Single cell analyses of cancer cells identified two regulatorily and functionally distinct categories in differentially expressed genes among tumor subclones.

To explore the feature of cancer cells and tumor subclones, we analyzed 101,065 single-cell transcriptomes from 12 colorectal cancer (CRC) patients and 92 single cell genomes from one of these patients. We found cancer cells, endothelial cells and stromal cells in tumor tissue expressed much more genes and had stronger cell-cell interactions than their counterparts in normal tissue. We identified copy number variations (CNVs) in each cancer cell and found correlation between gene copy number and expression level in cancer cells at single cell resolution. Analysis of tumor subclones inferred by CNVs showed accumulation of mutations in each tumor subclone along lineage trajectories. We found differentially expressed genes (DEGs) between tumor subclones had two populations: DEGCNV and DEGreg. DEGCNV, showing high CNV-expression correlation and whose expression differences depend on the differences of CNV level, enriched in housekeeping genes and cell adhesion associated genes. DEGreg, showing low CNV-expression correlation and mainly in low CNV variation regions and regions without CNVs, enriched in cytokine signaling genes. Furthermore, cell-cell communication analyses showed that DEGCNV tends to involve in cell-cell contact while DEGreg tends to involve in secreted signaling, which further support that DEGCNV and DEGreg are two regulatorily and functionally distinct categories.

Altered gut microbiome associated with metabolic-associated fatty liver disease in Chinese children.

BACKGROUND & AIM: Limited studies have investigated the association between gut microbiota and metabolic dysfunction-associated fatty liver disease (MAFLD) in children and adolescents. We aimed to identify differences in gut microbiota composition and diversity between children with MAFLD and healthy counterparts. METHODS: Data were collected from a nested case-control study (October to December, 2021) of the "Huantai Childhood Cardiovascular Health Cohort Study" in Huantai County, Zibo City, China. The study included 52 children aged 5-11 years with new-onset MAFLD and 52 healthy children matched by age and sex. Stool samples were collected and analyzed using 16S rRNA gene sequencing. Shannon index and Chao index were used to assess the α diversity of gut microbiota and Principal coordinates analysis (PCoA) was performed to evaluate ß diversity between the two groups. The differences in the relative abundance of gut microbiota between MAFLD group and control group were compared by the Wilcoxon rank-sum test after false discovery rate (FDR) correction. Additionally, the gut-microbial metabolic pathways were identified using the phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt). RESULTS: We found that children with MAFLD had significant different gut microbiota composition and reduced α diversity compared with the control group. PCoA showed that the two groups can be significantly distinguished based on the unweighted unifrac distance algorithm. Gut microbiota at the phylum level such as Verrucomicrobia and Desulfobacterial, genus level such as Blautia, Lachnospiraceae_NK4A136_group, Coprococcus, Erysipelotrichaceae_UCG-003, UCG-002 and Akkermansia, and species level such as Bifidobacterium_longum abundances were significantly decreased in children with MAFLD compared with that in children without MAFLD. Notably, the abundance of these bacteria were found to be associated with HDL-C, SBP, DBP, WC, BMI, etc. In addition, our analysis of gut-microbial metabolic pathways identified differences in carbohydrate transport and metabolism, as well as amino acid transport and metabolism between the two groups. CONCLUSION: Significant differences in gut microbiota composition are observed between children with and without MAFLD, which indicate that gut microbiota may be a potential contributor to the development of MAFLD in childhood.

Association between secondhand smoke exposure across the life course and depressive symptoms among Chinese older adults.

BACKGROUND: There are limited data on the association between secondhand smoke (SHS) exposure across the life course and depressive symptoms among older adults. We aimed to investigate the association of childhood household SHS exposure, adulthood household SHS exposure, lifetime social SHS exposure, and their coexistence with depressive symptoms in older adults. METHODS: Data were from the 2011-2012 and 2014 waves of the Chinese Longitudinal Healthy Longevity Survey. About 4000 participants (aged 60 years or older) were recruited in a randomly selected half of the counties and cities in China. Data on SHS exposure, past-year depressive symptoms, and covariates were collected using a questionnaire. The chi-square test (for categorical variables) and t-test (for continuous variables) were used to assess differences in the participant characteristics across groups of SHS exposures. We estimated the odds ratios (ORs) and 95 % confidence intervals (CIs) of depressive symptom according to different types of SHS exposure. RESULTS: Childhood household SHS exposure (OR = 1.42, 95%CI = 1.22-1.66), adulthood household SHS exposure (OR = 1.41, 95%CI = 1.21-1.63) and lifetime social SHS exposure (OR = 1.35, 95%CI = 1.14-1.58) were associated with higher odds of depressive symptoms. Additionally, those with a higher SHS exposure score had higher odds of depressive symptoms (1 point: OR = 1.56, 95%CI = 1.22-2.00; 2 points: OR = 1.77, 95%CI = 1.39-2.25; 3 points: OR = 1.83, 95%CI = 1.45-2.31). The results were similar when stratified by lifetime nonsmoking, former smoking, and current smoking. LIMITATIONS: Retrospective design may introduce recall bias. CONCLUSIONS: SHS exposure was associated with higher odds of depressive symptoms in older adults, with the effect seeming to be addictive.

Erythrocyte-brain endothelial interactions induce microglial responses and cerebral microhemorrhages in vivo.

BACKGROUND: Cerebral microhemorrhages (CMH) are associated with stroke, cognitive decline, and normal aging. Our previous study shows that the interaction between oxidatively stressed red blood cells (RBC) and cerebral endothelium may underlie CMH development. However, the real-time examination of altered RBC-brain endothelial interactions in vivo, and their relationship with clearance of stalled RBC, microglial responses, and CMH development, has not been reported. METHODS: RBC were oxidatively stressed using tert-butylhydroperoxide (t-BHP), fluorescently labeled and injected into adult Tie2-GFP mice. In vivo two-photon imaging and ex vivo confocal microscopy were used to evaluate the temporal profile of RBC-brain endothelial interactions associated with oxidatively stressed RBC. Their relationship with microglial activation and CMH was examined with post-mortem histology. RESULTS: Oxidatively stressed RBC stall significantly and rapidly in cerebral vessels in mice, accompanied by decreased blood flow velocity which recovers at 5 days. Post-mortem histology confirms significantly greater RBC-cerebral endothelial interactions and microglial activation at 24 h after t-BHP-treated RBC injection, which persist at 7 days. Furthermore, significant CMH develop in the absence of blood-brain barrier leakage after t-BHP-RBC injection. CONCLUSIONS: Our in vivo and ex vivo findings show the stalling and clearance of oxidatively stressed RBC in cerebral capillaries, highlighting the significance of microglial responses and altered RBC-brain endothelial interactions in CMH development. Our study provides novel mechanistic insight into CMH associated with pathological conditions with increased RBC-brain endothelial interactions.

Cigarette smoking in childhood and risk of all-cause and cause-specific mortality in adulthood.

Background: This study was aimed to examine the association between cigarette smoking in childhood and mortality in adulthood, and the impact of non-smoking duration among smokers who subsequently quit smoking. Methods: We used data from 472,887 adults aged 18-85 years examined once in the US National Health Interview Survey in 1997-2014, which was linked to mortality data from the National Death Index up to 31 December 2015. Cigarette smoking status in childhood (age 6 to 17 years) and adulthood (age 18 to 85 years) was self-reported using a standard questionnaire at the time of participation in the survey. The vital status of participants due all-causes, cardiovascular disease (CVD), cancer and chronic lower respiratory diseases was obtained using mortality data from the National Death Index. Results: During the mean follow-up of 8.75 years, compared with never smoking in childhood and adulthood, the risk of all-cause mortality among current adult smokers decreased slightly according to increasing age at smoking initiation: hazard ratios (HRs; 95% confidence intervals, CIs) were 2.54 (2.24-2.88) at age of 6-9 years, 2.44 (2.31-2.57) at age of 10-14 years, and 2.21 (2.12-2.31) at age of 15-17 years. Smoking cessation before the age of 30 years was not associated with increased risk of all-cause and cause-specific mortality (all p > 0.05) compared to never smoking. Conclusion: Mortality risk was higher in individuals who started smoking at an earlier age in childhood. Inversely, smoking cessation before the age of 30 years was not associated with an increased risk of mortality compared to never smoking.

Global, regional, and national burden of cardiovascular diseases in youths and young adults aged 15-39 years in 204 countries/territories, 1990-2019: a systematic analysis of Global Burden of Disease Study 2019.

BACKGROUND: Understanding the temporal trends in the burden of overall and type-specific cardiovascular diseases (CVDs) in youths and young adults and its attributable risk factors is important for effective and targeted prevention strategies and measures. We aimed to provide a standardized and comprehensive estimation of the prevalence, incidence, disability-adjusted life years (DALY), and mortality rate of CVDs and its associated risk factors in youths and young adults aged 15-39 years at global, regional, and national levels. METHODS: We applied Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2019 analytical tools to calculate the age-standardized incidence, prevalence, DALY, and mortality rate of overall and type-specific CVDs (i.e., rheumatic heart disease, ischemic heart disease, stroke, hypertensive heart disease, non-rheumatic valvular heart disease, cardiomyopathy and myocarditis, atrial fibrillation and flutter, aortic aneurysm, and endocarditis) among youths and young adults aged 15-39 years by age, sex, region, sociodemographic index and across 204 countries/territories from 1990 to 2019, and proportional DALY of CVDs attributable to associated risk factors. RESULTS: The global age-standardized DALY (per 100,000 population) for CVDs in youths and young adults significantly decreased from 1257.51 (95% confidence interval 1257.03, 1257.99) in 1990 to 990.64 (990.28, 990.99) in 2019 with an average annual percent change (AAPC) of - 0.81% (- 1.04%, - 0.58%, P < 0.001), and the age-standardized mortality rate also significantly decreased from 19.83 (19.77, 19.89) to 15.12 (15.08, 15.16) with an AAPC of - 0.93% (- 1.21%, - 0.66%, P < 0.001). However, the global age-standardized incidence rate (per 100,000 population) moderately increased from 126.80 (126.65, 126.95) in 1990 to 129.85 (129.72, 129.98) in 2019 with an AAPC of 0.08% (0.00%, 0.16%, P = 0.040), and the age-standardized prevalence rate significantly increased from 1477.54 (1477.03, 1478.06) to 1645.32 (1644.86, 1645.78) with an AAPC of 0.38% (0.35%, 0.40%, P < 0.001). In terms of type-specific CVDs, the age-standardized incidence and prevalence rate in rheumatic heart disease, prevalence rate in ischemic heart disease, and incidence rate in endocarditis increased from 1990 to 2019 (all P < 0.001). When stratified by sociodemographic index (SDI), the countries/territories with low and low-middle SDI had a higher burden of CVDs than the countries/territories with high and high-middle SDI. Women had a higher prevalence rate of CVDs than men, whereas men had a higher DALY and mortality rate than women. High systolic blood pressure, high body mass index, and low-density lipoprotein cholesterol were the main attributable risk factors for DALY of CVDs for all included countries and territories. Household air pollution from solid fuels was an additional attributable risk factor for DALY of CVDs in low and low-middle SDI countries compared with middle, high-middle, and high SDI countries. Compared with women, DALY for CVDs in men was more likely to be affected by almost all risk factors, especially for smoking. CONCLUSIONS: There is a substantial global burden of CVDs in youths and young adults in 2019. The burden of overall and type-specific CVDs varied by age, sex, SDI, region, and country. CVDs in young people are largely preventable, which deserve more attention in the targeted implementation of effective primary prevention strategies and expansion of young-people's responsive healthcare systems.

A Multicentre Randomized Controlled Clinical Study of Cross Electro-Nape-Acupuncture (CENA) for the Treatment of Pseudobulbar Palsy in Patients with Tracheotomy Intubation for Severe Cerebral Haemorrhage.

Objective: The objective is to evaluate the clinical efficacy of cross electro-nape-acupuncture (CENA) in the treatment of pseudobulbar palsy in patients with tracheotomy intubation for severe cerebral haemorrhage and to provide an innovative acupuncture method for the treatment of such patients. Methods: A total of 126 patients from six trial centres who met the inclusion criteria were randomly divided into three groups according to the random number table method in the ratio of 1 : 1 : 1, with 42 patients in each group, and the three groups were divided into CENA group, electro-acupuncture group, and acupuncture group. Each group's acupuncture treatment lasted for 30 minutes, and the needles were removed at the end of the treatment. Acupuncture was performed once a week on Sunday only and twice a day from Monday to Saturday, a total of 4 weeks of treatment. The SWT, FDA, ChSWAL-QOL, and TCRGS scores of the three groups of patients before and after treatment were compared to evaluate the effect of CENA on remodelling the function of swallowing reflex and cough reflex and promoting the recovery of dysarthria and swallowing quality of life in pseudobulbar palsy in patients with tracheotomy intubation for severe cerebral haemorrhage. Results: After treatment, the WST and TCRGS grade scores decreased and the FDA and ChSWAL-QOL scores increased significantly in all three groups compared with the pretreatment scores and were statistically significant. There was a significant difference between the three groups for these four indicators after treatment; the comparison between groups showed significant differences in the CENA group compared to the electro-acupuncture and acupuncture groups. The efficiency of the CENA group was significantly better than that of the electro-acupuncture and acupuncture groups. Conclusion: Compared with the acupuncture and electro-acupuncture groups, the CENA could better promote the remodelling of swallowing function and cough reflex function, promote the recovery of dysarthria, and better improve the quality of life of patients with pseudobulbar palsy from tracheotomy intubation in severe cerebral haemorrhage.

The Effects of a Blood-Brain Barrier Penetrating Erythropoietin in a Mouse Model of Tauopathy.

Erythropoietin (EPO), a hematopoietic neurotrophin, is a potential therapeutic for Alzheimer's disease (AD) but has limited blood-brain barrier (BBB) permeability. EPO fused to a chimeric transferrin receptor monoclonal antibody (cTfRMAb) enters the brain via TfR-mediated transcytosis across the BBB. We previously showed that cTfRMAb-EPO is protective in a mouse model of amyloidosis, but its effects on tauopathy are not known. Given that amyloid and tau pathology are characteristics of AD, the effects of cTfRMAb-EPO were studied in a tauopathy mouse model (PS19). Six-month-old PS19 mice were injected intraperitoneally with either saline (PS19-Saline; n = 9) or cTfRMAb-EPO (PS19-cTfRMAb-EPO, 10 mg/kg; n = 10); every two or three days on alternate weeks for 8 weeks. Age-matched, saline-treated, wildtype littermates (WT-Saline; n = 12) were injected using the same protocol. After 8 weeks, locomotion, hyperactivity, and anxiety were assessed via the open-field test, and brains were harvested and sectioned. Cerebral cortex, hippocampus, amygdala, and entorhinal cortex sections were analyzed for phospho-tau (AT8) and microgliosis (Iba1). Hippocampal cellular density (H&E) was also assessed. PS19-Saline mice were hyperactive and less anxious compared to WT-Saline mice, and these behavioral phenotypes were significantly reduced in the PS19-cTfRMAb-EPO mice compared to the PS19-Saline mice. cTfRMAb-EPO significantly reduced AT8 load by ≥50% in all of the brain regions analyzed and microgliosis in the entorhinal cortex and amygdala compared to the PS19-Saline mice. Hippocampal pyramidal and granule cell layer density did not differ significantly between the PS19-cTfRMAb-EPO and PS19-Saline mice. This proof-of-concept study demonstrates the therapeutic effects of the BBB-penetrating cTfRMAb-EPO in PS19 mice.

The number of metabolic syndrome risk factors predicts alterations in gut microbiota in Chinese children from the Huantai study.

BACKGROUND: Evidence on the effect of gut microbiota on the number of metabolic syndrome (MetS) risk factors among children is scarce. We aimed to examine the alterations of gut microbiota with different numbers of MetS risk factors among children. METHODS: Data were collected from a nested case-control study at the baseline of the Huantai Childhood Cardiovascular Health Cohort Study in Zibo, China. We compared the differences in gut microbiota based on 16S rRNA gene sequencing among 72 children with different numbers of MetS risk factors matched by age and sex (i.e., none, one, and two-or-more MetS risk factors; 24 children for each group). RESULTS: The community richness (i.e., the total number of species in the community) and diversity (i.e., the richness and evenness of species in the community) of gut microbiota decreased with an increased number of MetS risk factors in children (P for trend < 0.05). Among genera with a relative abundance greater than 0.01%, the relative abundance of Lachnoclostridium (PFDR = 0.009) increased in the MetS risk groups, whereas Alistipes (PFDR < 0.001) and Lachnospiraceae_NK4A136_group (PFDR = 0.043) decreased in the MetS risk groups compared to the non-risk group. The genus Christensenellaceae_R-7_group excelled at distinguishing one and two-or-more risk groups from the non-risk group (area under the ROC curve [AUC]: 0.84 - 0.92), while the genera Family_XIII_AD3011_group (AUC: 0.73 - 0.91) and Lachnoclostridium (AUC: 0.77 - 0.80) performed moderate abilities in identifying none, one, and two-or-more MetS risk factors in children. CONCLUSIONS: Based on the nested case-control study and the 16S rRNA gene sequencing technology, we found that dysbiosis of gut microbiota, particularly for the genera Christensenellaceae_R-7_group, Family_XIII_AD3011_group, and Lachnoclostridium may contribute to the early detection and the accumulation of MetS risk factors in childhood.

Dose-response association between maternal smoking during pregnancy and the risk of infant death: a nationwide, population-based, retrospective cohort study.

Background: Association of timing and intensity of maternal smoking during pregnancy with all-cause and cause-specific infant death remains inconclusive. We aimed to examine the dose-response association of maternal smoking during each of the three trimesters of pregnancy with all-cause and cause-specific infant death. Methods: In this nationwide, population-based, retrospective cohort study, data were extracted from the U.S. National Vital Statistics System, 2015-2019. We included mother-infant pairs after excluding twin or multiple births, newborns with gestation age <37 weeks and those with low birthweight, mothers aged <18 years or ≥50 years, mothers with pre-existing hypertension or diabetes, and those with missing values for variables of interest. Poisson regression models were used to examine the association of different intensities and doses of maternal smoking during each of the three trimesters of pregnancy with all-cause and cause-specific infant death attributed to congenital anomalies, preterm birth, other perinatal conditions, sudden unexpected infant death, and infection. Findings: A total of 13,524,204 mother-infant pairs were included in our analyses. Maternal smoking during the entire pregnancy was associated with infant all-cause death (relative risk [RR] 1.88, 95% confidence interval [95% CI] 1.79-1.97), cause-specific death due to preterm birth (1.57, 1.25-1.98), perinatal conditions excluding preterm birth (1.35, 1.10-1.65), sudden unexpected infant death (2.56, 2.40-2.73), and infection (1.51, 1.20-1.88). The risk of infant all-cause death (RR values from 1.80 to 2.15) and cause-specific infant death by preterm birth (RR values from 1.42 to 1.74), perinatal conditions excluding preterm birth (RR values from 1.46 to 1.53), sudden unexpected infant death (RR values from 2.37 to 3.04), and infection (RR values from 1.48 to 2.69) increased with the intensity of maternal cigarette use during the entire pregnancy from 1-5 to ≥11 cigarettes. Compared with mothers who smoked during their entire pregnancy, those who smoked in the first trimester and then quit smoking in the second or third trimesters of pregnancy had a reduced risk of infant all-cause death (0.71, 0.65-0.78) and sudden unexpected infant death (0.64, 0.57-0.72). Interpretation: There was a dose-response association of maternal cigarette use during each of the three trimesters of pregnancy with all-cause and cause-specific infant death. In addition, mothers who are smokers in the first trimester and then quit smoking in the subsequent two trimesters are at decreased risk of infant all-cause mortality and sudden unexpected infant death compared with those who smoked during the entire pregnancy. These findings suggest that there is no safe level of maternal smoking in any trimester of pregnancy and maternal smokers should stop smoking during pregnancy to improve the survival of infants. Funding: Youth Team of Humanistic and Social Science and the Innovation Team of the "Climbing" Program of Shandong University (20820IFYT1902).

Associations between tobacco and alcohol use and aggressive behavior among adolescents in 55 Low- and Middle-Income countries.

BACKGROUND: Aggressive behavior has become a serious public health problem among adolescents worldwide. We aimed to assess the associations between tobacco and alcohol use and aggressive behavior among adolescents in 55 Low- and Middle-Income countries (LMICs). METHODS: Data from 55 LMICs that had done a Global School-based Student Health Survey (GSHS) between 2009 and 2017, comprising 187,787 adolescents aged 12-17 years, were used to examine the associations between tobacco and alcohol use and aggressive behavior. RESULTS: Among adolescents in the 55 LMICs, the proportion of aggressive behavior was 5.7 %. Compared with none tobacco users, those who used tobacco on 1-5 days (odds ratio [OR] = 2.00, 95 % confidence interval [CI] = 1.89-2.11), 6-9 days (2.76, 2.48-3.08), 10-19 days (3.20, 2.88-3.55), and ≥20 days (3.88, 3.62-4.17) during the past 30 days were positively associated with aggressive behavior. Compared with none alcohol users, those who used alcohol on 1-5 days (1.44, 1.37-1.51), 6-9 days (2.38, 2.18-2.60), 10-19 days (3.04, 2.75-3.36), and ≥20 days (3.25, 2.93-3.60) during the past 30 days were positively associated with aggressive behavior. LIMITATIONS: Aggressive behavior, tobacco use and alcohol use were assessed by self-reported questionnaires, which might be prone to recall bias. CONCLUSIONS: Higher amounts of tobacco and alcohol use are associated with aggressive behavior among adolescents. These findings emphasize the need to strengthen tobacco and alcohol control efforts to reduce tobacco and alcohol use targeting adolescents in LMICs.

Association between gut microbiota and obesity combined with high carotid intima-media thickness among Chinese children.

BACKGROUND AND OBJECTIVES: Obesity and related target organ damage such as high carotid intima-media thickness (cIMT) in children is associated with cardiovascular disease (CVD) later in life. However, the asso-ciation between gut microbiota and obesity combined with high cIMT among children remains unclear. Therefore, we compared differences in composition, community diversity, and richness of gut microbiota among normal children and obesity combined with or without high cIMT to identify differential microbiota biomarkers. METHODS AND STUDY DESIGN: A total of 24 children with obesity combined with high cIMT (OB+high-cIMT), 24 with obesity but normal cIMT (OB+non-high cIMT), and 24 with normal weight and normal cIMT aged 10-11 years matched by age and sex from the "Huantai Childhood Cardiovascular Health Cohort Study" were included. All included fecal samples were tested using 16S rRNA gene sequencing. RESULTS: The community richness and diversity of gut microbiota in OB+high-cIMT children were decreased compared with OB+non-high cIMT children and normal children. At the genus level, the relative abundances of Christensenellaceae_R-7_group, UBA1819, Family_XIII_AD3011_group, and unclassi-fied_o_Bacteroidales were associated with reduced odds of OB+high-cIMT among children. Receiver operating characteristic (ROC) analysis showed that combined Christensenellaceae_R-7_group, UBA1819, Fami-ly_XIII_AD3011_group, and unclassified_o_Bacteroidales performed a high ability in identifying OB+high-cIMT. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) showed that several pathways such as biosynthesis of amino acids and aminoacyl-tRNA pathways were lower in the OB+high-cIMT group compared with the normal group. CONCLUSIONS: We found that the alteration of gut microbiota was associated with OB+high-cIMT among children, which indicates that the gut microbiota may be a marker for obesity and related cardiovascular damage among children.

Association of the American Heart Association's new "Life's Essential 8" with all-cause and cardiovascular disease-specific mortality: prospective cohort study.

BACKGROUND: The American Heart Association recently updated its construct of what constitutes cardiovascular health (CVH), called Life's Essential 8. We examined the association of total and individual CVH metrics according to Life's Essential 8 with all-cause and cardiovascular disease (CVD)-specific mortality later in  life. METHODS: Data were from the National Health and Nutrition Examination Survey (NHANES) 2005-2018 at baseline linked to the 2019 National Death Index records. Total and individual CVH metric scores including diet, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure were classified as 0-49 (low level), 50-74 (intermediate level), and 75-100 (high level) points. The total CVH metric score (the average of the 8 metrics) as a continuous variable was also used for dose-response analysis. The main outcomes included all-cause and CVD-specific mortality. RESULTS: A total of 19,951 US adults aged 30-79 years were included in this study. Only 19.5% of adults achieved a high total CVH score, whereas 24.1% had a low score. During a median follow-up of 7.6 years, compared with adults with a low total CVH score, those with an intermediate or high total CVH score had 40% (adjusted hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.51-0.71) and 58% (adjusted HR 0.42, 95% CI 0.32-0.56) reduced risk of all-cause mortality. The corresponding adjusted HRs (95%CIs) were 0.62 (0.46-0.83) and 0.36 (0.21-0.59) for CVD-specific mortality. The population-attributable fractions for high (score ≥ 75 points) vs. low or intermediate (score < 75 points) CVH scores were 33.4% for all-cause mortality and 42.9% for CVD-specific mortality. Among all 8 individual CVH metrics, physical activity, nicotine exposure, and diet accounted for a large proportion of the population-attributable risks for all-cause mortality, whereas physical activity, blood pressure, and blood glucose accounted for a large proportion of CVD-specific mortality. There were approximately linear dose-response associations of total CVH score (as a continuous variable) with all-cause and CVD-specific mortality. CONCLUSIONS: Achieving a higher CVH score according to the new Life's Essential 8 was associated with a reduced risk of all-cause and CVD-specific mortality. Public health and healthcare efforts targeting the promotion of higher CVH scores could provide considerable benefits to reduce the mortality burden later in life.

Proportions of and trends in exposure to pro-tobacco and anti-tobacco advertisements among young adolescents aged 12-16 years in 142 countries and territories, 1999-2018: an analysis of repeated cross-sectional surveys.

BACKGROUND: The proportions and trends in exposure to pro-tobacco and anti-tobacco advertisements among young people remain unknown globally. We determined recent (2010-18) proportions of exposure to pro-tobacco and anti-tobacco advertisements among young adolescents and their secular trends from 1999 to 2018. METHODS: In this analysis of repeated cross-sectional surveys, we used the most recent data from 142 countries and territories (hereafter referred to as countries) collected between Jan 1, 2010, and Dec 31, 2018, comprising 710 191 participants, to assess the proportions of exposure to pro-tobacco and anti-tobacco advertisements among young adolescents aged 12-16 years. Data from 120 countries that had performed two or more Global Youth Tobacco Surveys between Jan 1, 1999, and Dec 31, 2018, comprising 1 482 031 participants, were used to assess trends in the proportions of exposure to pro-tobacco and anti-tobacco advertisements over time. A χ2 test analysis was used for proportion comparisons between subgroups. Exposure to pro-tobacco and anti-tobacco advertisements were calculated as proportions using sampling weights, strata, and primary sampling units. FINDINGS: The most recent global proportion of past 30-day exposure to tobacco advertisements among young adolescents was 433 585 (64·6%) of 710 191 (95% CI 63·5-65·7; all final percentages were weighted) for messages on electronic media, 206 766 (33·1%) of 710 191 (31·9-34·4) for exposure at the point of sale, and 63 385 (10·2%) of 710 191 (9·7-10·6) for owning something with a tobacco brand logo. The most recent global proportion of exposure to anti-tobacco advertisements was 431 862 (63·6%) of 710 191 (62·3-64·9) for messages on electronic media and 227 658 (34·1%) of 710 191 (32·8-35·3) for exposure to gathering activities. The majority of included countries showed a decreasing trend in exposure to tobacco advertisements (111 [93%] of 120) and anti-tobacco advertisements (110 [92%] of 120) between 1999 and 2018. INTERPRETATION: Among young adolescents, exposure to tobacco advertisements remains high, and exposure to anti-tobacco advertisements is not high enough. The proportion of young adolescents exposed to pro-tobacco and anti-tobacco advertisements had decreased over time in the majority of included countries. These findings underscore the importance of strict implementation of regulation on tobacco control including strengthening anti-tobacco marketing and prohibiting tobacco marketing. FUNDING: Youth Team of Humanistic and Social Science of Shandong University. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Chronic kidney disease promotes cerebral microhemorrhage formation.

BACKGROUND: Chronic kidney disease (CKD) is increasingly recognized as a stroke risk factor, but its exact relationship with cerebrovascular disease is not well-understood. We investigated the development of cerebral small vessel disease using in vivo and in vitro models of CKD. METHODS: CKD was produced in aged C57BL/6J mice using an adenine-induced tubulointerstitial nephritis model. We analyzed brain histology using Prussian blue staining to examine formation of cerebral microhemorrhage (CMH), the hemorrhagic component of small vessel disease and the neuropathological substrate of MRI-demonstrable cerebral microbleeds. In cell culture studies, we examined effects of serum from healthy or CKD patients and gut-derived uremic toxins on brain microvascular endothelial barrier. RESULTS: CKD was induced in aged C57BL/6J mice with significant increases in both serum creatinine and cystatin C levels (p < 0.0001) without elevation of systolic or diastolic blood pressure. CMH was significantly increased and positively correlated with serum creatinine level (Spearman r = 0.37, p < 0.01). Moreover, CKD significantly increased Iba-1-positive immunoreactivity by 51% (p < 0.001), induced a phenotypic switch from resting to activated microglia, and enhanced fibrinogen extravasation across the blood-brain barrier (BBB) by 34% (p < 0.05). On analysis stratified by sex, the increase in CMH number was more pronounced in male mice and this correlated with greater creatinine elevation in male compared with female mice. Microglial depletion with PLX3397 diet significantly decreased CMH formation in CKD mice without affecting serum creatinine levels. Incubation of CKD serum significantly reduced transendothelial electrical resistance (TEER) (p < 0.01) and increased sodium fluorescein permeability (p < 0.05) across the endothelial monolayer. Uremic toxins (i.e., indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide) in combination with urea and lipopolysaccharide induced a marked drop in TEER compared with the control group (p < 0.0001). CONCLUSIONS: CKD promotes the development of CMH in aged mice independent of blood pressure but directly proportional to the degree of renal impairment. These effects of CKD are likely mediated in part by microglia and are associated with BBB impairment. The latter is likely related to gut-derived bacteria-dependent toxins classically associated with CKD. Overall, these findings demonstrate an important role of CKD in the development of cerebral small vessel disease.

Chili pepper intake and all-cause and disease-specific mortality.

Background: Chili pepper has been used for the treatment and prevention of multiple diseases. This may be due to its abundance of bioactive components, such as carotenoids, which are well known for their antioxidant properties. To date, several prospective cohort studies have examined the association between chili pepper intake and mortality, but the results have not been consistent. This study aimed to clarify the association between chili pepper intake and all-cause and disease-specific mortality using a meta-analysis. Methods: PubMed, Embase, and ISI Web of Science databases were searched up to December 20, 2020, and reference lists of included studies were manually reviewed. All prospective cohort studies on the association between chili pepper intake and all-cause, cardiovascular disease (CVD)-specific, and cancer-specific mortality were included in this study. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated in the meta-analysis. Between-study heterogeneity was assessed using I2 statistic and Q test. Results: A total of 4 cohort studies (N=564,748; all four studies had adjusted for important potential confounders such as demographic variables, dietary intake, and physical activity) were ultimately included in this meta-analysis. Among them, 31,527 died due to all causes, 10,184 died due to CVD, and 9,868 died due to cancer. Compared to none or rare consumption of chili pepper, consumption of chili pepper (ever or more than once a week) could significantly reduce the risk of all-cause mortality (summary adjusted HR: 0.87, 95% CI: 0.85, 0.90), CVD-specific mortality (summary adjusted HR: 0.89, 95% CI: 0.85, 0.93), and cancer-specific mortality (summary adjusted HR: 0.92, 95% CI: 0.88, 0.97). There was no significant between-study heterogeneity in the analyses (all-cause mortality: I2=0.7%, P=0.389; CVD-specific mortality: I2=21.8%, P=0.280; cancer-specific mortality: I2=0.0%, P=0.918). Conclusions: The present meta-analysis confirmed that chili pepper intake could reduce the risk of all-cause, CVD-specific, and cancer-specific mortality, suggesting that chili pepper may be a beneficial ingredient in the diets in prolonging life.

Maternal pre-pregnancy body mass index and offspring with overweight/obesity at preschool age: The possible role of epigenome-wide DNA methylation changes in cord blood.

BACKGROUND: Epigenome-wide association studies have identified some DNA methylation sites associated with body mass index (BMI) or obesity. Studies in the Asian population are lacking. OBJECTIVE: To examine the association of cord blood genome-wide DNA methylation (GWDm) changes with maternal pre-pregnancy BMI and children's BMI-z score at preschool age. Additionally, we also explored the genome-wide differentially methylated regions and differentially methylated probes between preschoolers with overweight/obesity and normal-weight counterparts. METHODS: This two-stage study design included (1) a GWDm analysis of 30 mother-child pairs from 633 participants of the Zhuhai birth cohort with data on newborn cord blood, maternal pre-pregnancy BMI, and children's BMI at 3 years of age; and (2) a targeted validation analysis of the cord blood of ten children with overweight/obesity and ten matched controls to validate the CpG sites. RESULTS: In the first stage, no significant CpG sites were found to be associated with children's BMI-z score at preschool age after FDR correction with the p-values of the CpG sites in FOXN3 (cg23501836) and ZNF264 (cg27437574) being close to 1 × 10-6 . In the second stage, a significant difference of CpG sites in AHRR (chr5:355067-355068) and FOXN3 (chr14: 89630264-89630272 and chr14: 89630387-89630388) was found between the ten children with overweight/obesity and ten controls (p < 0.05). The CpG sites in FOXN3 (chr14:89630264-89630272 and chr14:89630295-89630296) and ZNF264 (chr19: 57703104-57703107 and chr19: 57703301-57703307) were associated with children's BMI-z score; and the CpG sites in FOXN3 (chr14: 89630264-89630272 and chr14: 89630387-89630388) were associated with maternal pre-pregnancy BMI. CONCLUSIONS: DNA methylation in FOXN3 and AHRR is associated with overweight/obesity in preschool-aged children, and the methylation in FOXN3 and ZNF264 might be associated with children's BMI-z score. FOXN3 methylation may be associated with maternal pre-pregnancy BMI, suggesting its potential role in the children's BMI-z score or overweight/obesity. Our results provide novel insights into the mechanisms of children's obesity.

Association between secondhand smoke exposure in indoor public places and sleep deprivation in children / 中国学校卫生

Objective@#To examine the association between secondhand smoke (SHS) exposure in indoor public places and sleep deprivation, so as to provide a reference for strengthening the management of a smoking ban in public places and to promote better sleep in childhood.@*Methods@#Data were obtained from the second follow up survey of the Huantai Childhood Cardiovascular Health Cohort Study, which was conducted from November to December 2021. A total of 1 284 children aged 10-15 years old were included in the study. The participants were assigned to four groups (0, 1-2, 3-4 and ≥5 days) according to the frequency which they were exposed to SHS in indoor public places in the previous 7 days. Multiple linear regression was performed to examine the trend of children s sleep duration with the frequency of SHS exposure. Multivariate Logistic regression was carried out to determine the association between frequency of SHS and sleep deprivation.@*Results@#After adjusting for age, sex, grade, physical activity, intake of fruits/vegetables, intake of soft drinks, screen duration, body mass index (BMI) and blood pressure, the average sleep duration of children who were exposed to SHS for 0, 1-2, 3-4 and ≥5 days in the previous 7 days was 8.48, 8.41, 8.20 and 8.06 h/d , respectively, and the average sleep duration decreased with exposure frequency of SHS ( t=5.96, 5.89, 5.91, P < 0.01 ). The proportion of sleep deprivation among children who were exposed to SHS in public places for 0, 1-2, 3-4 and ≥5 days in the previous 7 days was 40.02%, 43.07%, 54.65% and 63.41%, respectively. Compared to children who were not exposed to SHS in indoor public places in the past 7 days, those exposed for 3-4 days ( OR=1.93, 95%CI =1.19-3.15) or ≥ 5 days ( OR=2.95, 95%CI = 1.76- 4.94) had a significantly increased risk of sleep deprivation ( P <0.05).@*Conclusion@#Children s sleep time decreases with increasing frequency of exposure to SHS, and children who are frequently exposed to SHS are more likely to experience insufficient sleep. Smoking ban management in public places should be strengthened to promote children s sleep health, especially indoor public places.

Association between secondhand smoke exposure in indoor public places and carotid intima media thickness in children and adolescents / 中国学校卫生

Objective@#To examine the association between secondhand smoke exposure (SHS) in indoor public places and carotid intima media thickness (cIMT) in children and adolescents, so as to provide guidance for the prevention of early abnormal vascular architecture.@*Methods@#The data were obtained from the second follow up of the Children Cardiovascular Health Cohort Study conducted from November to December 2021. A total of 1 297 children and adolescents for who completed data relating to sex, age, cIMT, physical examinations, questionnaires variables and blood biochemical indices, were included for analysis. Linear regression analysis was performed to examine trends in the levels of cIMT with exposure to SHS in indoor public places. Multiple linear regression analysis was carried out to assess the association between SHS exposure in indoor public places and cIMT after adjustment for potential covariates.@*Results@#During the previous 7 days, 407 (31.4%) children and adolescents were exposed to SHS in indoor public places for 1-2 days, 86 (6.6%) for 3-4 days, and 82 (6.3%) for ≥5 days. The levels of cIMT in youth increased on different models, with the duration of SHS exposure during the previous 7 days ( t=3.30, 3.05, 2.87, P <0.05). After adjusting for various covariates, the cIMT values of children and adolescents were[0 day:(551.5±29.3) μm, 1-2 days:(554.0±28.6) μm, 3-4 days:(557.0±27.7) μm, ≥5 days:(559.4±27.5) μm]. Compared to those who were not exposed to SHS in indoor public places during the previous 7 days, those exposed for ≥5 days had significantly higher cIMT levels ( β=7.91, 95%CI=1.47-14.34, P <0.05).@*Conclusion@#Among children and adolescents, exposure to SHS in indoor public places remains high and is significantly associated with cIMT. The findings highlight the need for stricter regulation and tobacco control policies to provide healthy smoke free environments for children and adolescents, and to reduce the risk of early abnormal vascular architecture.