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.

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.

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.

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.

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 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.

Cigarette access and purchase patterns among adolescent smokers aged 12-16 years in 140 countries/territories, Global Youth Tobacco Survey 2010-2018.

Background: Few studies have examined access to cigarettes among adolescents. To address this, we aimed to examine cigarette access and purchase patterns among adolescent cigarette smokers based on the most recent data from the Global Youth Tobacco Surveys (GYTS). Methods: We used the most recent school-based GYTS data (2010-2018) on 49 856 adolescent cigarette smokers aged 12-16 years in 140 countries/territories (hereafter "countries") to examine cigarette access and purchase patterns among adolescent smokers. Results: Over half (51.2%) of adolescent smokers bought cigarettes from commercial vendors (ie, stores/shops/street vendors/kiosks) and one-third of smokers (32.7%) got cigarettes from private persons (ie, peers or adults). Males (vs females), older adolescents (vs younger ones), and adolescent smokers from low-income countries (vs those from middle- or high-income countries) were more likely to buy cigarettes from commercial vendors. Younger adolescents (vs older ones) and adolescent smokers from low-income countries (vs those from middle- or high-income countries) were more likely to get cigarettes from private persons. As many as 39.6% of adolescent smokers reported that they were not denied buying cigarettes from commercial vendors due to age restrictions, especially among males (vs females), among older adolescents (vs younger ones), and among adolescent smokers from upper-middle-income or high-income countries (vs those from low-income countries). Purchasing cigarettes as single sticks was more likely to occur in males (vs females), in older adolescents (vs younger ones), and in adolescent smokers from low-income countries (vs those from upper-middle-income or high-income countries), with inverse findings for purchasing cigarettes in full packs. Conclusions: Adolescent smokers often obtained cigarettes from commercial vendors or private persons. Additionally, adolescent smokers often purchased cigarettes in packs and as individual sticks. These findings emphasize the need to strengthen measures to reduce the supply of cigarettes to minors.

Efficacy and Safety of a Brain-Penetrant Biologic TNF-α Inhibitor in Aged APP/PS1 Mice.

Tumor necrosis factor alpha (TNF-α) plays a vital role in Alzheimer's disease (AD) pathology, and TNF-α inhibitors (TNFIs) modulate AD pathology. We fused the TNF-α receptor (TNFR), a biologic TNFI that sequesters TNF-α, to a transferrin receptor antibody (TfRMAb) to deliver the TNFI into the brain across the blood-brain barrier (BBB). TfRMAb-TNFR was protective in 6-month-old transgenic APP/PS1 mice in our previous work. However, the effects and safety following delayed chronic TfRMAb-TNFR treatment are unknown. Herein, we initiated the treatment when the male APP/PS1 mice were 10.7 months old (delayed treatment). Mice were injected intraperitoneally with saline, TfRMAb-TNFR, etanercept (non-BBB-penetrating TNFI), or TfRMAb for ten weeks. Biologic TNFIs did not alter hematology indices or tissue iron homeostasis; however, TfRMAb altered hematology indices, increased splenic iron transporter expression, and increased spleen and liver iron. TfRMAb-TNFR and etanercept reduced brain insoluble-amyloid beta (Aß) 1-42, soluble-oligomeric Aß, and microgliosis; however, only TfRMAb-TNFR reduced Aß peptides, Thioflavin-S-positive Aß plaques, and insoluble-oligomeric Aß and increased plaque-associated phagocytic microglia. Accordingly, TfRMAb-TNFR improved spatial reference memory and increased BBB-tight junction protein expression, whereas etanercept did not. Overall, despite delayed treatment, TfRMAb-TNFR resulted in a better therapeutic response than etanercept without any TfRMAb-related hematology- or iron-dysregulation in aged APP/PS1 mice.

Ensemble Machine Learning Model for Accurate Air Pollution Detection Using Commercial Gas Sensors.

This paper presents the results on developing an ensemble machine learning model to combine commercial gas sensors for accurate concentration detection. Commercial gas sensors have the low-cost advantage and become key components of IoT devices in atmospheric condition monitoring. However, their native coarse resolution and poor selectivity limit their performance. Thus, we adopted recurrent neural network (RNN) models to extract the time-series concentration data characteristics and improve the detection accuracy. Firstly, four types of RNN models, LSTM and GRU, Bi-LSTM, and Bi-GRU, were optimized to define the best-performance single weak models for CO, O3, and NO2 gases, respectively. Next, ensemble models which integrate multiple single weak models with a dynamic model were defined and trained. The testing results show that the ensemble models perform better than the single weak models. Further, a retraining procedure was proposed to make the ensemble model more flexible to adapt to environmental conditions. The significantly improved determination coefficients show that the retraining helps the ensemble models maintain long-term stable sensing performance in an atmospheric environment. The result can serve as an essential reference for the applications of IoT devices with commercial gas sensors in environment condition monitoring.

Prevalence of E-Cigarette Use and Its Associated Factors Among Youths Aged 12 to 16 Years in 68 Countries and Territories: Global Youth Tobacco Survey, 2012‒2019.

Objectives. To describe the recent global prevalence of e-cigarette use and to investigate its associated factors among youths aged 12 to 16 years in 68 countries and territories (hereafter "countries"). Methods. We analyzed 485 746 youths aged 12 to 16 years from the population-based cross-sectional Global Youth Tobacco Survey conducted in 67 countries between 2012 and 2019 and the 2019 National Youth Tobacco Survey in the United States. We defined past-30-day e-cigarette use as using e-cigarettes on 1 or more days during the past 30 days. Results. The global prevalence of past-30-day e-cigarette use among youths was 9.2%, ranging from 1.9% in Kazakhstan to 33.2% in Guam. Maternal smoking (adjusted odds ratio [AOR] = 1.40; 95% confidence interval [CI] = 1.29, 1.52), paternal smoking (AOR = 1.13; 95% CI = 1.07, 1.19), secondhand smoke exposure (AOR = 1.74; 95% CI = 1.64, 1.84), youth cigarette smoking (AOR = 7.18; 95% CI = 6.84, 7.54), and youth other tobacco use (AOR = 3.88; 95% CI = 3.62, 4.15) were positively associated with e-cigarette use. Conclusions. E-cigarette use was moderately frequent among youths aged 12 to 16 years globally. Several important factors were associated with youth e-cigarette use. Public Health Implications. Our findings highlight the need for countries worldwide to develop policies to address e-cigarette use among youths. (Am J Public Health. 2022;112(4):650-661. https://doi.org/10.2105/AJPH.2021.306686).

Integrated metabolomics and lipidomics evaluate the alterations of flavor precursors in chicken breast muscle with white striping symptom.

White striping (WS) is the most common myopathy in the broiler chicken industry. To reveal flavor changes of WS meat objectively, flavor precursors of WS breast muscle were evaluated systematically with integrated metabolomics and lipidomics. The results showed that WS could be distinguished from normal controls by E-nose, and four volatile compounds (o-xylene, benzene, 1,3-dimethyl, 2-heptanone and 6-methyl and Acetic acid and ethyl ester) were detected as decreased compounds by gas chromatography-mass spectrometry. Lipidomic analysis showed that WS breast fillets featured increased neutral lipid (83.8%) and decreased phospholipid molecules (33.2%). Targeted metabolomic analysis indicated that 16 hydrophilic metabolites were altered. Thereinto, some water-soluble flavor precursors, such as adenosine monophosphate, GDP-fucose and L-arginine increased significantly, but fructose 1,6-bisphosphate and L-histidine significantly decreased in the WS group. These results provided a systematic evaluation of the flavor precursors profile in the WS meat of broiler chickens.

Dose-response association of leisure time physical activity with mortality in adults with major chronic diseases.

We aimed to evaluate the association between leisure-time physical activity (PA) and mortality risk in adults with major chronic diseases. A total of 170,579 adults with major chronic diseases aged 30-84 years from the U.S. National Health Interview Surveys (1997-2014) with linkage to the National Death Index (NDI) through December 31, 2015 were included in this study. During a median follow-up of 7.25 years, 36,914 adults with chronic diseases died from all causes, 8,767 died from cardiovascular disease (CVD), and 9,090 died from cancer. Compared with participants with no leisure-time PA, those with a low level (10-59 min/week) of total leisure-time PA had a 23% [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.73-0.82] reduced risk of all-cause mortality. Adults with higher levels of leisure time had more reduced risk of all-cause mortality, as well as CVD-specific and cancer-specific mortality. Adults with leisure-time PA ≥ 1,500 min/week had more reduced risk of CVD-specific mortality (61%) but less reduced risk of cancer-specific mortality (29%) compared with the reduced risk of all-cause mortality (43%). There was an inversely non-linear dose-response relationship between leisure-time PA and all-cause and cause-specific mortality. Reduced risk of all-cause and cancer-specific mortality between leisure-time light-to-moderate PA and vigorous-intensity PA time were largely comparable. Low and high levels of leisure-time PA showed substantial survival benefits compared with no leisure-time PA in adults with major chronic diseases. The light-to-moderate-intensity leisure-time PA is largely comparable with vigorous PA to provide survival benefits for all-cause and cancer-specific mortality.

Trends in Cardiometabolic and Cancer Multimorbidity Prevalence and Its Risk With All-Cause and Cause-Specific Mortality in U.S. Adults: Prospective Cohort Study.

Several prospective cohort studies have assessed the association between multimorbidity and all-cause mortality, but the findings have been inconsistent. In addition, limited studies have assessed the association between multimorbidity and cause-specific mortality. In this study, we used the population based cohort study of National Health Interview Survey (1997-2014) with linkage to the National Death Index records to 31 December 2015 to examine the trends in prevalence of multimorbidity from 1997 to 2014, and its association with the risk of all-cause and cause-specific mortality in the U.S. population. A total of 372,566 adults aged 30-84 years were included in this study. From 1997 to 2014, the age-standardized prevalence of specific chronic condition and multimorbidity increased significantly (P < 0.0001). During a median follow-up of 9.0 years, 50,309 of 372,566 participants died from all causes, of which 11,132 (22.1%) died from CVD and 13,170 (26.2%) died from cancer. Compared with participants without the above-mentioned chronic conditions, those with 1, 2, 3, and ≥4 of chronic conditions had 1.41 (1.37-1.45), 1.94 (1.88-2.00), 2.64 (2.54-2.75), and 3.68 (3.46-3.91) higher risk of all-cause mortality after adjustment for important covariates. Similarly, a higher risk of CVD-specific and cancer-specific mortality was observed as the number of chronic conditions increased, with the observed risk stronger for CVD-mortality compared with cancer-specific mortality. Given the prevalence of multimorbidity tended to increase from 1997 to 2014, our data suggest effective prevention and intervention programs are necessary to limit the increased mortality risk associated with multimorbidity.

Tri-Ponderal Mass Index as a Screening Tool for Identifying Body Fat and Cardiovascular Risk Factors in Children and Adolescents: A Systematic Review.

Because of the limitation of body mass index (BMI) in distinguishing adipose mass from muscle, the tri-ponderal mass index (TMI) has been proposed as a new indicator for better assessing adiposity in children and adolescents. However, it remains unclear whether TMI performs better than BMI or other adiposity indices in predicting obesity status in childhood and obesity-related cardiovascular risk factors (CVRFs) in childhood or adulthood. We searched PubMed, Cochrane Library, and Web of Science for eligible publications until June 15, 2021. A total of 32 eligible studies were included in this systematic review. We found that TMI had a similar or better ability to predict body fat among children and adolescents than BMI. However, most of the included studies suggested that TMI was similar to BMI in identifying metabolic syndrome although TMI was suggested to be a useful tool when used in combination with other indicators (e.g., BMI and waist circumference). In addition, limited evidence showed that TMI did not perform better than BMI for identifying specific CVRFs, including insulin resistance, high blood pressure, dyslipidemia, and inflammation in children and adolescents, as well as CVRFs in adults. Systematic Review Registration: https://www.crd.york.ac.uk/prospero, CRD42021260356.

The Tyrosine Kinase-Driven Networks of Novel Long Non-coding RNAs and Their Molecular Targets in Myeloproliferative Neoplasms.

Recent research has focused on the mechanisms by which long non-coding RNAs (lncRNAs) modulate diverse cellular processes such as tumorigenesis. However, the functional characteristics of these non-coding elements in the genome are poorly understood at present. In this study, we have explored several mechanisms that involve the novel lncRNA and microRNA (miRNA) axis participating in modulation of drug response and the tumor microenvironment of myeloproliferative neoplasms (MPNs). We identified novel lncRNAs via mRNA sequencing that was applied to leukemic cell lines derived from BCR-ABL1-positive and JAK2-mutant MPNs under treatment with therapeutic tyrosine kinase inhibitors (TKI). The expression and sequence of novel LNC000093 were further validated in both leukemic cells and normal primary and pluripotent cells isolated from human blood, including samples from patients with chronic myelogenous leukemia (CML). Downregulation of LNC000093 was validated in TKI-resistant CML while a converse expression pattern was observed in blood cells isolated from TKI-sensitive CML cases. In addition to BCR-ABL1-positive CML cells, the driver mutation JAK2-V617F-regulated lncRNA BANCR axis was further identified in BCR-ABL1-negative MPNs. Further genome-wide validation using MPN patient specimens identified 23 unique copy number variants including the 7 differentially expressed lncRNAs from our database. The newly identified LNC000093 served as a competitive endogenous RNA for miR-675-5p and reversed the imatinib resistance in CML cells through regulating RUNX1 expression. The extrinsic function of LNC000093 in exosomal H19/miR-675-induced modulation for the microenvironment was also determined with significant effect on VEGF expression.