The influence of exposure to inorganic arsenic and other arsenic species on early renal impairment among young adults in Taiwan.

Chronic kidney disease (CKD) poses a significant global public health challenge, with environmental toxins potentially contributing to its prevalence. In Taiwan, where arsenic (As) contamination is endemic in certain areas, assessing its impact on renal health is crucial due to the country's high rates of unexplained CKD. This cross-sectional study assessed associations between urinary As species and early renal impairment biomarkers-the microalbumin-to-creatinine ratio (ACR) and ß2-microglobulin (B2MG)-in 248 young Taiwanese adults (aged 20-29 years). We measured urinary As species (including arsenite [As3+], arsenate [As5+], monomethylarsonic acid [MMA], and dimethylarsinic acid [DMA]) and early renal impairment biomarkers (urinary microalbumin and B2MG levels). Median concentrations of urinary As3+, As5+, MMA, DMA, inorganic As (iAs), and the sum of inorganic and methylated As species (iSumAs) were 1.43, 1.02, 3.79, 31.53, 2.82, and 39.22 µg/g creatinine (Cre.), respectively. We also evaluated the first methylation ratio (FMR) and the second methylation ratio (SMR). After adjusting for potential confounding factors, a multivariate linear regression showed significant associations between B2MG and urinary As5+ (ß = 0.299, 95% confidence interval [CI]: 0.113-0.485) and iAs (ß = 0.281, 95% CI: 0.061-0.502) concentrations. A generalized additive model revealed non-linear relationships among As5+, iAs, and B2MG concentrations. Moreover, there were elevated risks associated with the highest tertile of B2MG concentrations compared to the highest tertile of urinary As5+ (odds ratio [OR] = 2.366, 95% CI: 1.196-4.682), MMA (OR = 1.917, 95% CI: 1.002-3.666), DMA (OR = 1.952, 95% CI: 1.015-3.753), and iSumAs (OR = 2.302, 95% CI: 1.182-4.483). These results indicated that exposure to As was associated with early renal impairment, particularly evidenced by increased urinary B2MG concentrations.

Comparative Effects of Diabetes Self-Management Programs on Type 2 Diabetes Clinical Outcomes: A Systematic Review and Network Meta-Analysis.

AIMS: This systematic review and network meta-analysis compared the effects of various diabetes self-management programs: Diabetes Self-Management Education (DSME), Diabetes Self-Management Support (DSMS), and Diabetes Self-Management Education and Support (DSMES). METHODS: We searched four electronic databases for eligible articles up to March 1, 2023. Only randomized controlled trials investigating the effects of DSME, DSMS, or DSMES on glycated haemoglobin (HbA1c) level, fasting blood glucose (FBG), total cholesterol (TC), systolic blood pressure (SBP), and diastolic blood pressure (DBP) in adults with type 2 diabetes were included. Cochrane Risk of Bias 2.0 tool was used to assess each study quality, and Confidence in Network Meta-Analysis was applied to evaluate the certainty of the evidence. Data were pooled with a random-effects model under a frequentist framework. RESULTS: A total of 108 studies encompassing 17,735 participants (mean age 57.4 years) were analysed. DSMES, compared with usual care, significantly reduced HbA1c level (mean difference = -0.61%, 95% confidence interval [CI] = -0.74 to -0.49; certainty of evidence = moderate), FBG (-23.33 mg/dL; -31.33 to -15.34; high), TC (-5.62 mg/dL; -8.69 to -2.55; high), SBP (-3.05 mmHg; -5.20 to -0.91; high), and DBP (-2.15 mmHg; -3.36 to -0.95; high). Compared with DSME, DSMES showed significantly greater improvements in HbA1c levels (-0.23%; -0.40 to -0.07; high) and DBP (-1.82 mmHg; -3.47 to -0.17; high). DSMES was ranked as the top treatment for improving diabetes clinical outcomes (0.82-0.97) in people with type 2 diabetes. CONCLUSIONS: DSMES, in people with type 2 diabetes, yields the greatest improvement in the key clinical outcomes of HbA1c, fasting blood glucose, and blood pressure levels. Healthcare providers should incorporate the DSMES approach into their daily care routines. Approximately 30% of the studies reviewed raised some concerns about their quality, underscoring the need for high-quality studies in this area.

Lipidomics reveals ceramide biomarkers for detecting central precocious puberty in girls.

BACKGROUND: Pubertal timing is modulated by complex interactions between the pituitary and gonadal sex steroid hormones. Evidence indicates that sphingolipids are involved in the biosynthesis of steroid hormones at multiple levels. METHOD: This study recruited adolescent female patients from pubertal and pediatric endocrine clinics in Northern and Southern Taiwan from the Taiwan Puberty Longitudinal Study. A total of 112 plasma samples (22 healthy control, 29 peripheral precocious puberty (PPP), and 61 CPP samples) were collected. We extracted lipids from the plasma samples using the modified Folch method. The un-targeted ultrahigh-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was employed for the lipid analysis. RESULTS: We identified sphingolipid-linked metabolites, including Cer(18:0/15:0), Cer(18:1/16:0), and Cer(18:1/26:0) as candidate biomarkers for distinguishing girls with CPP from the control group by using an excellent discrimination model (AUC = 0.964). Moreover, Cer(18:0/22:0) and Cer(d18:0/18:1) were identified as potential biomarkers of PPP, with an AUC value of 0.938. Furthermore, CerP(18:1/18:0) was identified as the sole candidate biomarker capable of differentiating CPP from PPP. CONCLUSIONS: The biomarkers identified in this study can facilitate the accurate detection of CPP in girls, provide insights into lipid-linked pathophysiology, and present a novel method of monitoring the progression of this disorder.

Natural sweetener glycyrrhizin protects against precocious puberty by modulating the gut microbiome.

AIMS: Precocious puberty (PP) may lead to many adverse outcomes. Recent evidence suggests that PP is a gut-brain disease. On the other hand, the use of glycyrrhizin, a natural sweetener, has become popular in the past decade. Glycyrrhizin possesses various health benefits, but its impact on PP has yet to be investigated. We aimed to explore the protective effects of glycyrrhizin against PP in both humans (observational) and animals (interventional). MATERIALS AND METHODS: In the human cohort, we investigated the association between glycyrrhizin consumption and risk of PP. In the animal experiment, we observed puberty onset after feeding danazol-induced PP rats with glycyrrizin. Blood, fecal, and hypothalamic samples were harvested to evaluate potential mechanistic pathways. We also performed a fecal microbiota transplantation to confirm to causal relationship between glycyrrhizin and PP risk. KEY FINDINGS: Glycyrrhizin exhibited a protective effect against PP in children (OR 0.60, 95%CI: 0.39-0.89, p = 0.013), primarily driven by its significance in girls, while no significant effect was observed in boys. This effect was consistent with findings in rodents. These benefits were achieved through the modulation of the gut microbiome, which functionally suppressed the hypothalamic-pituitary-gonadal axis and prevented PP progression. A fecal microbiota transplantation indicated that the causal correlation between glycyrrhizin intake and PP is mediated by the gut microbiome alterations. SIGNIFICANCE: Our findings suggest that glycyrrhizin can protect against PP by altering the gut microbiome. Long term use of glycyrrhizin is safe and tolerable. Therefore, glycyrrhizin can serve as a safe and affordable complementary therapy for PP.

The effects of dietary macronutrient composition on resting energy expenditure following active weight loss: A systematic review and meta-analysis.

A systematic review and meta-analysis was conducted to evaluate the relative effectiveness of different dietary macronutrient patterns on changes in resting energy expenditure (REE) in relation to weight loss, categorized as minimal (<5%) and moderate to high (>5%). Changes in REE were assessed using a DerSimonian and Laird random-effects meta-analysis. A diet lower in carbohydrates (CHO) or higher in fat and protein was associated with smaller reductions in REE, with these trends being more pronounced among participants who experienced moderate to high weight loss. Adjusted meta-regression analysis indicated that, within the participants who experienced moderate to high weight loss, each 1% increase in CHO intake was associated with a reduction of 2.30 kcal/day in REE (95% CI: -4.11 to -0.47, p = 0.013). In contrast, a 1% increase in protein and fat intake was correlated with an increase in REE by 3.00 (95% confidence interval [CI] [1.02, 5.07], p = 0.003) and 0.5 (95% CI [-2.43, 3.41], p = 0.740) kcal/day, respectively. No significant associations were found among participants who experienced minimal weight loss. These findings indicate that, under a caloric deficit, the impact of dietary macronutrient composition on REE may vary depending on the degree of weight loss and individual metabolic responses.

Systolic blood pressure as a critical mediator in the association between adult height and 25-year risk of stroke.

BACKGROUND: Adult height is associated with the risk of stroke. However, the underlying mechanism remains unclear. We explored the mediating role of metabolic factors in the association between adult height and stroke incidence. METHODS: We used data from 3306 community-dwelling participants with complete information on adult height, metabolic factors, and 25-year cardiovascular outcomes. Participants were classified into three adult height groups based on sex-specific height quartiles: short (Q1), average (Q2-Q3), and tall (Q4). The primary endpoint was the occurrence of cardiovascular disease, including coronary artery disease and stroke. RESULTS: Taller adult height was associated with a lower risk of stroke. Compared with the short group the risk of stroke reduced with taller height with a hazard ratio (HR) of 0.68 in the average group (95% confidence interval [CI]: 0.50-0.93), and 0.45 in the tall group (95% CI: 0.31-0.65). Low systolic blood pressure was considered as a protective mediator in the effect of adult height on the risk of stroke in the average (HR: 0.86; 95% CI: 0.82-0.93) and the tall group (HR: 0.85; 95% CI: 0.78-0.91). Systolic blood pressure significantly contributed to height-related stroke risk (proportion mediated: 0.41; 95% CI: 0.19-1.56). CONCLUSIONS: This study found an inverse association between adult height and stroke risk, which is partly driven by lower systolic blood pressure. These findings highlight the importance of systolic blood pressure management as a potential preventive strategy against stroke.

Aspartame Intake Delayed Puberty Onset in Female Offspring Rats and Girls.

SCOPE: The disturbance of the hypothalamic-pituitary-gonadal (HPG) axis, gut microbiota (GM) community, and short-chain fatty acids (SCFAs) is a triggering factor for pubertal onset. The study investigates the effects of the long-term intake of aspartame on puberty and GM in animals and humans. METHODS AND RESULTS: Aspartame-fed female offspring rats result in vaginal opening time prolongation, serum estrogen reduction, and serum luteinizing hormone elevation. , 60 mg kg-1 aspartame treatment decreases the mRNA levels of gonadotropin-releasing hormone (GnRH), Kiss1, and G protein-coupled receptor 54 (GPR54), increases the mRNA level of RFamide-related peptide-3 (RFRP-3), and decreases the expression of GnRH neurons in the hypothalamus. Significant differences in relative bacterial abundance at the genus levels and decreased fecal SCFA levels are noted by 60 mg kg-1 aspartame treatment. Among which, Escherichia-Shigella is negatively correlated with several SCFAs. In girls, high-dose aspartame consumption decreases the risk of precocious puberty. CONCLUSIONS: Aspartame reduces the chance of puberty occurring earlier than usual in female offspring and girls. Particularly, 60 mg kg-1 aspartame-fed female offspring delays pubertal onset through the dysregulation of HPG axis and GM composition by inhibiting the Kiss1/GPR54 system and inducing the RFRP-3. An acceptable dose of aspartame should be recommended during childhood.

Sleep deprivation alters pubertal timing in humans and rats: the role of the gut microbiome.

STUDY OBJECTIVES: Evidence implied that sleeping duration is associated with the timing of puberty and that sleep deprivation triggers early pubertal onset in adolescents. Sleep deprivation can affect metabolic changes and gut microbiota composition. This study investigated the effects of sleep deprivation on pubertal onset and gut microbiota composition in animal models and a human cohort. METHODS: This study comprised 459 boys and 959 girls from the Taiwan Pubertal Longitudinal Study. Sleep duration was evaluated using the self-report Pittsburgh Sleep Quality Index questionnaire. Early sexual maturation was defined by pediatric endocrinologist assessments. Mediation analyses were done to examine the association between sleep parameters, obesity, and early sexual maturation. Besides, Sprague Dawley juvenile rats were exposed to 4 weeks of chronic sleep deprivation. Vaginal opening (VO) and preputial separation (PS) were observed every morning to determine pubertal onset in female and male rats. RESULTS: The sleep-deprived juvenile rats in the sleep-deprived-female (SDF) and sleep-deprived-male (SDM) groups experienced delayed VO (mean VO days: 33 days in control; 35 days in SDF; p-value < 0.05) and PS (mean PS days: 42 days in control; 45 days in SDM; p-value < 0.05), respectively. Relative to their non-sleep-deprived counterparts, the sleep-deprived juvenile rats exhibited lower body weight and body fat percentage. Significant differences in relative bacterial abundance at genus levels and decreased fecal short-chain-fatty-acid levels were identified in both the SDF and SDM groups. In the human cohort, insufficient sleep increased the risk of early sexual maturation, particularly in girls (OR, 1.44; 95% CI: 1.09 to 1.89; p-value < 0.01). Insufficient sleep also indirectly affected early sexual maturation in girls, with obesity serving as the mediator. CONCLUSIONS: Overall, sleep deprivation altered the timing of puberty in both animal and human models but in different directions. In the rat model, sleep deprivation delayed the pubertal onset in juvenile rats through gut dysbiosis and metabolic changes, leading to a low body weight and body fat percentage. In the human model, sleep deprivation led to fat accumulation, causing obesity in girls, which increased the risk of early puberty.

Associations of central precocious puberty with blood pressure trajectories: prospective cohort study.

BACKGROUND: Sex differences in blood pressure (BP) appear during childhood and adolescence, but the role of central precocious puberty (CPP) remains unclear. In this study, we aimed to examine the association of CPP with the risk of early hypertension and BP trajectories in girls and boys. METHODS: We analyzed trajectories of BP before and after puberty in girls aged 6-13 years (n = 305) and boys aged 10-15 years (n = 153) in the Taiwan Pubertal Longitudinal Study. The timing of puberty onset was defined as the month at which the children reached Tanner stage 2. We examined the association of CPP with the risk of early hypertension and BP trajectories before and after puberty onset. RESULTS: Among boys, CPP was found to be associated with early hypertension (odds ratio, 7.45 [95% CI, 1.15-48.06]), whereas no such association was observed among girls. Boys with CPP had higher systolic BP than did those with normal puberty onset before puberty onset (mean difference, 6.51 [95% CI, 0.58-12.43]) and after puberty onset (mean difference, 8.92 [95% CI, 8.58-15.26]). CONCLUSION: A large proportion of the higher systolic BP observed in boys with CPP compared with in those with normal puberty onset is accrued after puberty. IMPACT: We examined the sex-specific association of central precocious puberty with blood pressure trajectories to better understand whether central precocious puberty was associated with early hypertension. Central precocious puberty was associated with differences in systolic blood pressure trajectories, especially after puberty onset in boys. For boys only, central precocious puberty was associated with early hypertension. A large proportion of the higher systolic blood pressure observed in boys with central precocious puberty compared with in those with normal puberty onset was accrued after puberty. Interventions targeting central precocious puberty are likely to influence systolic blood pressure in early adulthood.

Dietary nitrate, nitrite, and nitrosamine in association with diabetes: a systematic review and meta-analysis.

CONTEXT: Diabetes is a global health concern, and diet is a contributing factor to diabetes. Findings regarding the connection between nitrate, nitrite, and nitrosamine and diabetes risk are inconsistent. OBJECTIVE: The aim was to examine the effects of these dietary compounds on diabetes risk. DATA SOURCES: The data were sourced from PubMed, EMBASE, Scopus, and Web of Science until February 28, 2023. Studies that reported individual-level consumption of these compounds were included. Review articles or ecological studies were excluded. DATA EXTRACTION: The number of events and total observations were recorded. DATA ANALYSIS: The pooled odds ratio (OR) was calculated and displayed in a forest plot. Subgroup and sensitivity analyses were predefined. A dose-response meta-analysis was conducted to determine the exposure intervals that may increase the risk of disease. Six observational reports that met the inclusion criteria were included, involving 108 615 individuals. Participants in the highest quantile of nitrite intake had a greater risk of diabetes compared with those in the lowest quantile (OR, 1.61; 95% confidence interval [CI], 1.08-2.39; I2 = 74%, P = 0.02). Higher nitrosamine consumption tended to increase diabetes risk (OR, 1.52; 95% CI, 0.76-3.04; I2 = 76%; P = 0.24). The relationship was stronger for type 1 (OR, 1.79; 95% CI, 1.20-2.67; I2 = 58%; P < 0.01) than for type 2 diabetes (OR, 1.42; 95% CI, 0.86-2.37; I2 = 71%; P = 0.17). Additionally, nitrite consumption had a dose-dependent association with both phenotypes. No association was found between diabetes risk and high nitrate intake (OR, 1.01; 95% CI, 0.87-1.18; I2 = 28%; P = 0.87). CONCLUSION: Attention should be paid to the consumption of nitrite-containing foods. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42023394462 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=394462).

Comparative efficacy of digitally assisted interventions for glycated haemoglobin levels among patients with type 2 diabetes: A systematic review and component network Meta-Analysis.

AIMS: To compare the efficacy of digitally assisted interventions on the glycated haemoglobin (HbA1c) levels of patients with type 2 diabetes by performing a systematic review, network meta-analysis and component network meta-analysis. METHODS: Six databases were searched to identify eligible articles from the inception of each database until 17 March 2023. We included randomized controlled trials evaluating HbA1c levels. Data were pooled with a random-effects model under a frequentist framework. The evidence certainty was assessed using Confidence in Network MetaAnalysis (CINeMA). The PROSPERO registration number was CRD42021283815. RESULTS: In total, 75 trials involving 9764 participants were included. Results from standard network meta-analyses of 17 interventions revealed that compared with standard care, a mobile application (MA) combined with a professional education programme and peer support education (PSE; -1.98, 95% confidence interval = -2.90 to -1.06, CINeMA score: moderate to high) significantly reduced HbA1c levels. The component analysis found that PSE (-1.50, -2.36 to -0.64), SMS (-0.33, -0.56 to -0.11), MA (-0.30, -0.56 to -0.04) and telephone calls (-0.30, -0.53 to -0.06) most effectively reduced HbA1c levels among patients with type 2 diabetes. CONCLUSIONS: SMS and MA are the optimal digitally assisted interventions for reducing HbA1c levels. Educators can integrate digitally assisted interventions complemented by educational programmes, particularly MA combined with professional education programme and PSE, into daily care to control HbA1c. The limitations of included trials include a lack of information on allocation concealment and blinding and the fact that long-term follow-up effects were not investigated.

Effects of Testosterone Replacement Therapy on Muscle Strength in Older Men with Low to Low-Normal Testosterone Levels: A Systematic Review and Meta-Analysis.

BACKGROUND: Previous studies and meta-analyses have explored the relationship among testosterone, muscle strength, and physical function, to the best of our knowledge, no meta-analysis has investigated the effects of testosterone replacement therapy (TRT) on subgroup of relatively hypogonadal older men. OBJECTIVE: The aim of this study was to evaluate the effect of TRT in older men with low testosterone levels. METHODS: PubMed, Embase, and Web of Science were systematically searched for articles published between January 1990 and April 2020. We included randomized controlled studies that investigated the effect of TRT and included older men (age >60 years) with relatively low testosterone levels. Studies were extracted following the PRISMA flowchart, and the included randomized controlled trials were evaluated using RoB 2.0. Our main outcome was muscle strength changes after TRT evaluated using a metaregression of confounding factors. Secondary outcomes included changes in physical performance and the risk ratio of adverse events. Random-effects meta-analyses of TRT on muscle strength and physical function were performed. RESULTS: Thirteen studies with 2,043 patients were included. The mean age of subjects in various studies ranged from 65.9 years to 76 years. Transdermal testosterone dosages ranged from 5 to 10 g/day, while intramuscular options were 125 mg/week or 200 mg every 2 weeks. Oral testosterone supplementation was given at 160 mg/day in one study. Pooled meta-analyses revealed greater muscle strength improvement after TRT compared with placebo (Hedges' g = 0.21; 95% CI: = 0.15-0.28). Intramuscular administration of TRT had greater efficacy (Hedges' g = 0.74; 95% CI: = 0.34-1.14) than transdermal and oral TRT (p < 0.001). A metaregression revealed that baseline serum total testosterone was associated with muscle strength improvement (ß = -0.004, p = 0.002). The risk ratios of adverse events, including elevated prostate-specific antigen, acute coronary syndrome, and prostate cancer, were not significantly different. CONCLUSION: TRT improved muscle strength in older, relatively hypogonadal men. The effect was more pronounced in populations with lower baseline testosterone levels.

Maternal Omega-3 Supplementation During Pregnancy, but Not Childhood Supplementation, Reduces the Risk of Food Allergy Diseases in Offspring.

BACKGROUND: Omega-3 supplementation has been reported to modulate immune responses and prevent food allergies among children; however, findings are inconsistent, and the timing of supplementation, which is critical, has not been thoroughly investigated. OBJECTIVE: To assess optimal timing (maternal vs childhood intake) of omega-3 supplementation for reducing food allergy risk among children in 2 periods (the first 3 years and beyond 3 years of age). METHODS: We performed a meta-analysis to assess the effects of maternal or childhood omega-3 supplementation on preventing the development of infant food allergies and food sensitizations. The PubMed/MEDLINE, Embase, Scopus, and Web of Science databases were searched for related studies published until October 30, 2022. We conducted dose-response and subgroup analyses to investigate the effects of omega-3 supplementation. RESULTS: We found that maternal omega-3 supplementation during pregnancy and lactation was significantly associated with decreased risks of infant egg sensitization (relative risk [RR]: 0.58, 95% confidence interval [95% CI]: 0.47-0.73, P < .01) and peanut sensitization (RR: 0.62, 95% CI: 0.47-0.80, P < .01) among children. Similar results were found in subgroup analyses for food allergy, egg sensitization, and peanut sensitization during the first 3 years of age and peanut sensitization and cashew nut sensitization beyond 3 years of age. Dose-response analysis showed a linear relationship between maternal omega-3 supplementation and infant egg sensitization risk during early life. By contrast, intake of omega-3 polyunsaturated fatty acid during childhood did not appear to significantly protect against food allergies. CONCLUSIONS: Maternal omega-3 supplementation during pregnancy and lactation, rather than childhood intake, reduces the risk of infant food allergy and food sensitization.

Effects of Nonnutritive Sweeteners on Body Composition Changes during Pubertal Growth.

The effects of consuming specific types of nonnutritive sweeteners (NNSs) on adiposity changes in children have remained inconsistent. In this study, we aimed to investigate the effects of the intake of different kinds of NNSs on long-term adiposity changes during pubertal growth. Furthermore, we examined the above relationships among different sexes, pubertal stages, and levels of obesity. A total of 1893 6-15-year-old adults were recruited and followed-up every 3 months. The NNS-FFQ (Food Frequency Questionnaire) was conducted and urine samples were collected to investigate the effects of the selected sweeteners, which included acesulfame potassium, aspartame, sucralose, glycyrrhizin, steviol glycosides, and sorbitol. Multivariate linear mixed-effects models were used to examine the relationship between NNS intake and body composition. The consumption of aspartame, sucralose, glycyrrhizin, stevioside, and sorbitol was associated with decreased fat mass and increased fat-free mass. In the highest tertile group, the effects of NNS consumption on fat mass corresponded to values of -1.21 (95% CI: -2.04 to -0.38) for aspartame, -0.62 (95% CI: -1.42 to 0.19) for sucralose, -1.26 (95% CI: -2.05 to -0.47) for glycyrrhizin, -0.90 (95% CI: -2.28 to 0.48) for stevioside, and -0.87 (95% CI: -1.67 to -0.08) for sorbitol, while the effects on fat-free mass corresponded to values of 1.20 (95% CI: 0.36 to -0.38) for aspartame, 0.62 (95% CI: -0.19 to 1.43) for sucralose, 1.27 (95% CI: 0.48 to 2.06) for glycyrrhizin, 0.85 (95% CI: -0.53 to 2.23) for stevioside, and 0.87 (95% CI: 0.08 to 1.67) for sorbitol. Particularly, aspartame and sorbitol revealed a dose-responsiveness effect. The above finding was more prominent among girls than boys. Moreover, fat mass was significantly reduced in normal-weight children who consumed a moderate amount of aspartame and a large amount of glycyrrhizin and sorbitol compared with obese children. In conclusion, the NNS-specific and sex-specific effects of long-term NNS consumption revealed associations of decreasing fat mass and increasing fat-free mass for children undergoing pubertal growth.

Corrigendum: Systolic blood pressure as the mediator of the effect of early menarche on the risk of coronary artery disease: A Mendelian randomization study.

[This corrects the article DOI: 10.3389/fcvm.2022.1023355.].

Hypertension as a Novel Link for Shared Heritability in Age at Menarche and Cardiometabolic Traits.

CONTEXT: Extremely early age at menarche, also called precocious puberty, has been associated with various cardiometabolic traits, but their shared heritability remains unclear. OBJECTIVES: This work aimed to identify new shared genetic variants and their pathways for age at menarche and cardiometabolic traits and to investigate the influence of central precocious puberty on childhood cardiometabolic traits. METHODS: Using the conjunction false discovery rate method, this study analyzed genome-wide association study data from the menarche-cardiometabolic traits among 59 655 females of Taiwanese ancestry and systemically investigated pleiotropy between age at menarche and cardiometabolic traits. To support the novel hypertension link, we used the Taiwan Puberty Longitudinal Study (TPLS) to investigate the influence of precocious puberty on childhood cardiometabolic traits. RESULTS: We discovered 27 novel loci, with an overlap between age at menarche and cardiometabolic traits, including body fat and blood pressure. Among the novel genes discovered, SEC16B, CSK, CYP1A1, FTO, and USB1 are within a protein interaction network with known cardiometabolic genes, including traits for obesity and hypertension. These loci were confirmed through demonstration of significant changes in the methylation or expression levels of neighboring genes. Moreover, the TPLS provided evidence regarding a 2-fold higher risk of early-onset hypertension that occurred in girls with central precocious puberty. CONCLUSION: Our study highlights the usefulness of cross-trait analyses for identifying shared etiology between age at menarche and cardiometabolic traits, especially early-onset hypertension. The menarche-related loci may contribute to early-onset hypertension through endocrinological pathways.

Aspartame consumption during pregnancy impairs placenta growth in mice through sweet taste receptor-reactive oxygen species-dependent pathway.

The prevalence of obesity has risen dramatically over recent years, and so has the prevalence of adverse obesity-associated pregnancy outcomes. To combat obesity, the calorie contents of many foods and beverages may be reduced by the use of artificial sweeteners, such as aspartame. However, animal studies suggest that aspartame and its metabolites may exhibit toxicity, and the effects of aspartame on pregnancy are largely unknown. In this study, we treated pregnant mice with aspartame by oral gavage and found that the treatment decreased fasting blood glucose level, whereas systolic blood pressure was elevated. Importantly, the aspartame-treated animals also had low placenta and fetus weights, as well as reduced thickness of the placenta decidua layer. Moreover, aspartame decreased the expression of epithelial-mesenchymal transition proteins and manganese superoxide dismutase (MnSOD) in mouse placentae. In order to clarify the mechanisms though which aspartame affects placenta, we performed experiments on 3A-sub-E trophoblasts. In the cells, aspartame treatments induced cell cycle arrest and reduced the proliferation rate, epithelial-mesenchymal transition, migration activity and invasion activity. We also found that aspartame increased reactive oxygen species (ROS) levels to hyper-activate Akt and downregulate MnSOD expression. Pretreatment with antioxidants or sweet taste receptor inhibitors reversed the effects of aspartame on trophoblast function. We also found that the aspartame metabolite phenylalanine similarly induced ROS production and affected proliferation of trophoblasts. Taken together, our data suggest that aspartame consumption during pregnancy may impact the structure, growth and function of the placenta via sweet taste receptor-mediated stimulation of oxidative stress.

Predictors of time to relapse following ustekinumab withdrawal in patients with psoriasis who had responded to therapy: An 8-year multicenter study.

BACKGROUND: Data on predictors and time to relapse in patients with psoriasis who discontinue therapy in a real-world setting are scarce. OBJECTIVE: To investigate predictors of relapse after withdrawal of ustekinumab in patients with psoriasis. METHOD: This study screened 500 patients with psoriasis who received ustekinumab (669 treatment episodes) between 2011 and 2018. Overall, 202 patients (accounting for 304 treatment episodes) who had responded to therapy and were withdrawn from ustekinumab treatment were included. RESULTS: The cumulative probabilities of being relapse-free at 6, 12, 18, 24, and 36 months after withdrawal from ustekinumab treatment were 49.3%, 12.6%, 5.3%, 4.7%, and 1.6%, respectively. Multivariate regression analyses with a generalized estimating equation showed that after adjustments, biologic-naive status, maximum improvement in Psoriasis Area and Severity Index during ustekinumab treatment, time to achieve a 50% improvement in baseline Psoriasis Area and Severity Index score after initiation of ustekinumab, family history of psoriasis, chronic kidney disease, and immunosuppressant use while not taking ustekinumab were significant predictors of time to relapse following discontinuation of ustekinumab. LIMITATION: Nonrandomized allocation of duration of treatment and follow-up. CONCLUSION: Given the high rates of relapse, withdrawal of ustekinumab from patients with well-controlled psoriasis cannot be recommended.

Association between genetic risk score and tri-ponderal mass index growth trajectories among different dietary consumption adolescents in a prospective Taiwanese cohort.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in various genetic loci are associated with childhood obesity; however, their influence on adolescent growth patterns has rarely been explored. This study investigated whether genetic variants could predict tri-ponderal mass index (TMI)-derived growth trajectories and the interaction between genetic and dietary factors. METHODS: We conducted Taiwan Puberty Longitudinal Study, a prospective cohort that recruited 1,135 children since 2018. Anthropometric measurements were recorded every three months, while dietary nutrition assessment and biological sampling for genotyping were collected during the first visit. TMI growth trajectory groups were identified using growth mixture modeling. A multinomial logistic regression model for different growth trajectories was used to examine the effect of candidate SNPs, and the most related SNPs were used to establish the genetic risk score. We then explored the effect of the genetic risk score in subgroup analysis according to dietary calories and different dietary consumption patterns. RESULTS: Three TMI-based growth trajectory groups were identified among adolescents. The "increased weight" trajectory group accounted for approximately 9.7% of the participants. FTO/rs7206790 was associated with the increased weight growth trajectory after adjusting for the baseline TMI and other correlated covariates (OR: 2.13, 95% CI: 1.08-4.21). We generated the genetic risk score using 4 SNPs (FTO/rs7206790, ADCY9/rs2531995, TFAP2B/rs4715210, and TMEM18/rs6548238) and selected the threshold of 10 points to define risk categories. There were 11.66% and 3.24% of participants belonged to the increased weight trajectory in high- and low-risk groups, respectively; and the predictive ability of the genetic risk score was notable among low calories intake participants (OR: 1.90, 95% CI: 1.18-3.05 vs. OR: 1.17, 95% CI: 0.78-1.75 in high calories intake group). CONCLUSION: Our results offer a new perspective on the genetic and dietary basis of changes in adolescent obesity status. Individualized interventions for obesity prevention may be considered among high-risk children.

Association of the consumption of common drinks with early puberty in both sexes.

Background: We examined the effect of sugar-sweetened beverages (SSB) and common drink intake on pubertal development in both sexes. Methods: Data were retrieved from Taiwan Children Health Study, which involved detailed pubertal stage assessments of 2,819 schoolchildren aged 11 years in 2011-2012. Drawings of secondary sexual characteristics and self-reported age at menarche or voice breaking were used to assess pubertal stages. Dietary intake was assessed using a detailed semi-quantitative food frequency questionnaire. Generalized estimating equation modeling was applied to obtain odds ratios (ORs) and 95% confidence intervals (CIs) to represent the effects of each drink on early pubertal development outcomes. Results: In boys, an one cup/day increment of a SSB was associated with earlier voice breaking (ß = -0.12; 95% CI = -0.20, -0.04), whereas consuming yogurt (≥2 cups/day) was a protective factor against early puberty (OR = 0.78; 95% CI = 0.73, 0.83). In girls, SSB consumption was associated with increased risk of early puberty in a dose-response manner, and a similar protective effect of yogurt consumption and fermented probiotic drink (≥2 cups/day) against early puberty was observed (OR = 0.96; 95% CI = 0.94, 0.99). Furthermore, the intake of both total sugar and added sugar within SSBs increased risk of early puberty in girls but not in boys. Conclusions: Sugar-sweetened beverages were associated with early puberty, and probiotic drinks appeared to mitigate this link. These findings indicate that the gut-brain axis could play a crucial role in sexual maturation.