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.

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.

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.

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.

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.

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.

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.

Childhood diabetes mellitus and early-onset kidney diseases later in life: a nationwide population-based matched cohort study.

BACKGROUND: The empirical evidence remains inconclusive for an association between diabetes mellitus (DM) in children and early-onset kidney disease later in life, and little is known about the effects of DM types (i.e., type 1 diabetes [T1DM] and type 2 diabetes [T2DM]) in childhood on type-specific kidney diseases. We aimed to evaluate the association of childhood DM with overall and type-specific early-onset kidney diseases later in life. METHODS: The population-based matched cohort study included 9356 individuals with DM (T1DM: 8470, T2DM: 886) diagnosed in childhood (< 18 years) who were born between 1977 and 2016, and 93,560 individuals without DM matched on sex and year of birth in Denmark. The main outcomes were overall and type-specific early-onset kidney diseases. The follow-up period of all included participants was from the date of DM diagnosis in the exposure group until the first diagnosis of kidney disease, emigration, or 31 December 2018, whichever came first. RESULTS: During a median follow-up of 13 years, children with DM had a 154% increased risk of early-onset kidney diseases than children without DM (adjusted hazard ratios 2.54, 95% confidence intervals 2.38-2.72), and T1DM (2.48, 2.31-2.67) and T2DM (2.75, 2.28-3.31) showed similar results. Children with DM also had a higher risk of multiple specific kidney diseases including glomerular diseases, renal tubulo-interstitial diseases, renal failure, and urolithiasis. The risks of type-specific kidney diseases including glomerular diseases and renal failure tended to be higher for children with T2DM (glomerular diseases: 5.84, 3.69-9.24; renal failure: 14.77, 8.53-25.59) than those with T1DM (glomerular diseases: 3.14, 2.57-3.83; renal failure: 8.24, 6.66-10.20). CONCLUSIONS: Children with DM had a higher increased risk of early-onset overall and specific kidney diseases later in life. Early prevention and treatment of both T1DM and T2DM in childhood may significantly reduce the risk of kidney diseases later in life.

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).

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.

Biologic TNF-α inhibitors reduce microgliosis, neuronal loss, and tau phosphorylation in a transgenic mouse model of tauopathy.

BACKGROUND: Tumor necrosis factor-α (TNF-α) plays a central role in Alzheimer's disease (AD) pathology, making biologic TNF-α inhibitors (TNFIs), including etanercept, viable therapeutics for AD. The protective effects of biologic TNFIs on AD hallmark pathology (Aß deposition and tau pathology) have been demonstrated. However, the effects of biologic TNFIs on Aß-independent tau pathology have not been reported. Existing biologic TNFIs do not cross the blood-brain barrier (BBB), therefore we engineered a BBB-penetrating biologic TNFI by fusing the extracellular domain of the type-II human TNF-α receptor (TNFR) to a transferrin receptor antibody (TfRMAb) that ferries the TNFR into the brain via receptor-mediated transcytosis. The present study aimed to investigate the effects of TfRMAb-TNFR (BBB-penetrating TNFI) and etanercept (non-BBB-penetrating TNFI) in the PS19 transgenic mouse model of tauopathy. METHODS: Six-month-old male and female PS19 mice were injected intraperitoneally with saline (n = 12), TfRMAb-TNFR (1.75 mg/kg, n = 10) or etanercept (0.875 mg/kg, equimolar dose of TNFR, n = 10) 3 days/week for 8 weeks. Age-matched littermate wild-type mice served as additional controls. Blood was collected at baseline and 8 weeks for a complete blood count. Locomotion hyperactivity was assessed by the open-field paradigm. Brains were examined for phosphorylated tau lesions (Ser202, Thr205), microgliosis, and neuronal health. The plasma pharmacokinetics were evaluated following a single intraperitoneal injection of 0.875 mg/kg etanercept or 1.75 mg/kg TfRMAb-TNFR or 1.75 mg/kg chronic TfRMAb-TNFR dosing for 4 weeks. RESULTS: Etanercept significantly reduced phosphorylated tau and microgliosis in the PS19 mouse brains of both sexes, while TfRMAb-TNFR significantly reduced these parameters in the female PS19 mice. Both TfRMAb-TNFR and etanercept treatment improved neuronal health by significantly increasing PSD95 expression and attenuating hippocampal neuron loss in the PS19 mice. The locomotion hyperactivity in the male PS19 mice was suppressed by chronic etanercept treatment. Equimolar dosing resulted in eightfold lower plasma exposure of the TfRMAb-TNFR compared with etanercept. The hematological profiles remained largely stable following chronic biologic TNFI dosing except for a significant increase in platelets with etanercept. CONCLUSION: Both TfRMAb-TNFR (BBB-penetrating) and non-BBB-penetrating (etanercept) biologic TNFIs showed therapeutic effects in the PS19 mouse model of tauopathy.

Trends in the prevalence of overweight, obesity, and abdominal obesity among Chinese adults between 1993 and 2015.

BACKGROUND: Most previous studies on trends in the prevalence of obesity or abdominal obesity in Chinese adults were based on regional data and/or short time intervals, and recent trends are not available. We aimed to examine the secular trends in the prevalence of overweight, obesity, and abdominal obesity among Chinese adults at the national level from 1993 to 2015. METHODS: A total of 70,242 Chinese adults aged 18-80 years were from the cross-sectional surveys conducted from 1993 to 2015. According to the World Health Organization criteria, overweight was defined as body mass index (BMI) ≥23.0 kg/m2 and <27.5 kg/m2, and obesity was defined as BMI ≥27.5 kg/m2. According to the International Diabetes Federation criteria, abdominal obesity was defined as waist circumference (WC) ≥90 cm for men and ≥80 cm for women. Mean values and prevalence of adiposity markers were standardized to the age distribution of the China population in 2010. RESULTS: Between 1993 and 2015, and based on age-standardized values, mean BMI increased from 21.9 kg/m2 in 1993 to 23.9 kg/m2 (+2.0 kg/m2) in 2015 (P for trend < 0.001), and mean WC increased from 76.0 cm to 83.4 cm (+7.4 cm) (P for trend <0.001). From 1993 to 2015, the prevalence increased from 26.6% to 41.3% (+14.7%) for overweight, from 4.2% to 15.7% (+11.5%) for obesity, and from 20.2% to 46.9% (+26.7%) for abdominal obesity (all P for trends < 0.001). In multivariate linear regression analysis, time (calendar years), older age and urban regions were strongly and independently associated with BMI. CONCLUSIONS: The prevalence of overweight, obesity, and abdominal obesity increased markedly among Chinese adults during the past two decades. Weight control programs and public health measures to address the societal causes of obesity should be strengthened.

Parental tobacco and indoor secondhand smoking exposure and the risk of offspring under-five mortality in low- and middle-income countries.

Children are vulnerable to exposure of secondhand smoking (SHS) which is a major preventable cause of disease and death. This study aimed to investigate the association between parental tobacco use or SHS exposure, respectively, and under-five mortality. Data were obtained from the nationally representative and population-based Demographic and Health Surveys in low- and middle-income countries (LMICs) between 2000 and 2018. Cox proportional hazard regression models with complex survey design were conducted to examine the adjusted associations between parental smoking and SHS exposure and child under-five mortality. In the pooled analysis of parental smoking, 437 322 children were included. Compared with children whose parents are not smoking, those whose father or both parents smoked any form of tobacco had higher risks of mortality (hazard ratio [HR] = 1.08, 95% confidence interval [CI] = 1.03-1.13; HR = 1.18, 95% CI = 1.06-1.32, respectively). In addition, parental using smokeless tobacco, smoking tobacco, and using smokeless tobacco and smoking tobacco simultaneously was significantly associated with child under-five mortality (HR = 1.07, 95% CI = 1.01-1.12; HR = 1.12, 95%CI = 1.04-1.21; and HR = 1.17, 95%CI = 1.06-1.30, respectively). In the pooled analysis of SHS exposure, 605 442 children were included, and weekly and daily SHS exposure were significantly associated with child under-five mortality (HR = 1.11, 95% CI = 1.03-1.20, and HR = 1.10, 95% CI = 1.06-1.15, respectively). The results were robust in most stratification analyses and sensitivity analyses. Parental tobacco use and indoor SHS exposure were associated with increased risk of under-five mortality in LMICs. Comprehensive tobacco control programs should be considered by policymakers in LMICs to promote smoke-free environments for children.

Prevalence of thinness, overweight and obesity among Tibetan adolescents aged 12-17 years.

OBJECTIVE: To estimate the prevalence of thinness, overweight and obesity among Tibetan adolescents aged 12-17 years. DESIGN: Cross-sectional survey. SETTING: Shigatse City of Tibet municipality, with an average altitude of more than 4000 m. PARTICIPANTS: Study participants included 2642 adolescents aged 12-17 years selected from six schools using a convenient cluster sampling method. RESULTS: The prevalence of thinness/overweight/obesity among Tibetan adolescents was 9·4 %/5·4 %/1·4 % (China definition), 14·7 %/4·4 %/0·7 % (International Obesity Task Force (IOTF) definition), and 2·8 %/5·7 %/0·9 % (WHO definition). The prevalence of thinness and overweight was significantly different between both sexes based on each of three BMI classification criteria (P < 0·001). There was no significant difference in the prevalence of obesity between both sexes according to each of three BMI criteria. There was no clear trend in the prevalence of thinness across ages according to the China or IOTF definition (both P > 0·05), whereas an upward trend was observed for thinness in boys according to the IOTF definition (Pfor trend <0·05). In contrast, the prevalence of thinness tended to decrease with increasing age in girls according to the IOTF definition and in total sample according to the WHO definition (Pfor trend <0·05). CONCLUSIONS: Among Tibetan adolescents, the prevalence of overweight and obesity is relatively low, while the prevalence of thinness is high, especially in boys. These data suggest urgent attention is needed to control adolescent thinness in Tibet.

Identification of diverse cell populations in skeletal muscles and biomarkers for intramuscular fat of chicken by single-cell RNA sequencing.

BACKGROUND: The development of skeletal muscle is closely related to the efficiency of meat production and meat quality. Chicken skeletal muscle development depends on myogenesis and adipogenesis and occurs in two phases-hyperplasia and hypertrophy. However, cell profiles corresponding to the two-phase muscle development have yet to be determined. Single-cell RNA-sequencing (scRNA-seq) can elucidate the cell subpopulations in tissue and capture the gene expression of individual cells, which can provide new insights into the myogenesis and intramuscular adipogenesis. RESULTS: Ten cell clusters at the post-hatching developmental stage at Day 5 and seven cell clusters at the late developmental stage at Day 100 were identified in chicken breast muscles by scRNA-seq. Five myocyte-related clusters and two adipocyte clusters were identified at Day 5, and one myocyte cluster and one adipocyte cluster were identified at Day 100. The pattern of cell clustering varied between the two stages. The cell clusters showed clear boundaries at the terminal differentiation stage at Day 100; by contrast, cell differentiation was not complete at Day 5. APOA1 and COL1A1 were selected from up-regulated genes in the adipocyte cluster and found to be co-expressed with the ADIPOQ adipocyte marker gene in breast muscles by RNA in situ hybridization. CONCLUSIONS: This study is the first to describe the heterogeneity of chicken skeletal muscle at two developmental stages. The genes APOA1 and COL1A1 were identified as biomarkers for chicken intramuscular fat cells.

Pregnane X Receptor Regulates Liver Size and Liver Cell Fate by Yes-Associated Protein Activation in Mice.

Activation of pregnane X receptor (PXR), a nuclear receptor that controls xenobiotic and endobiotic metabolism, is known to induce liver enlargement, but the molecular signals and cell types responding to PXR-induced hepatomegaly remain unknown. In this study, the effect of PXR activation on liver enlargement and cell change was evaluated in several strains of genetically modified mice and animal models. Lineage labeling using AAV-Tbg-Cre-treated Rosa26EYFP mice or Sox9-CreERT , Rosa26EYFP mice was performed and Pxr-null mice or AAV Yap short hairpin RNA (shRNA)-treated mice were used to confirm the role of PXR or yes-associated protein (YAP). Treatment with selective PXR activators induced liver enlargement and accelerated regeneration in wild-type (WT) and PXR-humanized mice, but not in Pxr-null mice, by increase of cell size, induction of a regenerative hybrid hepatocyte (HybHP) reprogramming, and promotion of hepatocyte and HybHP proliferation. Mechanistically, PXR interacted with YAP and PXR activation induced nuclear translocation of YAP. Blockade of YAP abolished PXR-induced liver enlargement in mice. Conclusion: These findings revealed a function of PXR in enlarging liver size and changing liver cell fate by activation of the YAP signaling pathway. These results have implications for understanding the physiological functions of PXR and suggest the potential for manipulation of liver size and liver cell fate.

Eliminating Fc N-Linked Glycosylation and Its Impact on Dosing Consideration for a Transferrin Receptor Antibody-Erythropoietin Fusion Protein in Mice.

Erythropoietin (EPO), a hematopoietic growth factor and a promising therapy for Alzheimer's disease, has low permeability across the blood-brain barrier. The transferrin receptor antibody fused to EPO (TfRMAb-EPO) is a chimeric monoclonal antibody that ferries EPO into the brain via the transvascular route. However, TfRMAbs have Fc-effector function-related adverse effects including reticulocyte suppression. To overcome this, we recently developed an effectorless TfRMAb-EPO fusion protein, designated TfRMAb-N292G-EPO, by eliminating the Fc N-linked glycosylation site at position 292 of the antibody heavy chain. The mutant fusion protein showed enhanced plasma clearance and dramatically reduced plasma concentrations compared with the wild-type (WT) nonmutant fusion protein. This increased clearance of the aglycosylated TfRMAb is expected to increase the injection dose of the mutant fusion protein. To provide a basis for future therapeutic uses of this IgG-neurotrophin fusion protein, the current study aimed to characterize the pharmacokinetic profile of this effectorless TfRMAb-N292G-EPO at different doses following different routes of administration in the mouse. Adult C57BL/6J male mice were injected with a single dose (3, 6, 9, or 20 mg/kg; n = 3-6 per dose) of TfRMAb-N292G-EPO through either the subcutaneous (SQ) or intraperitoneal (IP) route. TfRMAb-N292G-EPO plasma concentrations were determined using an enzyme-linked immunosorbent assay. Mice were sacrificed 24 h after injection, and terminal blood was used for a complete blood count. Brain concentrations in the WT- and mutant fusion protein-treated mice were compared. We observed stark differences in the plasma pharmacokinetics of TfRMAb-N292G-EPO between the IP and SQ routes of administration. Dose escalation from 3 to 20 mg/kg increased the plasma Cmax only 3.5-fold for the SQ route, compared with a 35-fold increase for the IP route. The plasma Cmax was 15.0 ± 2.0, 21.3 ± 4.1, 21.3 ± 6.4, and 52.8 ± 27.9 ng/mL following SQ injection and 288 ± 47, 389 ± 154, 633 ± 194, and 10,066 ± 7059 ng/mL following IP injection for 3, 6, 9, and 20 mg/kg doses, respectively. The plasma Cmax following the SQ route was therefore 19- to 190-fold lower than that following the IP route. This finding is consistent with a 31-fold higher apparent clearance following the SQ route compared with the IP route at the highest dose administered. The brain concentrations in the mice treated with a 3 mg/kg dose of the mutant fusion protein were lower than those in the nonmutant WT-treated mice. No reticulocyte suppression was observed at the 3 mg/kg SQ dose of TfRMAb-N292G-EPO. However, reticulocyte suppression increased with an increase in dose and area under the plasma concentration-time curve (AUC) for both the IP and SQ routes. Overall, elimination of Fc N-linked glycosylation, to mitigate TfRMAb effector function side effects, has a profound effect on the plasma exposure of TfRMAb-N292G-EPO at therapeutic as well as high doses (3-20 mg/kg). This effect is more pronounced following SQ injection. The low plasma concentrations of the mutant fusion protein following a 3 mg/kg dose resulted in negligible brain uptake. The beneficial rescue of reticulocyte reduction by the N292G mutation is a function of AUC and is negated at high doses of the N292G mutant.

Astrocyte-Specific Deletion of Sox2 Promotes Functional Recovery After Traumatic Brain Injury.

Injury to the adult brain induces activation of local astrocytes, which serves as a compensatory response that modulates tissue damage and recovery. However, the mechanism governing astrocyte activation during brain injury remains largely unknown. Here we provide in vivo evidence that SOX2, a transcription factor critical for stem cells and brain development, is also required for injury-induced activation of adult cortical astrocytes. Genome-wide chromatin immunoprecipitation-seq analysis of mouse cortical tissues reveals that SOX2 binds to regulatory regions of genes associated with signaling pathways that control glial cell activation, such as Nr2e1, Mmd2, Wnt7a, and Akt2. Astrocyte-specific deletion of Sox2 in adult mice greatly diminishes glial response to controlled cortical impact injury and, most unexpectedly, dampens injury-induced cortical loss and benefits behavioral recovery of mice after injury. Together, these results uncover an essential role of SOX2 in somatic cells under pathological conditions and indicate that SOX2-dependent astrocyte activation could be targeted for functional recovery after traumatic brain injury.

Effects of carnitine palmitoyltransferases on cancer cellular senescence.

The carnitine palmitoyltransferase (CPT) family is essential for fatty acid oxidation. Recently, we found that CPT1C, one of the CPT1 isoforms, plays a vital role in cancer cellular senescence. However, it is unclear whether other isoforms (CPT1A, CPT1B, and CPT2) have the same effect on cellular senescence. This study illustrates the different effects of CPT knockdown on PANC-1 cell proliferation and senescence and MDA-MB-231 cell proliferation and senescence, as demonstrated by cell cycle kinetics, Bromodeoxyuridine incorporation, senescence-associated ß-galactosidase activity, colony formation, and messenger RNA (mRNA) expression of key senescence-associated secretory phenotype factors. CPT1C exhibits the most substantial effect on cell senescence. Lipidomics analysis was performed to further reveal that the knockdown of CPTs changed the contents of lipids involved in mitochondrial function, and lipid accumulation was induced. Moreover, the different effects of the isoform deficiencies on mitochondrial function were measured and compared by the level of radical oxygen species, mitochondrial transmembrane potential, and the respiratory capacity, and the expression of the genes involved in mitochondrial function were determined at the mRNA level. In summary, CPT1C exerts the most significant effect on mitochondrial dysfunction-associated tumor cellular senescence among the members of the CPT family, which further supports the crucial role of CPT1C in cellular senescence and suggests that inhibition of CPT1C may represent as a new strategy for cancer treatment through the induction of tumor senescence.

Correction to: Endometrium metabolomic profiling reveals potential biomarkers for diagnosis of endometriosis at minimal-mild stages.

The authors regret that the incorrect identification of "omega-3 arachidonic acid" published in the original manuscript [1].