay the degradation rate of propectin, cellulose, and pseudocellulose, and maintain higher fruit hardness and chewability. The results showed that H+S treatment could enhance free radical scavenging ability and reduce the cell wall metabolism of fresh-cut kiwifruit, maintaining the good texture found in fresh-cut fruit.

Risk factor analysis of omicron patients with mental health problems in the Fangcang shelter hospital based on psychiatric drug intervention during the COVID-19 pandemic in Shanghai, China.

Backgrounds: The widespread coronavirus disease 2019 (COVID-19) outbreak impacted the mental health of infected patients admitted to Fangcang shelter hospital a large-scale, temporary structure converted from existing public venues to isolate patients with mild or moderate symptoms of COVID-19 infection. Objective: This study aimed to investigate the risk factors of the infected patients from a new pharmacological perspective based on psychiatric drug consumption rather than questionnaires for the first time. Methods: We summarised the medical information and analysed the prevalence proportion, characteristics, and the related risk factors of omicron variants infected patients in the Fangcang Shelter Hospital of the National Exhibition and Convention Center (Shanghai) from 9 April 2022 to 31 May 2022. Results: In this study, 6,218 individuals at 3.57% of all admitted patients in the Fangcang shelter were collected suffering from mental health problems in severe conditions including schizophrenia, depression, insomnia, and anxiety who needed psychiatric drug intervention. In the group, 97.44% experienced their first prescription of psychiatric drugs and had no diagnosed historical psychiatric diseases. Further analysis indicated that female sex, no vaccination, older age, longer hospitalization time, and more comorbidities were independent risk factors for the drug-intervened patients. Conclusion: This is the first study to analyse the mental health problems of omicron variants infected patients hospitalised in Fangcang shelter hospitals. The research demonstrated the necessity of potential mental and psychological service development in Fangcang shelters during the COVID-19 pandemic and other public emergency responses.

Genetic risk score enhances the risk prediction of severe obesity in adult survivors of childhood cancer.

Adult survivors of childhood cancer have high rates of obesity, which, in combination with the cardiotoxic effects of specific cancer therapies, places them at high risk for cardiovascular morbidity. Here we show the contribution of genetic risk scores (GRSs) to increase prediction of those survivors of childhood cancer who are at risk for severe obesity (body mass index ≥40 kg m-2) as an adult. Among 2,548 individuals of European ancestry from the St. Jude Lifetime Cohort Study who were 5-year survivors of childhood cancer, the GRS was found to be associated with 53-fold-higher odds of severe obesity. Addition of GRSs to risk prediction models based on cancer treatment exposures and lifestyle factors significantly improved model prediction (area under the curve increased from 0.68 to 0.75, resulting in the identification of 4.3-times more high-risk survivors), which was independently validated in 6,064 individuals from the Childhood Cancer Survivor Study. Genetic predictors improve identification of patients who could benefit from heightened surveillance and interventions to mitigate the risk of severe obesity and associated cardio-metabolic complications.

A Novel Locus on 6p21.2 for Cancer Treatment-Induced Cardiac Dysfunction Among Childhood Cancer Survivors.

BACKGROUND: Adult survivors of childhood cancer are at increased risk of cardiac late effects. METHODS: Using whole-genome sequencing data from 1870 survivors of European ancestry in the St. Jude Lifetime Cohort (SJLIFE) study, genetic variants were examined for association with ejection fraction (EF) and clinically assessed cancer therapy-induced cardiac dysfunction (CCD). Statistically significant findings were validated in 301 SJLIFE survivors of African ancestry and 4020 survivors of European ancestry from the Childhood Cancer Survivor Study. All statistical tests were 2-sided. RESULTS: A variant near KCNK17 showed genome-wide significant association with EF (rs2815063-A: EF reduction = 1.6%; P = 2.1 × 10-8) in SJLIFE survivors of European ancestry, which replicated in SJLIFE survivors of African ancestry (EF reduction = 1.5%; P = .004). The rs2815063-A also showed a 1.80-fold (P = .008) risk of severe or disabling or life-threatening CCD and replicated in 4020 Childhood Cancer Survivor Study survivors of European ancestry (odds ratio = 1.40; P = .04). Notably, rs2815063-A was specifically associated among survivors exposed to doxorubicin only, with a stronger effect on EF (3.3% EF reduction) and CCD (2.97-fold). Whole blood DNA methylation data in 1651 SJLIFE survivors of European ancestry showed statistically significant correlation of rs2815063-A with dysregulation of KCNK17 enhancers (false discovery rate <5%), which replicated in 263 survivors of African ancestry. Consistently, the rs2815063-A was associated with KCNK17 downregulation based on RNA sequencing of 75 survivors. CONCLUSIONS: Leveraging the 2 largest cohorts of childhood cancer survivors in North America and survivor-specific polygenomic functional data, we identified a novel risk locus for CCD, which showed specificity with doxorubicin-induced cardiac dysfunction and highlighted dysregulation of KCNK17 as the likely molecular mechanism underlying this genetic association.

RNA Demethylase FTO Mediated RNA m6A Modification Is Involved in Maintaining Maternal-Fetal Interface in Spontaneous Abortion.

The N6-methyladenosine (m6A) RNA modification regulates the expression of genes associated with various biological and pathological processes, including spontaneous abortion (SA). The aim of this study was to determine the role of the m6A demethylase fat mass and obesity (FTO)- associated protein in SA. The FTO,IGF2BP1 and IGF2BP2 mRNA levels were significantly lower in the chorionic villi obtained from spontaneously aborted pregnancies compared to that of normal pregnancies, while the expression levels of METTL3 and WTAP were significantly elevated. However, ALKBH5, YTHDF2, and IGF2BP3 were elevated with no statistical significance between groups. In addition, MDA was elevated and SOD levels were decreased in the villi tissues of the SA group compared to the normal group, which was indicative of placental oxidative stress in the former. Furthermore, the expression of FTO and HLA-G were significantly decreased in the trophoblasts of the SA patients compared to that of normal pregnant women, while that of m6A was markedly higher in the former. In addition, the HLA-G and VEGFR mRNA levels were downregulated in the SA versus the control group, and that of MMP2, MMP7, MMP9 and VEGFA were upregulated. Finally, The RIP assay showed significantly decreased levels of FTO-bound HLA-G, VEGFR and MMP9 RNA in SA patients (P < 0.05), which corresponded to an increase in transcripts enriched with the m6A antibody (P < 0.05). However, compared with normal pregnant women, the levels of HLA-G, VEGFA, VEGFR, and MMP2 mRNA bound by YTHDF2 were significantly decreased in SA patients. Compared to the normal pregnant women, both FTO- and m6A-bound MMP7 were significantly increased in SA patients (P < 0.05), but YTHDF2 almost unbound to MMP7 mRNA. In summary, the downregulation of FTO in the chorionic villi disrupts immune tolerance and angiogenesis at the maternal-fetal interface, resulting in aberrant methylation and oxidative stress that eventually leads to SA.

Sex-Specific Associations Between Chemotherapy, Chronic Conditions, and Neurocognitive Impairment in Acute Lymphoblastic Leukemia Survivors: A Report From the Childhood Cancer Survivor Study.

BACKGROUND: The purpose was to examine associations between treatment and chronic health conditions with neurocognitive impairment survivors of acute lymphoblastic leukemia (ALL) treated with chemotherapy only. METHODS: This cross-sectional study included 1207 ALL survivors (54.0% female; mean age 30.6 years) and 2273 siblings (56.9% female; mean age 47.6 years), who completed the Childhood Cancer Survivor Study Neurocognitive Questionnaire. Multivariable logistic regression compared prevalence of neurocognitive impairment between survivors and siblings by sex. Associations between neurocognitive impairment with treatment exposures and chronic conditions (graded according to Common Terminology Criteria for Adverse Events) were also examined. Statistical tests were 2-sided. RESULTS: Relative to same-sex siblings, male and female ALL survivors reported increased prevalence of impaired task efficiency (males: 11.7% vs 16.9%; adjusted odds ratio [OR] = 1.89, 95% confidence interval [CI] = 1.31 to 2.74; females: 12.5% vs 17.6%; OR = 1.50, 95% CI = 1.07 to 2.14), as well as impaired memory (males: 11.6% vs 19.9%, OR = 1.89, CI = 1.31 to 2.74; females: 14.78% vs 25.4%, OR = 1.96, 95% CI = 1.43 to 2.70, respectively). Among male survivors, impaired task efficiency was associated with 2-4 neurologic conditions (OR = 4.33, 95% CI = 1.76 to 10.68) and with pulmonary conditions (OR = 4.99, 95% CI = 1.51 to 16.50), and impaired memory was associated with increased cumulative dose of intrathecal methotrexate (OR = 1.68, 95% CI = 1.16 to 2.46) and with exposure to dexamethasone (OR = 2.44, 95% CI = 1.19 to 5.01). In female survivors, grade 2-4 endocrine conditions were associated with higher risk of impaired task efficiency (OR = 2.19, 95% CI = 1.20 to 3.97) and memory (OR = 2.26, 95% CI = 1.31 to 3.92). CONCLUSION: Neurocognitive impairment is associated with methotrexate, dexamethasone, and chronic health conditions in a sex-specific manner, highlighting the need to investigate physiological mechanisms and monitor impact through survivorship.

Health-related quality of life and its determinants in paediatric arterial ischaemic stroke survivors.

OBJECTIVE: Health-related quality of life (HRQL) instruments are patient or proxy-reported outcome measures that provide a comprehensive and subjective assessment of patient's well-being and hence vital for health outcomes evaluation. A clear and thorough understanding of HRQL and its determinants is especially important to appropriately guide health-improving interventions. In this study, HRQL of paediatric arterial ischaemic stroke survivors was assessed using guidelines recommended for interpretation and reporting of the patient-reported outcome data. Determinants of HRQL were also explored. METHODS: Children diagnosed with arterial ischaemic stroke between 2003 and 2012 were assessed at least 1 year poststroke using the parent-proxy report versions of the Pediatric Quality of Life Inventory 4.0 and Pediatric Stroke Recurrence and Recovery Questionnaire. HRQL data were compared with population norms and used as outcome in multiple linear regression analysis. RESULTS: 59 children were evaluated. Mean age at diagnosis of stroke was 2.2 years. Mean age at assessment and time elapsed since stroke was 7 years and 5 years, respectively. A total of 41% children had normal global outcome, whereas 51% had moderate to severe deficits. A lower overall HRQL was observed in both self and proxy reports. Parents reported the maximum impairment in emotional domain, whereas children indicated physical functioning to be the most affected. Neurological outcome, site of stroke and socioeconomic status were independently associated with overall HRQL. CONCLUSIONS: Lower HRQL was demonstrated in children who survived arterial ischaemic stroke. Socioeconomic status of families was an important determinant of HRQL, over and above clinical parameters.

Pulsatilla decoction inhibits Candida albicans proliferation and adhesion in a mouse model of vulvovaginal candidiasis via the Dectin-1 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Pulsatilla decoction (PD) is a classical prescription in Traditional Chinese Medicine (TCM) and has been reported to have inhibitory effects on Candida albicans proliferation. STUDY AIM: To investigate the therapeutic effects of PD in the treatment of Vulvovaginal candidiasis (VVC) and elucidate the potential mechanism. MATERIALS AND METHODS: Female BALB/c mice (N = 90) were randomized to six treatment groups, including the Control group, Model group, three PD groups and Fluconazole group which served as a positive control (20 mg/kg weekly). The three PD groups (low dose group, medium dose group and high dose group) were given a daily intragastric gavage of PD at doses of 5, 10 and 20 g/kg, respectively. Five animals from each group were euthanized on Day 4, Day 7 and Day 14 after treatment. Colony forming unit (CFU) was measured by the serial dilution method. The degree of infection was assessed by Gram staining, Periodic acid schiff (PAS) staining, Hematoxylin and eosin (H&E) staining and Scanning electron microscopy (SEM). The serum inflammation levels were determined by a Luminex assay. Gene and protein expression levels of components of the Dectin-1 signaling pathway were determined by Real-time PCR, Western-blot and immunohistochemistry, respectively. RESULTS: The administration of PD significantly decreased the fungal load from Day 7 post-infection onwards and decreased the number of visible microorganisms based on findings from Gram staining, PAS staining and SEM. H&E staining indicated that the impaired histological profiles were improved in all three PD groups. PD led to a significantly lower level of IL-23 in the serum; the levels of IL-10 and TNF-α were also decreased, although the differences were not significant. Furthermore, a substantial downregulation of Dectin-1, CARD9 and NF-κB mRNA levels and Dectin-1, Syk, CARD9 and NF-κB protein levels was observed after the administration of PD. CONCLUSION: This study suggests that PD exerts inhibitory effects on C. albicans proliferation, adhesion and inflammation and simultaneously downregulates the expression levels of important genes and proteins associated with the Dectin-1 pathway, highlighting the potential application of PD to improve the clinical management of VVC.

Total flavonoids from Semen Cuscutae target MMP9 and promote invasion of EVT cells via Notch/AKT/MAPK signaling pathways.

Miscarriage is a common condition during pregnancy and its mechanisms remain largely unknown. Extravillous trophoblast (EVT) cell invasion is required to maintain normal pregnancy and its malfunction has been proposed as a major cause for miscarriage. Homeostasis of matrix metalloproteinase 9 (MMP9) is a key to regulate EVT cell invasion. Total flavonoids from Semen Cuscutae (TFSC) have been applied clinically used for preventing or treating miscarriage in the past. Given its potential clinical benefit on preventing miscarriage, this study aims at examining the therapeutic effect of TFSC in the prevention of premature birth by upregulating MMP9 and promote EVT cell invasion. HTR-8 cells migration and invasion functions were analyzed using wound healing and transwell assays. The regulatory effect of TFSC on MMP9 expression and relevant signaling pathways were analyzed by Western Blot. The results show compared to control group, TFSC significantly promoted the migration of EVT cells in a dose and time-dependent manner. The migration and invasion of EVT cells were maximized at the highest dosage of 5 µg/ml of TFSC. The expression of MMP9 in EVT cells was significantly increased after TFSC treatment. Furthermore, cells treated with TFSC significantly upregulated protein expressions in Notch, AKT and p38/MAPK signaling pathways. We believe TFSC can promote the migration and invasion of EVT cells by increasing MMP9 expression, and prevent miscarriage by activating Notch, AKT, and MAPK signaling pathways.

Effect of Total Flavones from Cuscuta Chinensis on Anti-Abortion via the MAPK Signaling Pathway.

For centuries, the Chinese herb Cuscuta chinensis has been applied clinically for abortion prevention in traditional Chinese medicine (TCM). Total flavones extracted from Cuscuta chinensis (TFCC) are one of the active components in the herb and also display anti-abortion effect similar to the unprocessed material. However, how TFCC exerts the anti-abortion effect remains largely unknown. In this study, we aim at characterizing the anti-abortion effects of TFCC and its underlying molecular mechanism in vitro and in vivo using human primary decidua cells and a mifepristone-induced abortion model in rat, respectively. The damage to the decidua caused by mifepristone in vivo was reversed by TFCC treatment in a dosage-dependent manner. High dosage of TFCC significantly upregulated the expression of estrogen receptor (ER), progesterone receptor (PR), and prolactin receptor (PRLR) in decidua tissue but downregulated the expression of p-ERK. Furthermore, we detected higher level of p-ERK and p-p38 in primary decidua cells from spontaneous abortion while treatment by TFCC downregulated their expression. Our results suggest TFCC mediates its anti-abortion effect by interfering with MAPK signaling pathway.