Circulating Metabolite Profiles and Risk of Coronary Heart Disease Among Racially and Geographically Diverse Populations.

BACKGROUND: Metabolomics may reveal novel biomarkers for coronary heart disease (CHD). We aimed to identify circulating metabolites and construct a metabolite risk score (MRS) associated with incident CHD among racially and geographically diverse populations. METHODS: Untargeted metabolomics was conducted using baseline plasma samples from 900 incident CHD cases and 900 age-/sex-/race-matched controls (300 pairs of Black Americans, White Americans, and Chinese adults, respectively), which detected 927 metabolites with known identities among ≥80% of samples. After quality control, 896 case-control pairs remained and were randomly divided into discovery (70%) and validation (30%) sets within each race. In the discovery set, conditional logistic regression and least absolute shrinkage and selection operator over 100 subsamples were applied to identify metabolites robustly associated with CHD risk and construct the MRS. The MRS-CHD association was evaluated using conditional logistic regression and the C-index. Mediation analysis was performed to examine if MRS mediated associations between conventional risk factors and incident CHD. The results from the validation set were presented as the main findings. RESULTS: Twenty-four metabolites selected in ≥90% of subsamples comprised the MRS, which was significantly associated with incident CHD (odds ratio per 1 SD, 2.21 [95% CI, 1.62-3.00] after adjusting for sociodemographics, lifestyles, family history, and metabolic health status). MRS could distinguish incident CHD cases from matched controls (C-index, 0.69 [95% CI, 0.63-0.74]) and improve CHD risk prediction when adding to conventional risk factors (C-index, 0.71 [95% CI, 0.65-0.76] versus 0.67 [95% CI, 0.61-0.73]; P<0.001). The odds ratios and C-index were similar across subgroups defined by race, sex, socioeconomic status, lifestyles, metabolic health, family history, and follow-up duration. The MRS mediated large portions (46.0%-74.2%) of the associations for body mass index, smoking, diabetes, hypertension, and dyslipidemia with incident CHD. CONCLUSIONS: In a diverse study sample, we identified 24 circulating metabolites that, when combined into an MRS, were robustly associated with incident CHD and modestly improved CHD risk prediction beyond conventional risk factors.

Mapping the gut microecological multi-omics signatures to serum metabolome and their impact on cardiometabolic health in elderly adults.

BACKGROUND: Mapping gut microecological features to serum metabolites (SMs) will help identify functional links between gut microbiome and cardiometabolic health. METHODS: This study encompassed 836-1021 adults over 9.7 year in a cohort, assessing metabolic syndrome (MS), carotid atherosclerotic plaque (CAP), and other metadata triennially. We analyzed mid-term microbial metagenomics, targeted fecal and serum metabolomics, host genetics, and serum proteomics. FINDINGS: Gut microbiota and metabolites (GMM) accounted for 15.1% overall variance in 168 SMs, with individual GMM factors explaining 5.65%-10.1%, host genetics 3.23%, and sociodemographic factors 5.95%. Specifically, GMM elucidated 5.5%-49.6% variance in the top 32 GMM-explained SMs. Each 20% increase in the 32 metabolite score (derived from the 32 SMs) correlated with 73% (95% confidence interval [CI]: 53%-95%) and 19% (95% CI: 11%-27%) increases in MS and CAP incidences, respectively. Among the 32 GMM-explained SMs, sebacic acid, indoleacetic acid, and eicosapentaenoic acid were linked to MS or CAP incidence. Serum proteomics revealed certain proteins, particularly the apolipoprotein family, mediated the relationship between GMM-SMs and cardiometabolic risks. INTERPRETATION: This study reveals the significant influence of GMM on SM profiles and illustrates the intricate connections between GMM-explained SMs, serum proteins, and the incidence of MS and CAP, providing insights into the roles of gut dysbiosis in cardiometabolic health via regulating blood metabolites. FUNDING: This study was jointly supported by the National Natural Science Foundation of China, Key Research and Development Program of Guangzhou, 5010 Program for Clinical Research of Sun Yat-sen University, and the 'Pioneer' and 'Leading goose' R&D Program of Zhejiang.

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.

Blood Lipids, Lipoproteins, and Apolipoproteins With Risk of Coronary Heart Disease: A Prospective Study Among Racially Diverse Populations.

BACKGROUND: Comprehensive blood lipoprotein profiles and their association with incident coronary heart disease (CHD) among racially and geographically diverse populations remain understudied. METHODS AND RESULTS: We conducted nested case-control studies of CHD among 3438 individuals (1719 pairs), including 1084 White Americans (542 pairs), 1244 Black Americans (622 pairs), and 1110 Chinese adults (555 pairs). We examined 36 plasma lipids, lipoproteins, and apolipoproteins, measured by nuclear magnetic resonance spectroscopy, with incident CHD among all participants and subgroups by demographics, lifestyle, and metabolic health status using conditional or unconditional logistic regression adjusted for potential confounders. Conventionally measured blood lipids, that is, total cholesterol, triglycerides, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol, were each associated with incident CHD, with odds ratios (ORs) being 1.33, 1.32, 1.24, and 0.79 per 1-SD increase among all participants. Seventeen lipoprotein biomarkers showed numerically stronger associations than conventional lipids, with ORs per 1-SD among all participants ranging from 1.35 to 1.57 and a negative OR of 0.78 (all false discovery rate <0.05), including apolipoprotein B100 to apolipoprotein A1 ratio (OR, 1.57 [95% CI, 1.45-1.7]), low-density lipoprotein-triglycerides (OR, 1.55 [95% CI, 1.43-1.69]), and apolipoprotein B (OR, 1.49 [95% CI, 1.37-1.62]). All these associations were significant and consistent across racial groups and other subgroups defined by age, sex, smoking, obesity, and metabolic health status, including individuals with normal levels of conventionally measured lipids. CONCLUSIONS: Our study highlighted several lipoprotein biomarkers, including apolipoprotein B/ apolipoprotein A1 ratio, apolipoprotein B, and low-density lipoprotein-triglycerides, strongly and consistently associated with incident CHD. Our results suggest that comprehensive lipoprotein measures may complement the standard lipid panel to inform CHD risk among diverse populations.

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.

Metabolite Signature of Life's Essential 8 and Risk of Coronary Heart Disease Among Low-Income Black and White Americans.

BACKGROUND: Life's essential 8 (LE8) is a comprehensive construct of cardiovascular health. Yet, little is known about the LE8 score, its metabolic correlates, and their predictive implications among Black Americans and low-income individuals. METHODS: In a nested case-control study of coronary heart disease (CHD) among 299 pairs of Black and 298 pairs of White low-income Americans from the Southern Community Cohort Study, we estimated LE8 score and applied untargeted plasma metabolomics and elastic net with leave-one-out cross-validation to identify metabolite signature (MetaSig) of LE8. Associations of LE8 score and MetaSig with incident CHD were examined using conditional logistic regression. The mediation effect of MetaSig on the LE8-CHD association was also examined. The external validity of MetaSig was evaluated in another nested CHD case-control study among 299 pairs of Chinese adults. RESULTS: Higher LE8 score was associated with lower CHD risk (standardized odds ratio, 0.61 [95% CI, 0.53-0.69]). The MetaSig, consisting of 133 metabolites, showed significant correlation with LE8 score (r=0.61) and inverse association with CHD (odds ratio, 0.57 [0.49-0.65]), robust to adjustment for LE8 score and across participants with different sociodemographic and health status ([odds ratios, 0.42-0.69]; all P<0.05). MetaSig mediated a large portion of the LE8-CHD association: 53% (32%-80%). Significant associations of MetaSig with LE8 score and CHD risk were found in validation cohort (r=0.49; odds ratio, 0.57 [0.46-0.69]). CONCLUSIONS: Higher LE8 score and its MetaSig were associated with lower CHD risk among low-income Black and White Americans. Metabolomics may offer an objective measure of LE8 and its metabolic phenotype relevant to CHD prevention among diverse populations.

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.

Microbiota-assisted iron uptake promotes immune tolerance in the intestine.

Iron deficiencies are the most common nonenteric syndromes observed in patients with inflammatory bowel disease, but little is known about their impacts on immune tolerance. Here we show that homeostasis of regulatory T cells in the intestine was dependent on high cellular iron levels, which were fostered by pentanoate, a short-chain fatty acid produced by intestinal microbiota. Iron deficiencies in Treg caused by the depletion of Transferrin receptor 1, a major iron transporter, result in the abrogation of Treg in the intestine and lethal autoimmune disease. Transferrin receptor 1 is required for differentiation of c-Maf+ Treg, major constituents of intestinal Treg. Mechanistically, iron enhances the translation of HIF-2α mRNA, and HIF-2α in turn induces c-Maf expression. Importantly, microbiota-produced pentanoate promotes iron uptake and Treg differentiation in the intestine. This subsequently restores immune tolerance and ameliorated iron deficiencies in mice with colitis. Our results thus reveal an association between nutrient uptake and immune tolerance in the intestine.

Metabolite Signature of Life's Essential 8 and Risk of Coronary Heart Disease among Low-Income Black and White Americans.

Background and Aims: Life's Essential 8 (LE8) is a comprehensive construct of cardiovascular health. Yet, little is known about LE8 score, its metabolic correlates, and their predictive implications among Black Americans and low-income individuals. Methods: In a nested case-control study of coronary heart disease (CHD) among 598 Black and 596 White low-income Americans, we estimated LE8 score, conducted untargeted plasma metabolites profiling, and used elastic net with leave-one-out cross-validation to identify metabolite signature (MetaSig) of LE8. Associations of LE8 score and MetaSig with incident CHD were examined using conditional logistic regression. Mediation effect of MetaSig on the LE8-CHD association was also examined. The external validity of MetaSig was evaluated in another nested CHD case-control study among 598 Chinese adults. Results: Higher LE8 score was associated with lower CHD risk [standardized OR (95% CI)=0.61 (0.53-0.69)]. The identified MetaSig, consisting of 133 metabolites, showed strong correlation with LE8 score ( r =0.61) and inverse association with CHD risk [OR (95% CI)=0.57 (0.49-0.65)], robust to adjustment for LE8 score and across participants with different sociodemographic and health status (ORs: 0.42-0.69; all P <0.05). MetaSig mediated a large portion of the LE8-CHD association: 53% (32%-80%) ( P <0.001). Significant associations of MetaSig with LE8 score and CHD risk were found in validation cohort [ r =0.49; OR (95% CI)=0.57 (0.46-0.69)]. Conclusions: Higher LE8 score and its MetaSig were associated with lower CHD risk among low-income Black and White Americans. Metabolomics may offer an objective and comprehensive measure of LE8 score and its metabolic phenotype relevant to CHD prevention among diverse populations.

E2EFP-MIL: End-to-end and high-generalizability weakly supervised deep convolutional network for lung cancer classification from whole slide image.

Efficient and accurate distinction of histopathological subtype of lung cancer is quite critical for the individualized treatment. So far, artificial intelligence techniques have been developed, whose performance yet remained debatable on more heterogenous data, hindering their clinical deployment. Here, we propose an end-to-end, well-generalized and data-efficient weakly supervised deep learning-based method. The method, end-to-end feature pyramid deep multi-instance learning model (E2EFP-MIL), contains an iterative sampling module, a trainable feature pyramid module and a robust feature aggregation module. E2EFP-MIL uses end-to-end learning to extract generalized morphological features automatically and identify discriminative histomorphological patterns. This method is trained with 1007 whole slide images (WSIs) of lung cancer from TCGA, with AUCs of 0.95-0.97 in test sets. We validated E2EFP-MIL in 5 real-world external heterogenous cohorts including nearly 1600 WSIs from both United States and China with AUCs of 0.94-0.97, and found that 100-200 training images are enough to achieve an AUC of >0.9. E2EFP-MIL overperforms multiple state-of-the-art MIL-based methods with high accuracy and low hardware requirements. Excellent and robust results prove generalizability and effectiveness of E2EFP-MIL in clinical practice. Our code is available at https://github.com/raycaohmu/E2EFP-MIL.

Nutri-microbiome epidemiology, an emerging field to disentangle the interplay between nutrition and microbiome for human health.

Diet and nutrition have a substantial impact on the human microbiome, and interact with the microbiome, especially gut microbiome, to modulate various diseases and health status. Microbiome research has also guided the nutrition field to a more integrative direction, becoming an essential component of the rising area of precision nutrition. In this review, we provide a broad insight into the interplay among diet, nutrition, microbiome, and microbial metabolites for their roles in the human health. Among the microbiome epidemiological studies regarding the associations of diet and nutrition with microbiome and its derived metabolites, we summarize those most reliable findings and highlight evidence for the relationships between diet and disease-associated microbiome and its functional readout. Then, the latest advances of the microbiome-based precision nutrition research and multidisciplinary integration are described. Finally, we discuss several outstanding challenges and opportunities in the field of nutri-microbiome epidemiology.

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.

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.

SLFN5 promotes reversible epithelial and mesenchymal transformation in ovarian cancer.

Ovarian cancer is a disease with increasing incidence worldwide, and there is an urgent need for chemotherapy and biological targeted therapy. Epithelial-mesenchymal transformation (EMT) is an important initiation stage for tumor cells to acquire the ability to invade and metastasize. A growing number of findings suggest that human Schlafen family member 5(SLFN5) plays a key role in malignancy. However, the role of SLFN5 in ovarian cancer cells has not been fully elucidated. Samples were collected from patients with ovarian cancer diagnosed in Hangzhou First People's Hospital, and the expression of SLFN5 was detected by fluorescence quantitative PCR. The relationship between SLFN5 expression and the progression and malignancy of ovarian cancer was analyzed by using the expression profile data from the Cancer Genome Atlas (TCGA) database. The mRNA expression levels of SLFN5 related upstream and downstream signaling pathways were studied by fluorescence quantitative PCR. Silencing SLFN5 was performed by siRNA transfection. The expression of SLFN5 and transfer-related proteins was examined by Western blot. Transwell and wound healing experiments investigated the migration and invasion ability of ovarian cancer cells. TCGA database analysis results showed that in the population with high SLFN5 expression, compared with the group with low SLFN5 expression, OS was worse (P = 0.011). SLFN5 silencing had a significant inhibitory effect on EMT and invasion movement of ovarian cancer cells. RT-PCR method was used to detect the mRNA changes of SLFN5 in ovarian cancer tissue and adjacent tissue. It was found that the expression of SLFN5 in ovarian cancer tissue was increased, with a significant difference (P < 0.05). Together, these results suggest that SLFN5 may play a synergistic role in tumorigenesis and development of ovarian cancer cells, providing a potential target for future drug development for the treatment of ovarian cancer.

Comparison of fecal and blood metabolome reveals inconsistent associations of the gut microbiota with cardiometabolic diseases.

Blood metabolome is commonly used in human studies to explore the associations of gut microbiota-derived metabolites with cardiometabolic diseases. Here, in a cohort of 1007 middle-aged and elderly adults with matched fecal metagenomic (149 species and 214 pathways) and paired fecal and blood targeted metabolomics data (132 metabolites), we find disparate associations with taxonomic composition and microbial pathways when using fecal or blood metabolites. For example, we observe that fecal, but not blood butyric acid significantly associates with both gut microbiota and prevalent type 2 diabetes. These findings are replicated in an independent validation cohort involving 103 adults. Our results suggest that caution should be taken when inferring microbiome-cardiometabolic disease associations from either blood or fecal metabolome data.

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.

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.

The gut microbiota-bile acid axis links the positive association between chronic insomnia and cardiometabolic diseases.

Evidence from human cohorts indicates that chronic insomnia is associated with higher risk of cardiometabolic diseases (CMD), yet whether gut microbiota plays a role is unclear. Here, in a longitudinal cohort (n = 1809), we find that the gut microbiota-bile acid axis may link the positive association between chronic insomnia and CMD. Ruminococcaceae UCG-002 and Ruminococcaceae UCG-003 are the main genera mediating the positive association between chronic insomnia and CMD. These results are also observed in an independent cross-sectional cohort (n = 6122). The inverse associations between those gut microbial biomarkers and CMD are mediated by certain bile acids (isolithocholic acid, muro cholic acid and nor cholic acid). Habitual tea consumption is prospectively associated with the identified gut microbiota and bile acids in an opposite direction compared with chronic insomnia. Our work suggests that microbiota-bile acid axis may be a potential intervention target for reducing the impact of chronic insomnia on cardiometabolic health.

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.

Methylation biomarkers with discriminating ability are potential therapeutic targets in lung adenocarcinoma.

Aims: Given the reversibility of methylation, biomarkers with discriminating ability are of great interest for targeted therapeutic sites. Materials & methods: Methylation array data of 461 lung adenocarcinoma (LUAD) patients comprising of 458 tumor and 32 LUAD paracancerous samples were compared using partial least squares discrimination analysis and receiver operating characteristics analysis. Results: A six-DNA methylation signature (corresponding to five genes) was found to significantly discriminate normal and LUAD samples. Kyoto Encyclopedia of Genes and Genomes analysis indicated enrichment of methylation sites in the Wnt pathway in LUAD compared with controls. Conclusion: This six-DNA methylation signature demonstrated potential as a novel biomarker for diagnosis and therapeutic targets. Further, inhibition of Wnt signaling pathway may be an important step in LUAD progression.