Associations of neighborhood sociodemographic environment with mortality and circulating metabolites among low-income black and white adults living in the southeastern United States.

BACKGROUND: Residing in a disadvantaged neighborhood has been linked to increased mortality. However, the impact of residential segregation and social vulnerability on cause-specific mortality is understudied. Additionally, the circulating metabolic correlates of neighborhood sociodemographic environment remain unexplored. Therefore, we examined multiple neighborhood sociodemographic metrics, i.e., neighborhood deprivation index (NDI), residential segregation index (RSI), and social vulnerability index (SVI), with all-cause and cardiovascular disease (CVD) and cancer-specific mortality and circulating metabolites in the Southern Community Cohort Study (SCCS). METHODS: The SCCS is a prospective cohort of primarily low-income adults aged 40-79, enrolled from the southeastern United States during 2002-2009. This analysis included self-reported Black/African American or non-Hispanic White participants and excluded those who died or were lost to follow-up ≤ 1 year. Untargeted metabolite profiling was performed using baseline plasma samples in a subset of SCCS participants. RESULTS: Among 79,631 participants, 23,356 deaths (7214 from CVD and 5394 from cancer) were documented over a median 15-year follow-up. Higher NDI, RSI, and SVI were associated with increased all-cause, CVD, and cancer mortality, independent of standard clinical and sociodemographic risk factors and consistent between racial groups (standardized HRs among all participants were 1.07 to 1.20 in age/sex/race-adjusted model and 1.04 to 1.08 after comprehensive adjustment; all P < 0.05/3 except for cancer mortality after comprehensive adjustment). The standard risk factors explained < 40% of the variations in NDI/RSI/SVI and mediated < 70% of their associations with mortality. Among 1110 circulating metabolites measured in 1688 participants, 134 and 27 metabolites were associated with NDI and RSI (all FDR < 0.05) and mediated 61.7% and 21.2% of the NDI/RSI-mortality association, respectively. Adding those metabolites to standard risk factors increased the mediation proportion from 38.4 to 87.9% and 25.8 to 42.6% for the NDI/RSI-mortality association, respectively. CONCLUSIONS: Among low-income Black/African American adults and non-Hispanic White adults living in the southeastern United States, a disadvantaged neighborhood sociodemographic environment was associated with increased all-cause and CVD and cancer-specific mortality beyond standard risk factors. Circulating metabolites may unveil biological pathways underlying the health effect of neighborhood sociodemographic environment. More public health efforts should be devoted to reducing neighborhood environment-related health disparities, especially for low-income individuals.

RIPK1 polymorphisms and expression levels: impact on genetic susceptibility and clinical outcome of epithelial ovarian cancer.

BACKGROUND: The aim of this study was to explore the associations of RIPK1 polymorphisms, plasma levels and mRNA expression with susceptibility to epithelial ovarian cancer (EOC) and clinical outcome. METHODS: Three hundred and nineteen EOC patients included in a 60-month follow-up program and 376 controls were enrolled. Two tag SNPs (rs6907943 and rs9392453) of RIPK1 were genotyped using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. Plasma levels of RIPK1 and RIPK1 mRNA expression in white blood cells were determined by ELISA and qPCR, respectively. RESULTS: For rs9392453, significantly increased EOC risk was found to be associated with C allele (P = 0.002, OR = 1.49, 95%CI 1.15-1.92), and with CT/CC genotypes in the dominant genetic model (P = 0.006, OR = 1.54, 95%CI 1.12-2.08). CC haplotype (rs6907943-rs9392453) was associated with increased EOC susceptibility. CC genotype of rs6907943 and CT/CC genotypes of rs9392453 were associated with early onset (age ≤ 50 years) of EOC (OR = 2.5, 95%CI 1.03-5.88, and OR = 1.64, 95%CI 1.04-2.63, respectively). AC genotype of rs6907943 was associated with better overall survival of EOC patients in the over-dominant genetic model (P = 0.035, HR = 0.41, 95%CI 0.18-0.94). Multivariate survival analysis identified the AC genotype of rs6907943 as an independent protective factor for survival of early onset patients (P = 0.044, HR = 0.12, 95%CI 0.02-0.95). Compared to controls, significantly increased plasma levels of RIPK1 and reduced RIPK1 mRNA expression were observed in patients. CONCLUSIONS: Our results suggest that tag SNPs of RIPK1, increased plasma levels of RIPK1 protein and reduced RIPK1 mRNA expression in white blood cells, may influence the susceptibility to EOC. SNP rs6907943 may be a useful marker to distinguish EOC patients with high risk of death.

Increased incidence of congenital hypothyroidism in China: An analysis of 119 million screened newborns.

Despite the lack of nationwide epidemiological studies, congenital hypothyroidism (CH) incidence in China has increased. We aimed to evaluate the trends of CH and the possible reasons behind them. Data from screened newborns from the Chinese Newborn Screening Information System from 2012 to 2019 was collected. We applied the Bayesian hierarchical Poisson regression model and meta-analysis to estimate incidence or proportion over the years. The estimated CH incidence increased from 4.01 per 10,000 births in 2012 to 5.77 per 10,000 births in 2019. The average annual growth rate (ARG) of CH incidence for all provinces varied from 0.59 to 20.96%. The most rapid rise in incidence was observed in cases with an initial thyroid stimulating hormone (TSH) concentration of < 10 mIU/L. The meta-analysis results showed that the proportion of permanent CH increased by 0.024% (95%CI: 0.011%, 0.037%) annually. Each 1 mIU/L decrease in TSH cutoff value was associated with a 2.96% increase in CH incidence. In the same period, the proportion of premature CH cases increased from 6.60 to 9.10%, which was much higher than the increase in preterm births. A significant relationship was not found between provincial growth rates in screening coverage and provincial baseline incidences of CH.  Conclusion: CH incidence has substantially increased in China. The slight adjustment of the TSH cutoff value and increasing preterm birth rate contribute to such a trend; however, the contribution is limited. What is Known: • An uptrend in congenital hypothyroidism (CH) incidence has been reported in many European and American countries in the last two decades; however, no studies have been conducted in China to explain the increased CH incidence. • We provide a detailed epidemiological report on the trends of CH during 2012-2019 in China, with an attempt to explore the reasons behind it. What is New: • This first-ever national-wide epidemiological report in China showed an uptrend in CH incidence with variations over regions and CH subtypes. The mild lowering of TSH cutoff values and the increasing preterm birth rate contributed to this uptrend.

Global prevalence of congenital hypothyroidism among neonates from 1969 to 2020: a systematic review and meta-analysis.

Little is known about the global prevalence of congenital hypothyroidism (CH), though it is known to vary across countries and time periods. This meta-analysis aims to estimate the global and regional prevalence of CH among births between 1969 and 2020. PubMed, Web of Sciences, and Embase databases were searched for relevant studies between January 1, 1975, and March 2, 2020. Pooled prevalence was calculated using a generalized linear mixed model, and expressed as a rate per 10,000 neonates. The meta-analysis involved 116 studies, which analyzed 330,210,785 neonates, among whom 174,543 were diagnosed with CH. The pooled global prevalence of CH from 1969 to 2020 was 4.25 (95% confidence interval (CI) 3.96-4.57). The geographic region with highest prevalence was the Eastern Mediterranean (7.91, 95% CI 6.09-10.26), where the prevalence was 2.48-fold (95% CI 2.04-3.01) that in Europe. The national income level with the highest prevalence was upper-middle (6.76, 95% CI 5.66-8.06), which was 1.91-fold (95% CI 1.65-2.22) that in high-income countries. Global prevalence of CH was 52% (95% CI 4-122%) higher in 2011-2020 than in 1969-1980, after adjusting for geographic region, national income level, and screening strategy.  Conclusion: The global prevalence of CH increased from 1969 to 2020, which may reflect the implementation of national neonatal screening, neonatal testing for thyroid-stimulating hormone, and a lowering of the diagnostic level of this hormone. Additional factors are likely to be driving the increase, which should be identified in future research. What is Known: • Cumulated evidence had suggested that the occurrences of congenital hypothyroidism (CH) among newborns were varied in different countries.. • Up-trends of the birth prevalence of CH were observed in many European and American countries. What is New: • This is the first meta-analysis to estimate global and regional prevalence of CH among newborns. • The global prevalence of CH has increased by 127% since 1969. The Eastern Mediterranean has the highest prevalence and stands out with the most pronounced escalation in the prevalence of CH.

Non-invasive prenatal testing for the detection of trisomies 21, 18, and 13 in pregnant women with various clinical indications: A multicenter observational study of 1,854,148 women in China.

OBJECTIVE: This study aimed to evaluate the performance of noninvasive prenatal testing (NIPT) for detecting three common trisomies (T21, T18, and T13) in pregnant women with diverse clinical indications. METHODS: Frequencies of NIPT, of high chance of having one of the three trisomies, and of confirmed trisomies were determined for women with each of seven clinical indications in a national cross-sectional survey of approximately 300 prenatal diagnosis centers. Data were collected for the period from October 1, 2016 to September 30, 2018 using the Prenatal Diagnosis Technology Management On-line Information System. The performance of NIPT for detecting the three trisomies in pregnant women with different clinical indications was assessed in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value, and the corresponding 95% confidence intervals. RESULTS: A total of 5766 true positive cases for T21, T18, and T13 were detected among 1,854,148 samples, giving an overall detection rate of 0.31% (95% CI: 0.30%-0.32%). Most positive cases were associated with "NT thickening" (1.18%) and "advanced maternal age" (0.51%). The detection sensitivities of NIPT were 99.60% for T21, 99.14% for T18, and 100% for T13, while the corresponding specificities were 99.90%, 99.94%, and 99.95%. The corresponding PPVs were 69.77%, 47.24%, and 22.36%. NIPT showed high sensitivity and specificity, regardless of clinical indication. In contrast, PPV for three trisomies varied widely between 9.09% and 66.46% depending on the clinical indication. Across seven clinical indications, PPV ranged from 50.62% to 73.09% for T21, 20.00%-58.33% for T18, and 4.17%-47.37% for T13. The highest PPVs were 73.09% for T21 in pregnancies involving "advanced maternal age", 58.33% for T18 in pregnancies with "NT thickening", and 47.37% for T13 in pregnancies with "NT thickening". CONCLUSIONS: NIPT shows high sensitivity and specificity for detecting T21, T18, and T13 in pregnant women with different clinical indications. However, PPV depends strongly on clinical indication, highlighting the need to strengthen education and genetic counseling about prenatal screening.

The trend of unintentional injury-related mortality among children aged under-five years in China, 2010-2020: a retrospective analysis from a national surveillance system.

BACKGROUND: In this study, we estimated the trend of unintentional injury mortality among children aged under-five years in China during 2010-2020. METHODS: Data were obtained from China's Under 5 Child Mortality Surveillance System (U5CMSS). The total unintentional injury mortality and all specific-causes unintentional injury mortality was calculated, annual numbers of deaths and live births were adjusted by a 3-year moving average under-reporting rate. The Poisson regression model and the Cochran-Mantel-Haenszel method were used to calculate the average annual decline rate (AADR) and the adjusted relative risk (aRR) of the unintentional injury mortality. RESULTS: In 2010-2020, a total of 7,925 unintentional injury-related deaths were reported in U5CMSS, accounting for 18.7% of all reported deaths. The overall proportion of unintentional injury-related deaths to total under-five children deaths has increased from 15.2% to 2010 to 23.8% in 2020 (χ2 = 227.0, p < 0.001), the unintentional injury mortality significantly decreased from 249.3 deaths per 100,000 live births in 2010 to 178.8 deaths per 100,000 live births in 2020, with an AADR 3.7% (95%CI 3.1-4.4). The unintentional injury mortality rate decreased from 2010 to 2020 in both urban (from 68.1 to 59.7 per 100,000 live births) and rural (from 323.1 to 230.0 per 100,000 live births) areas (urban: χ2 = 3.1, p < 0.08; rural: χ2 = 113.5, p < 0.001). The annual rates of decline in rural areas and urban areas were 4.2% (95%CI 3.4-4.9) and 1.5% (95%CI 0.1-3.3), respectively. The leading causes of unintentional injury mortality were suffocation (2,611, 32.9%), drowning (2,398, 30.3%), and traffic injury (1,428, 12.8%) in 2010-2020. The cause-specific of unintentional injury mortality rates decreased with varying AADRs in 2010-2020, except for traffic injury. The composition of unintentional injury-related deaths also varied by age group. Suffocation was the leading cause in infants, drowning and traffic injury were the leading causes in children aged 1-4 years. Suffocation and poisoning has high incidence in October to March and drowning has high in June to August. CONCLUSION: The unintentional injury mortality rate of children aged under-five years decreased significantly from 2010 to 2020 in China, but great inequity exists in unintentional injury mortality in urban and rural areas. Unintentional injuries are still an important public health problem affecting the health of Chinese children. Effective strategies should be strengthened to reduce unintentional injury in children and these policies and programmes should be targeted to more specific populations, such as rural areas and males.

Temporal relationship among adiposity, gut microbiota, and insulin resistance in a longitudinal human cohort.

BACKGROUND: The temporal relationship between adiposity and gut microbiota was unexplored. Whether some gut microbes lie in the pathways from adiposity to insulin resistance is less clear. Our study aims to reveal the temporal relationship between adiposity and gut microbiota and investigate whether gut microbiota may mediate the association of adiposity with insulin resistance in a longitudinal human cohort study. METHODS: We obtained repeated-measured gut shotgun metagenomic and anthropometric data from 426 Chinese participants over ~3 years of follow-up. Cross-lagged path analysis was used to examine the temporal relationship between BMI and gut microbial features. The associations between the gut microbes and insulin resistance-related phenotypes were examined using a linear mixed-effect model. We examined the mediation effect of gut microbes on the association between adiposity and insulin resistance-related phenotypes. Replication was performed in the HMP cohort. RESULTS: Baseline BMI was prospectively associated with levels of ten gut microbial species. Among them, results of four species (Adlercreutzia equolifaciens, Parabacteroides unclassified, Lachnospiraceae bacterium 3 1 57FAA CT1, Lachnospiraceae bacterium 7 1 58FAA) were replicated in the independent HMP cohort. Lachnospiraceae bacterium 3 1 57FAA CT1 was inversely associated with HOMA-IR and fasting insulin. Lachnospiraceae bacterium 3 1 57FAA CT1 mediated the association of overweight/obesity with HOMA-IR (FDR<0.05). Furthermore, Lachnospiraceae bacterium 3 1 57FAA CT1 was positively associated with the butyrate-producing pathway PWY-5022 (p < 0.001). CONCLUSIONS: Our study identified one potentially beneficial microbe Lachnospiraceae bacterium 3 1 57FAA CT1, which might mediate the effect of adiposity on insulin resistance. The identified microbes are helpful for the discovery of novel therapeutic targets, as to mitigate the impact of adiposity on insulin resistance.

A systematic review of newborn and childhood hearing screening around the world: comparison and quality assessment of guidelines.

BACKGROUND: This study aimed to assess the quality of global guidelines or consensus statements for newborn and childhood hearing screening, as well as to compare various guidelines between other countries and China. METHODS: A PROSPERO registered systematic review (number CRD42021242198) was conducted. Multiple electronic databases and government websites including PubMed, EMBASE, Web of Science, CENTRAL, Cochrane Library, and BMJ Best Practice were searched from inception until May 2021. The latest national and international guidelines, consensus statements, technical specifications, and recommendations regarding newborn or childhood hearing screening that were published in Chinese or English medical journals or elsewhere with the full version available online. The following information was extracted independently by two reviewers for comparative analysis: titles, authors, publication year, country, the source organization, and main key recommendations using systems for assigning the level of evidence and strength of recommendations. The quality of the guidelines was assessed by three independent reviewers using the Appraisal of Guidelines for Research and Evaluation, 2nd edition. Intraclass correlation coefficients (ICCs) were calculated to assess among-reviewer agreement. RESULTS: We assessed 15 newborn and 6 childhood hearing screening guidelines, respectively. Most newborn guidelines recommend the 1-3-6 guidelines and pre-discharge screening; however, the specific screening times differ. 93.33% of newborn hearing guidelines recommend "primary screening-re-screening-diagnosis-intervention" for well-babies while 73.33% of the guidelines recommend "initial screening-diagnosis-intervention" for newborns in neonatal intensive care unit (NICU); 33.33% of the newborn hearing guidelines recommended initial screening coverage of > 95% while 46.66% did not mention it. Further, 26.66% of the newborn hearing guidelines recommended a referral rate to diagnosis within 4% while 60% did not mention it. Regarding childhood hearing screening guidelines, the screening populations differed across guidelines (age range: 0-9 years); most guidelines recommend pediatric hearing screening for all preschoolers. Only 50% of the guidelines specify screening and re-screening techniques, including pure-tone hearing screening, OAE, tympanometry, and others. The "Clarity of Presentation" domain achieved the highest mean score, and the lowest was "Editorial Independence" both in newborn and childhood guidelines. Overall score of newborn hearing screening guidelines ranged from 3 (2018 Europe) to 7 (2019 America), with an average score of 5.33. Average score of childhood hearing screening guidelines was 4.78, with the score ranging from 4 (2017 England, 2012 Europe, 2016 WHO) to 6.67 (2011 America). ICC analysis revealed excellent agreement across 21 guidelines (> 0.75). CONCLUSIONS: These findings indicated newborn hearing screening guidelines had superior quality over childhood ones. Comparative analysis suggested that recommendations of the Chinese newborn and pediatric hearing screening protocols are consistent with the mainstream international opinion. Moreover, this analysis demonstrated that "Editorial Independence" and "Stakeholder Involvement" have the greatest opportunities for improvement. These results may help to advance the quality of hearing screening guidelines in clinical practice and guide evidence-based updates.

Transcriptome revealed the molecular mechanism of Glycyrrhiza inflata root to maintain growth and development, absorb and distribute ions under salt stress.

BACKGROUND: Soil salinization extensively hampers the growth, yield, and quality of crops worldwide. The most effective strategies to counter this problem are a) development of crop cultivars with high salt tolerance and b) the plantation of salt-tolerant crops. Glycyrrhiza inflata, a traditional Chinese medicinal and primitive plant with salt tolerance and economic value, is among the most promising crops for improving saline-alkali wasteland. However, the underlying molecular mechanisms for the adaptive response of G. inflata to salinity stress remain largely unknown. RESULT: G. inflata retained a high concentration of Na+ in roots and maintained the absorption of K+, Ca2+, and Mg2+ under 150 mM NaCl induced salt stress. Transcriptomic analysis of G. inflata roots at different time points of salt stress (0 min, 30 min, and 24 h) was performed, which resulted in 70.77 Gb of clean data. Compared with the control, we detected 2645 and 574 differentially expressed genes (DEGs) at 30 min and 24 h post-salt-stress induction, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that G. inflata response to salt stress post 30 min and 24 h was remarkably distinct. Genes that were differentially expressed at 30 min post-salt stress induction were enriched in signal transduction, secondary metabolite synthesis, and ion transport. However, genes that were differentially expressed at 24 h post-salt-stress induction were enriched in phenylpropane biosynthesis and metabolism, fatty acid metabolism, glycerol metabolism, hormone signal transduction, wax, cutin, and cork biosynthesis. Besides, a total of 334 transcription factors (TFs) were altered in response to 30 min and 24 h of salt stress. Most of these TFs belonged to the MYB, WRKY, AP2-EREBP, C2H2, bHLH, bZIP, and NAC families. CONCLUSION: For the first time, this study elucidated the salt tolerance in G. inflata at the molecular level, including the activation of signaling pathways and genes that regulate the absorption and distribution of ions and root growth in G. inflata under salt stress conditions. These findings enhanced our understanding of the G. inflata salt tolerance and provided a theoretical basis for cultivating salt-tolerant crop varieties.

WaveICA 2.0: a novel batch effect removal method for untargeted metabolomics data without using batch information.

INTRODUCTION: Untargeted metabolomics based on liquid chromatography-mass spectrometry is inevitably affected by batch effects that are caused by non-biological systematic bias. Previously, we developed a novel method called WaveICA to remove batch effects for untargeted metabolomics data. To detect batch effect information, the method relies on a batch label. However, it cannot be used in the scenario in which there is only one batch of data or the batch label is unknown. OBJECTIVES: We aim to improve the WaveICA method to remove batch effects for untargeted metabolomics data without using batch information. METHODS: We improved the WaveICA method by developing WaveICA 2.0 to remove batch effects for metabolomics data, and provided an R package WaveICA_2.0 to implement this method. RESULTS: The performance of the WaveICA 2.0 method was evaluated on real metabolomics data. For metabolomics data with three batches, the performance of the WaveICA 2.0 method was similar to that of the WaveICA method in terms of gathering quality control samples (QCSs) and subject samples together in principle component analysis score plots, increasing the similarity of QCSs, increasing differential peaks, and improving classification accuracy. For metabolomics data with only one batch, the WaveICA 2.0 method had a strong ability to remove intensity drift and reveal more biological information and outperformed the QC-RLSC and QC-SVRC methods in our study using our metabolomics data. CONCLUSION: Our results demonstrated that the WaveICA 2.0 method can be used in practice to remove batch effects for untargeted metabolomics data without batch information.

Protocol of a prospective and multicentre China Teratology Birth Cohort (CTBC): association of maternal drug exposure during pregnancy with adverse pregnancy outcomes.

BACKGROUND: As reported, 27-93 % of pregnant women take at least one drug during pregnancy. However, drug exposure during pregnancy still lacks sufficient foetal safety evidence of human origin. It is urgent to fill the knowledge gap about medication safety during pregnancy for optimization of maternal disease treatment and pregnancy drug consultation. METHODS AND ANALYSIS: The China Teratology Birth Cohort (CTBC) was established in 2019 and is a hospital-based open-ended prospective cohort study with the aim of assessing drug safety during pregnancy. Pregnant women who set up the pregnancy health records in the first trimester or who seek drug consultation regardless of gestational age in the member hospitals are recruited. Enrolled pregnant women need to be investigated four times, namely, 6-14 and 24-28 weeks of gestational age, before discharge after hospital delivery, and 28-42 days after birth. Maternal medication exposure during pregnancy is the focus of the CTBC. For drugs, information on the type, name, and route of medication; start and end time of medication; single dose; frequency of medication; dosage form; manufacturer; and reason for medication is collected. The adverse pregnancy outcomes collected in the study include birth defects, stillbirth, spontaneous abortion, preterm birth, post-term birth, low birth weight, macrosomia, small for gestational age, large for gestational age and low Apgar score. CTBC uses an electronic questionnaire for data collection and a cloud system for data management. Biological samples are collected if informed consents are obtained. Multi-level logistic regression, mixed-effect negative binomial distribution regression and spline function regression are used to explore the effect of drugs on the occurrence of birth defects. DISCUSSION: The findings of the study will assist in further understanding the risk of birth defects and other adverse pregnancy outcomes associated with maternal drug exposure and developing the optimal treatment plans and drug counselling for pregnant women. TRIAL REGISTRATION: This study was approved by the Research Ethics Committee of the West China Second Hospital of Sichuan University and registered at the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/index.aspx , registration number ChiCTR1900022569 ).

MiR-30c-5p Directly Targets MAPK1 to Regulate the Proliferation, Migration and Invasion of Adenomyotic Epithelial Cells in Adenomyosis.

The purpose of our study was to elucidate the functions of miR-30c-5p on adenomyosis for exploring novel treatment strategies. We first detected the expression of miR-30c-5p in clinical adenomyotic tissues and isolated endometrial cells from adenomyotic tissues. Next, gain and loss-of-function assays were performed to detect the effect of miR-30c-5p on adenomyotic endometrial cells. Further, luciferase assay and real-time polymerase chain reaction as well as western blot were conducted to investigate the potential target of miR-30c-5p; and transwell assay, wound-healing assay and CCK-8 assay were used to evaluate the effects of miR-30c-5p and its target on regulating biological functions of adenomyotic endometrial cells. Our results found that miR-30c-5p was down-regulated in both adenomyosis tissues and adenomyotic epithelial cells, which correlated with dysmenorrhea, longer duration of symptoms and more menstrual bleeding. Moreover, the overexpression of miR-30c-5p inhibited the proliferation, migration and invasion of adenomyotic epithelial cells, where miR-30c-5p knockdown had an opposite effect. Furthermore, we confirmed mitogen-activated protein kinase 1 (MAPK1) was one of the direct targets of miR-30c-5p, indicating its important role in miR-30c-5p-mediated suppression of proliferation, invasion and migration in adenomyotic epithelial cells. This study showed that the interaction of miR-30c-5p with MAPK1 can regulate the proliferation, invasion and migration in adenomyotic epithelial cells.

Incidence of and risk factors associated with lung metastases in newly diagnosed epithelial ovarian cancer with a look on prognosis after diagnosis: a population-based cohort study of the SEER database.

PURPOSE: Patients with lung metastases (LM) from epithelial ovarian cancer (EOC) (EOCLM) usually have a poor prognosis. However, there is no consensus on the optimal management of these patients. In this study, we aimed to take a look at the incidence of LM and factors associated with its occurrence as well as the prognosis in newly diagnosed EOC with LM on a population level. METHODS: EOC patients diagnosed between the years 2010 and 2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) program database. Multivariable logistic regression and multivariable Cox regression were used to investigate the factors that could predict the occurrence of and prognosis after diagnosis of EOC with LM. RESULTS: Of the 33,418 qualified EOC patients, 2240 (6.7%) were noted to have LMs at the time of EOC diagnosis. Higher T stage, N1 stage, advanced tumor grade, and elevated cancer antigen-125 levels were found to be associated with a higher risk of having LM at the time of EOC diagnosis. The median survival time after diagnosis with EOCLM was found to be 13.0 months (interquartile range: 3.0-34.0 months). Being unmarried and having mucinous histology were both associated with increased all-cause death risk from EOCLM. However, the primary tumor originated from the midline of ovaries, surgical management, and whether patient received chemotherapy or not predicted improved overall survival. The median survival time of patients was significantly longer for EOCLM cases managed surgically (31.0 months) versus those who did not have surgery (4.0 months), as well as EOCLM cases received chemotherapy (23.0 months) versus those who did not have chemotherapy (2.0 months). CONCLUSION: This retrospective cohort study showed that de novo LM was infrequent in EOC patients overall and when present predicted poor prognosis. The findings can be potentially useful in formulating for follow-up strategies, screening tools, and personalized interventions.

The risk spillover effect of the COVID-19 pandemic on energy sector: Evidence from China.

Detecting the adverse effects of major emergencies on financial markets and real economy is of great importance not only for short-term policy reactions but also for economic and financial stability. This is the lesson we learnt from the COVID-19 pandemic. This paper focuses on the risk spillover effect of the COVID-19 on Chinese energy industry using a high-dimensional and time-varying factor-augmented VAR model. The results show that the net volatility spillovers of the pandemic remain positive to all underlying energy sectors during January to June of 2020 and February to April of 2021. For the former sub-period, the volatility spillover of the COVID-19 is not only the highest, but also lasts longest for oil exploitation sector, followed by the power and gas sectors. While for the latter sub-period, the COVID-19 has relatively higher volatility spillovers to the power, coal mining and petrochemical sectors. These findings suggest that the COVID-19 has significant risk spillover effects on Chinese energy sectors, and the effects vary among different energy sub-sectors and across different periods of time.

Identification immunophenotyping of lung adenocarcinomas based on the tumor microenvironment.

The tumor immune microenvironment is heterogeneous, and its impact on treatment responses is not well understood. It is still a challenge to analyze the interaction between malignant cells and the tumor microenvironment to apply suitable immunotherapy in lung adenocarcinoma. We performed the nonnegative matrix factorization method to 513 messenger RNA expression profiles of lung adenocarcinomas (LUADs) from The Cancer Genome Atlas (TCGA) to obtain an immune-related expression pattern. Subsequently, we characterized the immune-related gene signatures and clinical and survival characteristics. We used 576 patients from Gene Expression Omnibus to confirm our findings. Of the patients in the training cohort, 51% had a high immune enrichment score, high expression of immune cell signaling, cytolytic activity, and interferon (IFN)-related signatures (all P < .05). We denoted these as the Immune Class. We further subdivided the Immune Class into two subclasses based on the tumor microenvironment. These were denoted the Active Immune Class and Exhausted Immune Class. The former showed significant IFN, T-cells, M1 macrophage signatures, and better prognosis (all P < .05), while the latter presented an exhausted immune response with activated stromal enrichment, M2 macrophage signatures, and immunosuppressive factors such as WNT/transforming growth factor-ß (all P < .05). Furthermore, we predicted the response of our immunophenotypes to immunological checkpoint inhibitors (P < .05). Our findings provide a novel insight into the immune-related state of LUAD and can identify the patients who will be receptive to suitable immunotherapeutic treatments.

Maternal mortality ratios in 2852 Chinese counties, 1996-2015, and achievement of Millennium Development Goal 5 in China: a subnational analysis of the Global Burden of Disease Study 2016.

BACKGROUND: As one of only a handful of countries that have achieved both Millennium Development Goals (MDGs) 4 and 5, China has substantially lowered maternal mortality in the past two decades. Little is known, however, about the levels and trends of maternal mortality at the county level in China. METHODS: Using a national registration system of maternal mortality at the county level, we estimated the maternal mortality ratios for 2852 counties in China between 1996 and 2015. We used a state-of-the-art Bayesian small-area estimation hierarchical model with latent Gaussian layers to account for space and time correlations among neighbouring counties. Estimates at the county level were then scaled to be consistent with country-level estimates of maternal mortality for China, which were separately estimated from multiple data sources. We also assessed maternal mortality ratios among ethnic minorities in China and computed Gini coefficients of inequality of maternal mortality ratios at the country and provincial levels. FINDINGS: China as a country has experienced fast decline in maternal mortality ratios, from 108·7 per 100 000 livebirths in 1996 to 21·8 per 100 000 livebirths in 2015, with an annualised rate of decline of 8·5% per year, which is much faster than the target pace in MDG 5. However, we found substantial heterogeneity in levels and trends at the county level. In 1996, the range of maternal mortality ratios by county was 16·8 per 100 000 livebirths in Shantou, Guangdong, to 3510·3 per 100 000 livebirths in Zanda County, Tibet. Almost all counties showed remarkable decline in maternal mortality ratios in the two decades regardless of those in 1996. The annualised rate of decline across counties from 1996 to 2015 ranges from 4·4% to 12·9%, and 2838 (99·5%) of the 2852 counties had achieved the MDG 5 pace of decline. Decline accelerated between 2005 and 2015 compared with between 1996 and 2005. In 2015, the lowest county-level maternal mortality ratio was 3·4 per 100 000 livebirths in Nanhu District, Zhejiang Province. The highest was still in Zanda County, Tibet, but the fall to 830·5 per 100 000 livebirths was only 76·3%. 26 ethnic groups had population majorities in at least one county in China, and all had achieved declines in maternal mortality ratios in line with the pace of MDG 5. Intercounty Gini coefficients for maternal mortality ratio have declined at the national level in China, indicating improved equality, whereas trends in inequality at the provincial level varied. INTERPRETATION: In the past two decades, maternal mortality ratios have reduced rapidly and universally across China at the county level. Fast improvement in maternal mortality ratios is possible even in less economically developed places with resource constraints. This finding has important implications for improving maternal mortality ratios in developing countries in the Sustainable Development Goal era. FUNDING: National Health and Family Planning Commission of the People's Republic of China, China Medical Board, WHO, University of Washington Center for Demography and Economics of Aging, Bill & Melinda Gates Foundation.

NormAE: Deep Adversarial Learning Model to Remove Batch Effects in Liquid Chromatography Mass Spectrometry-Based Metabolomics Data.

Untargeted metabolomics based on liquid chromatography-mass spectrometry is affected by nonlinear batch effects, which cover up biological effects, result in nonreproducibility, and are difficult to be calibrate. In this study, we propose a novel deep learning model, called Normalization Autoencoder (NormAE), which is based on nonlinear autoencoders (AEs) and adversarial learning. An additional classifier and ranker are trained to provide adversarial regularization during the training of the AE model, latent representations are extracted by the encoder, and then the decoder reconstructs the data without batch effects. The NormAE method was tested on two real metabolomics data sets. After calibration by NormAE, the quality control samples (QCs) for both data sets gathered most closely in a PCA score plot (average distances decreased from 56.550 and 52.476 to 7.383 and 14.075, respectively) and obtained the highest average correlation coefficients (from 0.873 and 0.907 to 0.997 for both). Additionally, NormAE significantly improved biomarker discovery (median number of differential peaks increased from 322 and 466 to 1140 and 1622, respectively). NormAE was compared with four commonly used batch effect removal methods. The results demonstrated that using NormAE produces the best calibration results.

Metabolic phenotyping to monitor chronic enteritis canceration.

INTRODUCTION: Colorectal cancer (CRC) remains an incurable disease. Previous metabolomic studies show that metabolic signatures in plasma distinguish CRC patients from healthy controls. Chronic enteritis (CE) represents a risk factor for CRC, with a 20 fold greater incidence than in healthy individuals. However, no studies have performed metabolomic profiling to investigate CRC biomarkers in CE. OBJECTIVE: Our aims were to identify metabolomic signatures in CRC and CE and to search for blood-derived metabolite biomarkers distinguishing CRC from CE, especially early-stage biomarkers. METHODS: In this case-control study, 612 subjects were prospectively recruited between May 2015 and May 2016, and including 539 CRC patients (stage I, 102 cases; stage II, 259 cases; stage III, 178 cases) and 73 CE patients. Untargeted metabolomics was performed to identify CRC-related metabolic signatures in CE. RESULTS: Five pathways were significantly enriched based on 153 differential metabolites between CRC and CE. 16 biomarkers were identified for diagnosis of CRC from CE and for guiding CRC staging. The AUC value for CRC diagnosis in the external validation set was 0.85. Good diagnostic performances were also achieved for early-stage CRC (stage I and stage II), with an AUC value of 0.84. The biomarker panel could also stage CRC patients, with an AUC of 0.72 distinguishing stage I from stage II CRC and AUC of 0.74 distinguishing stage II from stage III CRC. CONCLUSIONS: The identified metabolic biomarkers exhibit promising properties for CRC monitoring in CE patients and are superior to commonly used clinical biomarkers (CEA and CA19-9).

Macroeconomic environment and insurance-mortality relationship: An analysis of gender-based disparity among non-elderly adult patients of melanoma and lung cancer.

OBJECTIVE: Cancer patients exhibit disparity in mortality risks across demographic divisions as well as insurance groups. The effects of macroeconomic environment also vary for such strata. This study analyses the gaps between mortality risks for male and female cancer patients with and without insurance and examines how such gaps transform over time with macroeconomic shifts. METHODS: Demographic, clinical and treatment records of 45,750 melanoma and 91,157 lung cancer patients diagnosed in 2007-2009 and 2011-2013 were extracted from Surveillance, Epidemiology and End Results (SEER) database. Kaplan-Meier test was applied to ascertain survival probability of each insurance group, while Cox proportional hazard model was used to assess relative mortality risk for Medicaid and uninsured patients, for the whole data as well as separately for both time periods and genders. RESULTS: Both the hazard ratios and change thereof over time are greater for female patients without insurance, than for male patients. More than any insurance-gender subgroup, uninsured female patients of melanoma have much increased hazard ratios, from 1.41 [95% confidence interval (CI), 1.04-1.92] to 2.22 [95% CI, 1.67-2.94]. CONCLUSION: Despite diagnostic improvements and technology advancements, the adverse effects of macroeconomic crisis are associated with increased relative mortality risks for cancer patients without insurance, more for women than men.

Newborn hearing screening coverage and detection rates of hearing impairment across China from 2008-2016.

BACKGROUND: Newborn hearing screening (NHS) can reduce the economic and social burden of hearing impairment. To track the progress of the goal set by the National Program of Action for Child Development (NPACD) and to estimate the detection rates of hearing impairment, the present study examined NHS coverage in 2008-2010 and 2016 and the detection of hearing impairment across China in 2016. METHODS: Licensed medical institutions across China were surveyed in 2012 and 2018 by the National Center for Birth Defects Monitoring of China to collect data for the 2008-2010 period and for 2016 on live births, initial screening rates (total and referral), secondary screening rates (total and referral), and rates of hearing impairment diagnosis among infants who were referred in the secondary screening. To calculate universal newborn hearing screening (UNHS) coverage, the number of newborns who received NHS within 4 weeks after birth was divided by the number of live births. The detection rate of hearing impairment was calculated by combining referral rates on primary and secondary screening with the rate of diagnosis. RESULTS: National UNHS coverage increased from 29.9% in 2008 to 86.5% in 2016, with different regions showing different increases. During this period, the number of provinces with UNHS coverage over 90.0% increased from 2 to 17, with UNHS coverage in 2016 being substantially higher in eastern provinces (93.1%) than in western provinces (79.4%). In 2016, the detection rate of hearing impairment across the country was 0.23% (95% CI 0.15-0.25%), and it varied from 0.17% in western provinces to 0.22% in central provinces and 0.28% in eastern provinces. The lowest rate was 0.02% in Heilongjiang Province and the highest rate was 0.63% in Hainan Province. CONCLUSIONS: National UNHS coverage increased substantially from 2008 to 2016, although provinces and regions still showed differences. The detection rate of infant hearing impairment in China is comparable to that in other countries. A national individual-level information system is urgently needed in China to facilitate the integration of screening, diagnosis and treatment of infant hearing impairment, which may also lead to a more accurate estimate of the detection rate.