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Background Accumulating evidence suggests that consuming coffee may lower the risk of death, but evidence regarding tea consumption in Asians is limited. We examined the association between coffee and tea consumption and mortality in Asian populations. Methods We used data from 12 prospective cohort studies including 248 050 men and 280 454 women from the Asia Cohort Consortium conducted in China, Japan, Korea and Singapore. We estimated the study-specific association of coffee, green tea and black tea consumption with mortality using Cox proportional-hazards regression models and the pooled study-specific hazard ratios (HRs) using a random-effects model. Results In total, 94 744 deaths were identified during the follow-up, which ranged from an average of 6.5 to 22.7 years. Compared with coffee non-drinkers, men and women who drank at least five cups of coffee per day had a 24% [95% confidence interval (CI) 17%, 29%] and a 28% (95% CI 19%, 37%) lower risk of all-cause mortality, respectively. Similarly, we found inverse associations for coffee consumption with cardiovascular disease (CVD)-specific and cancer-specific mortality among both men and women. Green tea consumption was associated with lower risk of mortality from all causes, CVD and other causes but not from cancer. The association of drinking green tea with CVD-specific mortality was particularly strong, with HRs (95% CIs) of 0.79 (0.68, 0.91) for men and 0.78 (0.68, 0.90) for women who drank at least five cups per day of green tea compared with non-drinkers. The association between black tea consumption and mortality was weak, with no clear trends noted across the categories of consumption. Conclusions In Asian populations, coffee consumption is associated with a lower risk of death overall and with lower risks of death from CVD and cancer. Green tea consumption is associated with lower risks of death from all causes and CVD.

Background: Limited research has been conducted on the effect of quality diet index (QDI), which represents a comprehensive assessment of healthy diet quality and quantity, on pancreatic cancer risk in Asian populations. Methods: Using data from the Singapore Chinese Health Study, a prospective cohort of 63,257 middle-aged or older Chinese men and women, four QDI scores: the Alternative Health Eating Index-2010 (AHEI-2010), the alternate Mediterranean Diet (aMED), the Dietary Approaches to Stop Hypertension (DASH), and the Heathy Diet Indicator (HDI), at baseline were calculated. After 25 years of follow-up, 311 cohort participants developed pancreatic cancer. Cox proportional hazard regression method was used to estimate HR and 95% confidence interval (CI) for pancreatic cancer associated with higher QDI scores. Results: Higher scores of AHEI-2010, aMED, and DASH were significantly associated with lower pancreatic cancer risk (all Ptrend < 0.05). Compared with the lowest quartile, HRs (95% CIs) of pancreatic cancer for the highest quartiles of AHEI-2010, aMED, and DASH scores were 0.65 (0.46–0.90), 0.57 (0.38–0.85), and 0.66 (0.46–0.95), respectively. These associations were more apparent among men. Overall, there was no statistically significant difference in the QDI–pancreatic cancer risk association between subgroups stratified by levels of body mass index, history of diabetes, and smoking status. Conclusions: Higher QDI scores were significantly associated with reduced risk of pancreatic cancer. Impact: The consistent results across multiple QDIs shows that adherence to a healthy diet may lower pancreatic cancer risk, suggesting that dietary modification may be a promising approach for primary prevention of pancreatic cancer.

Background Little is known about the time course of mortality reduction following smoking cessation in Asians who have smoking behaviours distinct from their Western counterparts. We evaluated the level of reduction in all-cause, cardiovascular disease (CVD) and lung cancer mortality by years since quitting smoking, in Asia. Methods Using Cox regression, we analysed individual participant data (n = 709 151) from 16 prospective cohorts conducted in China, Japan, Korea/Singapore, and India/Bangladesh, separately by cohorts. Cohort-specific hazard ratios (HRs) were combined using a random-effects meta-analysis. Results During a mean follow-up of 12.0 years, 108 287 deaths were ascertained—35 658 from CVD and 7546 from lung cancer. Among Asian men, a dose-response relationship of risk reduction in deaths from all causes, CVD and lung cancer was observed with an increase in years after smoking cessation. Compared with never smokers, however, all-cause and CVD mortality among former smokers remained elevated 10–14 years after quitting [multivariable-adjusted HR (95% confidence interval (CI) = 1.25 (1.13–1.37) and 1.20 (1.02–1.41), respectively]. Lung cancer mortality stayed almost 2-fold higher than among never smokers 15–19 years after smoking cessation [1.97 (1.41–2.73)], particularly among former heavy smokers [2.62 (1.71–4.00)]. Women who quitted for ≥5 years retained a significantly elevated mortality from all causes, CVD and lung cancer. Overall patterns of the cessation-mortality associations were similar across countries. Conclusions Our findings suggest that adverse effects of tobacco smoking persist for an extended time period, even for more than two decades, which is beyond the time windows defined in current clinical guidelines for risk assessment of lung cancer and CVD.

Background Blood type has been associated with the risk of gastric cancer, but few studies have examined the association with esophageal squamous cell carcinoma (ESCC). Methods We conducted a case-control study using genotyping data of Chinese individuals, including cases of 2022 ESCC, 1189 gastric cardia adenocarcinoma, 1161 gastric noncardia adenocarcinoma, and 2696 controls. Genetic blood type was imputed using three single nucleotide polymorphisms. We used logistic regression to examine the association between blood type and the risk of each cancer. Results Compared to blood type O, the risk of ESCC was significantly elevated for blood type B and AB, with the highest risk for type AB (OR, 95%CI: 1.34, 1.07–1.67). Analysis of genotype suggested that the association of ESCC was from carrying the B allele. Similarly, blood type was significantly associated with gastric noncardia adenocarcinoma (P P = 0.13). Conclusions This study provides novel insights into the association between blood type and the risk of ESCC and restricted previously observed association to only gastric noncardia cancer, providing important evidence to clarify the pattern of association and suggesting mechanisms of action.

Background The role of smoking in nasopharyngeal carcinoma (NPC) remains uncertain, especially in endemic regions. We conducted an individual participant data (IPD) meta-analysis of prospective cohort studies to investigate the associations between smoking exposure and risk of NPC. Methods We obtained individual participant data of 334 935 male participants from six eligible population-based cohorts in NPC-endemic regions, including two each in Guangzhou and Taiwan, and one each in Hong Kong and Singapore. We used one- and two-stage approaches IPD meta-analysis and Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of NPC for smoking exposure adjusting for age and drinking status. Results During 2 961 315 person-years of follow-up, 399 NPC evens were ascertained. Risks of NPC were higher in ever versus never smokers (HRone-stage = 1.32, 95% CI = 1.07-1.63, P = 0.0088; HRtwo-stage = 1.27, 1.01-1.60, 0.04). These positive associations appeared to be stronger in ever smokers who consumed 16+ cigarettes/day (HRone-stage = 1.67, 95% CI = 1.29-2.16, P = 0.0001), and in those who started smoking at age younger than 16 (2.16, 1.33-3.50, 0.0103), with dose-response relationships (P-values for trend = 0.0028 and 0.0103, respectively). Quitting (versus daily smoking) showed a small reduced risk (stopped for 5+ years: HRone-stage = 0.91, 95% CI = 0.60-1.39, P = 0.66; for former smokers: HRtwo-stage = 0.84, 0.61-1.14, 0.26). Conclusions This first IPD meta-analysis from six prospective cohorts in endemic regions has provided robust observational evidence that smoking increased NPC risk in men. NPC should be added to the 12–16 cancer sites known to be tobacco-related cancers. Strong tobacco control policies, preventing young individuals from smoking, would reduce NPC risk in endemic regions.

BACKGROUND. Since previous epidemiological studies reported inconsistent associations between dietary vitamin B(12) intake and lung cancer risk, more studies are warranted to clarify this association in different populations. METHODS. The association between dietary B(12) intake and lung cancer risk was examined in the Singapore Chinese Health Study, an ongoing prospective cohort study of 63,257 Singaporean Chinese men and women, 45–74 years of age at enrollment during 1993–1998 and were followed up for incidence of lung cancer for up to 25 years. Dietary vitamin B(12) intake was derived from a validated food frequency questionnaire. Cox proportional hazard regression method was used to estimate hazard ratio (HR) and 95% confidence interval (CI) of lung cancer associated with dietary vitamin B(12) intake with adjustment for multiple potential confounders. RESULTS. After a mean follow-up of 17.64 years, 2,001 study participants developed lung cancer. High levels of vitamin B(12) intake were associated with significantly increased risk of lung cancer (P(trend)= 0.03). Compared with the lowest quintile, HRs (95% CIs) of lung cancer for quintile 2, 3, 4, and 5 of vitamin B(12) intake were 1.09 (0.95–1.25), 1.11 (0.96–1.28), 1.11 (0.97–1.29) and 1.18 (1.03–1.35), respectively. This positive association was more apparent in men than in women, in adenocarcinoma patients, or in participants with equal or less than 2 years follow-up than those with longer duration of follow-up. CONCLUSION. Higher intake of dietary vitamin B(12) was associated with increased risk of lung cancer. This highlights the potential harmful effect of vitamin B(12) supplementation for lung cancer.

Background: While the associations between individual lifestyle factors and risk of hepatocellular carcinoma (HCC) have been described previously, their combined impact on HCC risk is unknown. Methods: The association of a composite score of healthy lifestyle factors, including body mass index, alcohol consumption, cigarette smoking, alternative Mediterranean diet, and sleep duration, and HCC risk was examined in the Singapore Chinese Health Study, an ongoing prospective cohort study of 63,257 Chinese men and women. Cox proportional hazard regression method was used to estimate HR and its 95% confidence interval (CI). Conditional logistic regression method was used to evaluate this composite lifestyle score–HCC risk association among a subset of individuals who tested negative for hepatitis B surface antigen (HBsAg) and anti–hepatitis C antibody. Results: After a mean follow-up of 17.7 years, 561 participants developed HCC. Individuals with higher composite scores representing healthier lifestyles (range 0–8) were at significantly lower risk of HCC. Compared with the lowest composite score category (0–4), the HRs (95% CIs) for the composite scores of 5, 6, 7, and 8 were 0.67 (0.62–0.85), 0.61 (0.48–0.77), 0.49 (0.37–0.65), and 0.13 (0.06–0.30), respectively (Ptrend < 0.0001). A similar inverse association was observed in participants with negative HBsAg and anti–hepatitis C virus (HCV)-negative serology (HR, 0.38; 95% CI, 0.19–0.79; for the highest vs. the lowest category of the composite scores; Ptrend = 0.001). Conclusions: Healthy lifestyles protect against HCC development, especially for individuals without hepatitis B virus and HCV infections. Impact: This study highlights the importance of a comprehensive lifestyle modification strategy for HCC primary prevention.

Background The aim of the study was to examine the relations of individual lifestyle factors and its composite score with healthy ageing among Chinese adults. Method We included 14 159 participants aged 45–74 years at baseline from the Singapore Chinese Health Study, a population-based prospective cohort. A protective lifestyle score (0–5 scale) was calculated at baseline (1993–1998) and updated at the second follow-up visit (2006–2010) on the basis of optimal body mass index (18.5–22.9 kg/m2), healthy diet (upper 40% of the Alternative Healthy Eating Index score), being physically active (≥2 h/wk of moderate activity or ≥0.5 h/wk of strenuous activity), nonsmoking (never smoking), and low-to-moderate alcohol drinking (>0 to ≤14 drinks/wk for men and >0 to ≤7 drinks/wk for women). Healthy ageing was assessed at the third follow-up visit (2014–2016) and was defined as absence of specific chronic diseases, absence of cognitive impairment and limitations in instrumental activities of daily living, good mental and overall self-perceived health, good physical functioning, and no function-limiting pain. Results About 20.0% (2834) of the participants met the criteria of healthy ageing after a median follow-up of 20 years. Each 1-point increase in the protective lifestyle score computed at baseline and second follow-up visits was associated with higher likelihood of healthy ageing by 25% (95% CI: 20%–30%) and 24% (18%–29%), respectively. The population-attributable risk percent of adherence to 4–5 protective lifestyle factors was 34.3% (95% CI: 25.3%–42.3%) at baseline and 31.3% (23.0%–38.7%) at second follow-up visits for healthy ageing. In addition, positive increase in lifestyle scores from baseline to second follow-up visits was also significantly associated with a higher likelihood of healthy ageing with an odds ratio of 1.18 (95% CI: 1.12%–1.24%) for each increment in protective lifestyle score. Conclusions Our findings confirmed that adopting healthy lifestyle factors, even after midlife, was associated with healthy ageing at old age.

Early natural menopause has been regarded as a biomarker of reproductive and somatic aging. Cigarette smoking is the most harmful factor for lung health and also an established risk factor for early menopause. Understanding the effect of early menopause on health outcomes in middle-aged and older female smokers is important to develop preventive strategies.This study aimed to examine the associations of early menopause with multiple lung health and aging biomarkers, lung cancer risk, and all-cause and cause-specific mortality in postmenopausal women who were moderate or heavy smokers.This study was conducted on postmenopausal women with natural (n=1038) or surgical (n=628) menopause from the Pittsburgh Lung Screening Study. The Pittsburgh Lung Screening Study is a community-based research cohort of current and former smokers, screened with low-dose computed tomography and followed up for lung cancer. Early menopause was defined as occurring before 45 years of age. The analyses were stratified by menopause types because of the different biological and medical causes of natural and surgical menopause. Statistical methods included linear model, generalized linear model, linear mixed-effects model, and time-to-event analysis.The average age of the 1666 female smokers was 59.4±6.7 years, with 1519 (91.2%) of the population as non-Hispanic Whites and 1064 (63.9%) of the population as current smokers at baseline. Overall, 646 (39%) women reported early menopause, including 198 (19.1%) women with natural menopause and 448 (71.3%) women with surgical menopause (P.001). Demographic variables did not differ between early and nonearly menopause groups, regardless of menopause type. Significant associations were identified between early natural menopause and higher risk of wheezing (odds ratio, 1.65; P.01), chronic bronchitis (odds ratio, 1.73; P.01), and radiographic emphysema (odds ratio, 1.70; P.001) and lower baseline lung spirometry in an obstructive pattern (-104.8 mL/s for forced expiratory volume in the first second with P.01, -78.6 mL for forced vital capacity with P=.04, and -2.1% for forced expiratory volume in the first second-to-forced vital capacity ratio with P=.01). In addition, early natural menopause was associated with a more rapid decline of forced expiratory volume in the first second-to-forced vital capacity ratio (-0.16% per year; P=.01) and incident airway obstruction (odds ratio, 2.02; P=.04). Furthermore, women early natural menopause had a 40% increased risk of death (P=.023), which was mainly driven by respiratory diseases (hazard ratio, 2.32; P.001). Mediation analyses further identified that more than 33.3% of the magnitude of the associations between early natural menopause and all-cause and respiratory mortality were explained by baseline forced expiratory volume in the first second. Additional analyses in women with natural menopause identified that the associations between continuous smoking and subsequent lung cancer risk and cancer mortality were moderated by early menopause status, and females with early natural menopause who continued smoking had the worst outcomes (hazard ratio,4.6; P.001). This study did not find associations reported above in female smokers with surgical menopause.Early natural menopause was found to be a risk factor for malignant and nonmalignant lung diseases and mortality in middle-aged and older female smokers. These findings have strong public health relevance as preventive strategies, including smoking cessation and chest computed tomography screening, should target this population (ie, female smokers with early natural menopause) to improve their postmenopausal health and well-being.

Background Telomere attrition has been proposed as a hallmark of aging. We previously reported on the association between blood leukocyte telomere length (LTL) at midlife and risk of chronic diseases and mortality. Methods In this study, we investigated the effect of midlife LTL and genetic proxies on 5 markers of aging outcomes, namely handgrip strength, timed up-and-go (TUG), Singapore-modified Mini-Mental State Examination (SM-MMSE) scores, anxiety, and depression indices, measured after a median 20-year follow-up in the Singapore Chinese Health Study (N = 9581). Results We observed a significant association between midlife LTL and handgrip strength later in life (p = .004, padjust = .020), as well as a nominal significant association between midlife LTL and TUG later in life (p = .036, padjust = .180). The weighted Genetic Risk Score (wGRS) comprising 15 previously reported LTL reducing loci in East Asians was not significantly associated with handgrip strength. However, results from Structural Equation Modeling showed that the effect of this wGRS on handgrip strength was mediated through LTL (proportion of wGRS effect on handgrip strength mediated through LTL = 33.3%, p = .010). Conclusions Longer midlife LTL was associated with increased handgrip strength later in life.

Telomeres play a key role in chromosomal maintenance and stability. To date, few studies have investigated the association of leukocyte telomere length with risk of cancer incidence and all-cause mortality in a large prospective cohort, particularly of the Asian population. Relative telomere lengths in genomic DNA from peripheral blood samples were quantified using a validated quantitative real-time PCR among 26 540 middle-aged or older Chinese adults. Hazard ratios (HRs) and 95% confidence intervals (CIs) of cancer and deaths by quintiles of telomere length were calculated using the Cox proportional hazards regression method with adjustment for age, sex and other potential confounders. After baseline blood collection, 4353 persons developed cancer and 7609 died. Participants with the longest decile of telomeres had a 26% (95% CI: 11%-44%) higher risk of total cancer incidence compared to the shortest decile after controlling for age, sex and other potential founders (Ptrend < .0001). In contrast, longer telomeres were associated with lower risk of all-cause mortality (HR = 0.93; 95% CI: 0.84-1.03), noncancer death (HR = 0.81; 95% CI: 0.71-0.92), specifically, death from chronic obstructive pulmonary disease and pneumonia (HR = 0.79, 95% CI: 0.70-0.89) and digestive diseases (HR = 0.60, 95% CI: 0.42-0.88). Our findings demonstrated that longer telomeres are associated with increased risk of cancer development overall and several common cancer types including breast, rectal, prostate, pancreatic cancer and lung adenocarcinoma. Our study also confirmed that longer telomeres are associated with a reduced risk of noncancer related death.

Background Despite experimental evidence implicating oxidative stress in the pathogenesis of PD, epidemiological studies have provided inconsistent associations between dietary antioxidants and risk of developing PD. Furthermore, no study has been done in any Asian population. Objectives We examined the associations for intake levels of dietary carotenoids (α‐carotene, β‐carotene, lycopene, β‐cryptoxanthin, and lutein) and vitamins (vitamin A, C and E) and the risk of developing PD. Methods We used data from the Singapore Chinese Health Study, a population‐based prospective cohort of 63,257 men and women aged 45 to 74 years during enrollment in 1993–1998. Antioxidant intake was derived from a validated semiquantitative food frequency questionnaire. Incident cases were identified through follow‐up interviews, hospital records, or PD registries through 31 July 2018. Hazard ratios and corresponding 95% confidence intervals were derived from multivariable Cox proportional hazard regression models with adjustment for other lifestyle and dietary factors. Results During an average 19.4 years of follow‐up, 544 incident PD cases were identified. No association was found for dietary carotenoids, individually or summed. Hazard ratio comparing highest to lowest quartile for total carotenoids was 0.98 (95% confidence interval: 0.76–1.28; P trend = 0.83). There were also no clear dose‐dependent associations of dietary vitamins A, C, and E with risk of developing PD (all P trend ≥ 0.10). Sensitive analyses with lag time and excluding supplement use did not materially alter results. Conclusions Intake of dietary antioxidants, such as carotenoids and vitamins, was not associated with the risk of developing PD in Singaporean Chinese. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Deficiencies in methyl donor status may render DNA methylation changes and DNA damage, leading to carcinogenesis. Epidemiological studies reported that higher dietary intake of choline is associated with lower risk of pancreatic cancer, but no study has examined the association of serum choline and its metabolites with risk of pancreatic cancer. Two parallel case-control studies, one nested within the Shanghai Cohort Study (129 cases and 258 controls) and the other within the Singapore Chinese Health Study (58 cases and 104 controls), were conducted to evaluate the associations of baseline serum concentrations of choline, betaine, methionine, total methyl donors (i.e., sum of choline, betaine and methionine), dimethylglycine and trimethylamine N-oxide (TMAO) with pancreatic cancer risk. In the Shanghai cohort, odds ratios and 95% confidence intervals of pancreatic cancer for the highest quartile of choline, betaine, methionine, total methyl donors and TMAO were 0.27 (0.11-0.69), 0.57 (0.31-1.05), 0.50 (0.26-0.96), 0.37 (0.19-0.73) and 2.81 (1.37-5.76), respectively, compared to the lowest quartile. The corresponding figures in the Singapore cohort were 0.85 (0.23-3.17), 0.50 (0.17-1.45), 0.17 (0.04-0.68), 0.33 (0.10-1.16) and 1.42 (0.50-4.04). The inverse associations of methionine and total methyl donors including choline, betaine and methionine with pancreatic cancer risk in both cohorts support that DNA repair and methylation play an important role against the development of pancreatic cancer. In the Shanghai cohort, TMAO, a gut microbiota-derived metabolite of dietary phosphatidylcholine, may contribute to higher risk of pancreatic cancer, suggesting a modifying role of gut microbiota in the dietary choline-pancreatic cancer risk association.

The relationship between alcohol intake and end-stage kidney disease (ESKD) risk is controversial. Moreover, while evidence has shown that the relationship between alcohol and atherosclerosis may be modified by diabetes, whether this applies to ESKD is unknown.We examined these associations in the Singapore Chinese Health Study, a prospective cohort of 63 257 adults aged 45 to 74 years. Information on alcohol intake, diet, lifestyle factors, and medical history was collected at recruitment. We identified 1217 ESKD cases via linkage with the Singapore Renal Registry after a mean follow-up of 17.5 years. Cox regression models were used to estimate hazard ratios (HRs) and 95% CI of ESKD.Among the participants without diabetes at baseline, monthly to weekly drinking was associated with a decreased risk of ESKD (HR 0.69; 95% CI, 0.54-0.87) compared to nondrinkers. In contrast, this association was attenuated and not significant among those with diabetes (HR 0.82; 95% CI, 0.58-1.16; PLow-dose drinking is associated with a reduced risk of ESKD among individuals without diabetes. However, joint exposure to heavy drinking and diabetes is associated with a substantially higher risk of ESKD.背景: 酒精的摄入与终末期肾病(ESKD)风险之间的关系仍存在着争议。此外, 有证据表明糖尿病可能会影响酒精与动脉粥样硬化之间的关联, 但这是否适用于ESKD尚不清楚。 方法: 利用前瞻性队列“新加坡华人健康研究”探讨酒精的摄入与ESKD风险的关联, 该研究由63257名45-74岁的成年人组成。基线收集了关于酒精摄入量、饮食习惯、生活方式及疾病史的资料。经过平均17.5年的随访, 通过新加坡肾脏病登记处的链接, 确定了1,217例ESKD病例。使用比例风险(Cox)回归模型估算ESKD的风险比(HRs)和95%置信区间(CI)。 结果: 在无基线糖尿病的参与者中, 与非饮酒者相比, 每月至每周饮酒与ESKD风险降低相关(HR 0.69, 95%置信区间0.54-0.87)。相反, 该关联在基线糖尿病患者中减弱并且不再显著(HR 0.82, 95%置信区间0.58-1.16; P交互作用= 0.19)。相比之下, 在基线糖尿病患者中, 与非饮酒者相比, 每天摄入≥2个标准饮酒单位与ESKD风险增加显著相关(HR 2.00, 95%置信区间1.14-3.53), 而在无基线糖尿病参与者中无统计学意义(HR 0.91, 95%置信区间0.53-1.56; P相互作用= 0.01)。与无基线糖尿病的非饮酒者相比, 患有糖尿病且每天饮酒≥2个标准饮酒单位的人患ESKD的风险增加了近12倍(HR 11.6, 95%置信区间6.73-19.9)。 结论: 在非糖尿病患者中, 低剂量饮酒与ESKD风险降低显著相关。然而, 大量饮酒和糖尿病的联合效应与ESKD的风险大幅增高显著相关。.

BACKGROUND Few prospective studies with long duration of follow-up have assessed the relations of body mass index (BMI) and weight change with cognitive function, especially in Asian populations. OBJECTIVE To investigate whether BMI and weight change in midlife are associated with cognitive impairment in old age. METHODS We used data from 14,691 participants in the Singapore Chinese Health Study and computed weight change as the difference between weight reported at baseline (1993-1998) at mean age of 53.0 years and follow-up 1 (1999-2004) at mean age of 58.6 years. Cognitive impairment was determined using education-specific cut-offs of the Singapore Modified Mini-Mental State Examination at follow-up 3 (2014-2016) at mean age of 72.9 years. We used multivariable logistic regression models to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the associations. RESULTS Obesity (as defined BMI ≥27.5 kg/m2) was associated with a higher risk of cognitive impairment at baseline (OR 1.33, 95% CI 1.12-1.58) and follow-up 1 (OR 1.30, 95% CI 1.10-1.54) compared to BMI of 18.5-22.9 kg/m2. Underweight (BMI

2-Phenethyl isothiocyanate (PEITC) is a natural product found as a conjugate in cruciferous vegetables. It has been reported to have preventative properties against lung cancer and to inhibit metabolic activation of tobacco carcinogens. In this study, we evaluated the ability of PEITC to influence the metabolism of the human carcinogen 1,3-butadiene in current smokers in a phase II clinical trial with a crossover design. Urinary mercapturic acids of 1,3-butadiene were quantified at baseline and during PEITC treatment. Seventy-nine smokers were randomly assigned to one of two arms: PEITC followed by placebo or placebo followed by PEITC. During the 1-week treatment period, each subject took PEITC (10 mg in 1 mL of olive oil, 4 times per day). There was a 1-week washout period between the PEITC and placebo periods. Oral ingestion of PEITC increased urinary levels of BD-mercapturic acids (MHBMA and DHBMA) by 11.1% and 3.7%, respectively, but these increases were not statistically significant (P = 0.17 and 0.64, respectively). A much stronger effect was observed among subjects with the null genotype of both GSTM1 and GSTT1: in these individuals, PEITC increased urinary levels of MHBMA by 58.7% (P = 0.004) and 90.0% (P = 0.001), respectively, but did not have a significant effect on urinary DHBMA. These results reveal a potentially protective effect of PEITC treatment with respect to the detoxification of 1,3-butadiene in cigarette smokers, specifically in those null for GSTT1, and provide further evidence in support of stronger chemopreventive effects from consumption of dietary isothiocyanates in these individuals.

Prostate cancer (PCa) is the most commonly diagnosed cancer in men, resulting in a large cancer burden given a relatively higher 5-year survival rate of patients after cancer diagnosis. The underlying etiology of prostate cancer is not well understood. Chronic inflammation plays a significant role in carcinogenesis overall and may be involved in the development of PCa, but immune-related biomarker studies in prostate cancer are limited.The associations of serum concentrations of cytokines, systemic immune biomarkers, with risk of PCa were assessed in a randomly selected sub-cohort (n = 798, mean age = 73 years) of the Osteoporotic Fractures in Men (MrOS) study, a prospective cohort of older men. At baseline, we measured serum interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor alpha (TNFα), soluble receptors (SR) of IL-6 (IL-6SR) and TNF (TNFαSR1 and TNFαSR2), and IL-10. The risk of PCa was calculated for higher tertile levels of measured individual cytokines relative to the lowest tertile using Cox proportional hazards regression models.After an average 6 years of follow-up, 59 men developed incident PCa. Men in the middle or highest tertile of IL-10 had a statistically significant 50% lower risk of PCa compared to the lowest tertile (hazard ratio = 0.50, 95% confidence interval = 0.30-0.84). There was no significant association between any of the other cytokines measured and PCa risk.IL-10, an anti-inflammatory cytokine, was associated with lower risk of PCa. Further research of IL-10 and inflammation in relation to PCa development is warranted.

This study was conducted to investigate the effects of naturally oxidized corn oil on the inflammatory reaction and intestinal health of broilers. Total 450, one-day-old Arbor Acres male broilers were randomly divided into 5 treatments with 6 replicate cages (15 birds in each replicate cage). The dietary treatment array consisted of the varying ratio of nonoxidized corn oil to naturally oxidized corn oil from 0:100, 25:75, 50:50, 75:25, and 100:0, respectively. The experimental period was 42 d. Serum, jejunum, and contents of cecum samples were taken at the age of 42 d of broilers. The results showed no significant difference in the body weight gain (BWG) with a different proportion of oxidized corn oil compared with the 0% oxidized oil group on d 42. The feed intake (FI), the concentration of immunoglobulin G (IgG), interferon-γ (IFN-γ), and interleukin-10 (IL10) in serum showed a significant quadratic response with the increase of oxidized oil concentration on d 42. The serum's concentration of IgG, IFN-γ, and IL-10 reached the highest value at 75% oxidized corn oil. In addition, the mRNA expression levels of interleukin-1β (IL-1β), IFN-γ, nuclear factor kappa B (NF-κB), tumor necrosis factor α (TNF-α), and myeloid differentiation factor-88 (MyD88) in the jejunum were significantly affected by different proportions of oxidized corn oil, and the gene expression levels were highest at 75% oxidized corn oil on d 42. The mRNA expression of Bcl2-associated X (Bax) in the jejunum showed a significantly quadratic curve with the increase of oxidized oil concentration, and its gene expression was the highest after adding 50% oxidized corn oil according to the regression equation on d 42. The villus height/crypt depth and goblet cells of jejunum decreased linearly with the increasing proportion of oxidized corn oil and reached the lowest point after adding 100% oxidized corn oil on d 42. The β diversity showed the remarkable differentiation of microbial communities among 5 groups, and the microbial community of the 0% oxidized oil group was significantly separated from that of 75 and 100% oxidized oil groups in the cecum. Taken together, these results showed that a low dose of naturally oxidized corn oil is not harmful to the growth of broilers, while a high dose of oxidized corn oil will trigger the inflammatory response and adversely affect the gut health of broilers.

Tea and coffee are widely consumed beverages. Tea flavonoids have been shown to inhibit lung tumorigenesis using in vitro and in vivo models. Conversely, coffee contains complex mixtures of biochemically active compounds, some of which may have genotoxic and mutagenic properties. However, previous epidemiologic studies have shown inconsistent results on tea and coffee in relation to lung cancer risk. The Singapore Chinese Health Study is a population-based prospective cohort of 63,257 Singaporean Chinese men and women, with an average of 17.7 years of follow-up. Information on tea and coffee consumption and other lifestyle factors was collected through in-person interviews at baseline. Multivariable Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations with adjustment for potential confounders. There were 1486 incident lung cancer cases. Compared to non-daily coffee drinkers, HRs (95% CIs) of lung cancer risk for those consuming one, two, and three or more cups of coffee per day were 1.18 (1.02–1.36), 1.21 (1.05–1.40), and 1.32 (1.08–1.62) respectively (P for trend = 0.0034). The highest category of black tea consumption (at least 2 cups per day) was inversely associated with risk of lung cancer [HR (95% CI) = 0.73 (0.53–0.99)], particularly among men [HR (95% CI) = 0.67 (0.47–0.95)], compared to less-than-weekly black tea drinkers, although the interaction by sex was not statistically significant. Coffee beverage consumption was associated with higher risk of developing lung cancer. On the other hand, black tea intake was associated with lower risk of lung cancer among men in our cohort, and further studies are needed to confirm this association.

The substantial social and economic burden attributable to smoking is well-known, with heavy smokers at higher risk of chronic disease and premature mortality than light smokers and nonsmokers. In aging societies with high rates of male smoking such as in East Asia, smoking is a leading preventable risk factor for extending lives (including work-lives) and healthy aging. However, little is known about whether smoking interventions targeted at heavy smokers relative to light smokers lead to disproportionately larger improvements in life expectancy and prevalence of chronic diseases and how the effects vary across populations. Using a microsimulation model, we examined the health effects of smoking reduction by simulating an elimination of smoking among subgroups of smokers in South Korea, Singapore, and the United States. We found that life expectancy would increase by 0.2 to 1.5 years among light smokers and 2.5 to 3.7 years among heavy smokers. Whereas both interventions led to an increased life expectancy and decreased the prevalence of chronic diseases in all three countries, the life-extension benefits were greatest for those who would otherwise have been heavy smokers. Our findings illustrate how smoking interventions may have significant economic and social benefits, especially for life extension, that vary across countries.

Background: Although previous meta-analyses have suggested a dose-response relationship between body mass index (BMI) and thyroid cancer risk, limited evidence has been presented about Asian populations. To assess this association among Asian populations, where underweight is more prevalent than in other regions, a pooled analysis from the Asia Cohort Consortium was conducted.Methods: Baseline height and weight were measured in five cohorts and self-reported in eight cohorts. Thyroid cancer incidence was ascertained by linkage to local cancer registries. Cohorts were treated as a stratum in the Cox proportional hazard model to estimate the pooled hazard ratios (HRs) and corresponding confidence intervals (CIs) from the estimates for each cohort. All analyses were stratified by sex.Results: A total of 538,857 men and women from 13 cohorts from mainland China, Korea, Japan, and Singapore were included in the analysis. During a mean of 15.1 years of follow-up, 1132 thyroid cancer cases were ascertained. Using a BMI of 18.5-22.9 kg/m(2) as a reference, an elevated risk of thyroid cancer was observed for groups with a BMI between 25 and 29.9 kg/m(2) (HR: 1.31, [CI: 0.95-1.80]) and a BMI of 30 kg/m(2) and greater (HR: 1.84, [CI: 0.89-3.81]) in men. Thyroid cancer risk was elevated in women with a BMI of 23-24.9 kg/m(2) (HR: 1.26, [CI: 1.07-1.48]). The HRs for 5-U increment of BMI showed a linear association among men (HR: 1.25, [CI 1.10-1.55]) but not among women (HR: 1.07, [CI: 0.97-1.18]). Although the overall thyroid cancer risk was lower among underweight men and women, the papillary cancer risk may be elevated among underweight men (HR: 2.24, [CI: 0.75-6.66]).Conclusion: While higher BMI is associated with an elevated risk of thyroid cancer in both men and women, the association of underweight BMI may differ by sex and histological subtype.

Background Family history, and genetic and non-genetic risk factors can stratify women according to their individual risk of developing breast cancer. The extent of overlap between these risk predictors is not clear. Methods In this case-only analysis involving 7600 Asian breast cancer patients diagnosed between age 30 and 75 years, we examined identification of high-risk patients based on positive family history, the Gail model 5-year absolute risk [5yAR] above 1.3%, breast cancer predisposition genes (protein-truncating variants [PTV] in ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, or TP53), and polygenic risk score (PRS) 5yAR above 1.3%. Results Correlation between 5yAR (at age of diagnosis) predicted by PRS and the Gail model was low (r=0.27). Fifty-three percent of breast cancer patients (n=4041) were considered high risk by one or more classification criteria. Positive family history, PTV carriership, PRS, or the Gail model identified 1247 (16%), 385 (5%), 2774 (36%), and 1592 (21%) patients who were considered at high risk, respectively. In a subset of 3227 women aged below 50 years, the four models studied identified 470 (15%), 213 (7%), 769 (24%), and 325 (10%) unique patients who were considered at high risk, respectively. For younger women, PRS and PTVs together identified 745 (59% of 1276) high-risk individuals who were not identified by the Gail model or family history. Conclusions Family history and genetic and non-genetic risk stratification tools have the potential to complement one another to identify women at high risk.

Background: Nonalcoholic fatty liver disease (NAFLD) has become a major contributor to the rising incidence of hepatocellular carcinoma (HCC) in the United States and other developed countries. Iron, an essential metal primarily stored in hepatocytes, may play a role in the development of NAFLD-related HCC. Epidemiologic data on iron overload without hemochromatosis in relation to HCC are sparse. This study aimed to examine the associations between serum biomarkers of iron and the risk of HCC in patients with NAFLD. Methods: We identified 18,569 patients with NAFLD using the University of Pittsburgh Medical Center electronic health records from 2004 through 2018. After an average 4.34 years of follow-up, 244 patients developed HCC. Cox proportional hazard regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) of HCC incidence associated with elevated levels of iron biomarkers with adjustment for age, sex, race, body mass index, history of diabetes, and tobacco smoking. Results: The HRs (95% CIs) of HCC for clinically defined elevation of serum iron and transferrin saturation were 2.91 (1.34–6.30) and 2.02 (1.22–3.32), respectively, compared with their respective normal range. No statistically significant association was observed for total iron-binding capacity or serum ferritin with HCC risk. Conclusions: Elevated levels of serum iron and transferrin saturation were significantly associated with increased risk of HCC among patients with NAFLD without hemochromatosis or other major underlying causes of chronic liver diseases. Impact: Clinical surveillance of serum iron level may be a potential strategy to identify patients with NAFLD who are at high risk for HCC.

BACKGROUND: Combinations of circulating fatty acids may affect the risk of type 2 diabetes (T2D) and coronary artery disease (CAD). No previous studies have identified a dietary pattern predicting fatty acid profiles using reduced rank regression (RRR) and evaluated its associations with the risk of T2D and CAD. OBJECTIVE: The aim of this study was to derive a dietary pattern to explain variation in plasma fatty acid concentrations using RRR and evaluate these in relation to risk of T2D and CAD. METHODS: We derived a dietary pattern using fatty acid concentrations from 711 controls of a nested case-control study in the Singapore Chinese Health Study using RRR with 36 food and beverages as predictors and 19 fatty acid biomarkers as responses. Dietary pattern scores were then calculated for the full cohort of men and women (mean age: 56 y). We followed up 45,411 and 58,065 participants for incident T2D and CAD mortality, respectively. Multivariable Cox regression models were used to estimate HRs and 95% CIs. RESULTS: We identified a dietary pattern high in soy, vegetables, fruits, tea, tomato products, bread, fish, margarine and dairy, and low in rice, red meat, coffee, alcohol, sugar-sweetened beverages, and eggs. This pattern predicted higher circulating n–3 (ω-3) PUFAs (18:3n–3, 20:3n–3, 20:5n–3), odd-chain fatty acids (15:0, 17:0), 18:2n–6 and 20:1, and lower 20:4n–6 and 16:1. During a mean follow-up of 11 y and 19 y, 5207 T2D and 3016 CAD mortality events, respectively, were identified. Higher dietary pattern scores were associated with a lower risk of T2D [multivariable-adjusted HR comparing extreme quintiles, 0.86 (95% CI: 0.79, 0.95); P-trend

Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m2 increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19–1.36), IHBDC (HR = 1.32; 95% CI, 1.21–1.45), and EHBDC (HR = 1.13; 95% CI, 1.03–1.23), but not AVC (HR = 0.99; 95% CI, 0.88–1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers. Significance: These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases.

Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci (P, Shortening of leukocyte telomere length (LTL) is associated with age and increased risk for various chronic diseases. Here, the authors report genome-wide association studies for LTL in Singaporean Chinese populations and find that longer LTL associates with less severe outcomes of respiratory disease phenotypes.

Infants and children are particularly vulnerable to in utero and early-life exposures. Thus, a mother’s exposures before and during pregnancy could have important consequences for her child’s health, including cancer development. We examined whether birth certificate–derived maternal anthropometric characteristics were associated with increased risk of subsequent childhood cancer development, accounting for established maternal and infant risk factors. Pennsylvania birth and cancer registry files were linked by the state Department of Health, yielding a virtual cohort of births and childhood cancers from 2003 through 2016. The analysis included 1,827,875 infants (13,785,309 person-years at risk), with 2,352 children diagnosed with any cancer and 747 with leukemia before age 14 years. Children born to mothers with a body mass index (weight (kg)/height (m)2) of ≥40 had a 57% (95% confidence interval: 12, 120) higher leukemia risk. Newborn size of ≥30% higher than expected was associated with 2.2-fold and 1.8-fold hazard ratios for total childhood cancer and leukemia, respectively, relative to those with expected size. Being

Background Dietary intakes of B vitamins (eg, folate) are related to cognitive function according to epidemiological studies in western countries. But prospective studies in Asian populations are scarce. This study evaluated the relationships of dietary intakes of six B vitamins in midlife with cognitive impairment in old age in a Chinese population living in Singapore. Methods This study included 16,948 participants from the Singapore Chinese Health Study, a population-based prospective cohort. Baseline dietary intakes of B vitamins were assessed using a validated 165-item food frequency questionnaire when the participants were aged 45–74 years (1993–1998). After an average follow-up of 20 years, cognitive function was examined using a Singapore-modified version of Mini-Mental State Examination scale in 2014–2016, and cognitive impairment was defined using education-specific cutoffs. Logistic regression models were applied to estimate the association between B vitamins and cognitive impairment. All the six B vitamins were mutually adjusted in the final model. Results In the 2014–2016 interview, 2,443 participants were defined as cognitive impairment. Riboflavin and folate were significantly and independently associated with cognitive impairment in a dose-dependent manner: the odds ratio (95% confidence interval) comparing the highest with the lowest quartile was 0.82 (0.69, 0.97) for riboflavin and 0.83 (0.70, 0.98) for folate (both p-trend Conclusions Higher dietary intakes of riboflavin and folate in midlife were associated with a lower risk of cognitive impairment in late-life in the Chinese population.

Specific organochlorines (OCs) have been associated with non-Hodgkin lymphoma (NHL) with varying degrees of evidence. These associations have not been evaluated in Asia, where the high exposure and historical environmental contamination of certain OC pesticides (e.g. dichlorodiphenyltrichloroethane (DDT), hexachlorocyclohexane (HCH)) are different from Western populations. We evaluated NHL risk and pre-diagnostic blood levels of OC pesticides/metabolites and polychlorinated biphenyl (PCB) congeners in a case-control study of 167 NHL cases and 167 controls nested within three prospective cohorts in Shanghai and Singapore. Conditional logistic regression was used to analyze lipid-adjusted OC levels and NHL risk. Median levels of p,p’-dichlorodiphenyldichloroethylene (p,p’-DDE), the primary DDT metabolite, and β-HCH were up to 12 and 65 times higher, respectively, in samples from the Asian cohorts compared to several cohorts in the United States and Norway. An increased risk of NHL was observed among those with higher β-HCH levels both overall (3(rd) vs. 1(st) tertile OR=1.8, 95%CI=1.0-3.2; p(trend) =0.049) and after excluding cases diagnosed within two years of blood collection (3(rd) vs. 1(st) tertile OR = 2.0, 95%CI =1.1-3.9; p(trend) = 0.03), and the association was highly consistent across the three cohorts. No significant associations were observed for other OCs, including p,p’-DDE. Our findings provide support for an association between β-HCH blood levels and NHL risk. This is a concern because substantial quantities of persistent, toxic residues of HCH are present in the environment worldwide. Although there is some evidence that DDT is associated with NHL, our findings for p,p’-DDE do not support an association.

IntroductionLow-dose CT (LDCT) is currently used in lung cancer screening of high-risk populations for early lung cancer diagnosis. However, 96% of individuals with detected nodules are false positives.MethodsIn order to develop an efficient early lung cancer predictor from clinical, demographic and LDCT features, we studied a total of 218 subjects with lung cancer or benign nodules. Probabilistic graphical models (PGMs) were used to integrate demographics, clinical data and LDCT features from 92 subjects (training cohort) from the Pittsburgh Lung Screening Study cohort.ResultsLearnt PGMs identified three variables directly (causally) linked to malignant nodules and the largest benign nodule and used them to build the Lung Cancer Causal Model (LCCM), which was validated in a separate cohort of 126 subjects. Nodule and vessel numbers and years since the subject quit smoking were sufficient to discriminate malignant from benign nodules. Comparison with existing predictors in the training and validation cohorts showed that (1) incorporating LDCT scan features greatly enhances predictive accuracy; and (2) LCCM improves cancer detection over existing methods, including the Brock parsimonious model (p<0.001). Notably, the number of surrounding vessels, a feature not previously used in predictive models, significantly improves predictive efficiency. Based on the validation cohort results, LCCM is able to identify 30% of the benign nodules without risk of misclassifying cancer nodules.DiscussionLCCM shows promise as a lung cancer predictor as it is significantly improved over existing models. Validated in a larger, prospective study, it may help reduce unnecessary follow-up visits and procedures.

OBJECTIVES: Although epidemiological evidence suggests that short sleep duration may affect renal function, the influence of long sleep and risk of end-stage renal disease (ESRD) is unclear. We examined the association between sleep duration and risk of ESRD. METHODS: We investigated sleep duration and ESRD risk in the Singapore Chinese Health Study, a prospective population-based cohort of 63,257 Chinese in Singapore, who were aged 45–74 years at recruitment (1993–1998). Information on daily sleep duration (including naps), diet, medical history and other lifestyle factors was collected at recruitment from in-person interviews. ESRD cases were identified via linkage with the nationwide Singapore Renal Registry through year 2014. We used the Cox proportional hazards regression method to estimate hazard ratio (HR) and 95% confidence interval (CI) of ESRD in relation to sleep duration. RESULTS: After an average 16.8 years of follow-up, 1,143 (1.81%) ESRD cases were documented. Sleep duration had a U-shaped association with risk of ESRD (P for quadratic trend < 0.001). Compared with participants with 7 hours/day of sleep, the multivariable adjusted HR (95% CI) of ESRD was 1.43 (1.18–1.74) for short sleep (≤ 5 hours/day) and 1.28 (1.03–1.60) for long sleep duration (≥ 9 hours/day). The increased risk was stronger in participants with more than 10 years of follow-up compared to those with shorter follow-up time, especially for long sleep (P for interaction = 0.003). CONCLUSIONS: Our findings demonstrated that both short and long sleep durations were associated with a higher risk of ESRD in this Asian population.

Vitamin B supplementation can have side effects for human health, including cancer risk. We aimed to elucidate the role of vitamin B12 in lung cancer aetiology via direct measurements of pre‐diagnostic circulating vitamin B12 concentrations in a nested case‐control study, complemented with a Mendelian randomization (MR) approach in an independent case‐control sample. We used pre‐diagnostic biomarker data from 5,183 case‐control pairs nested within 20 prospective cohorts, and genetic data from 29,266 cases and 56,450 controls.Exposures included directly measured circulating vitamin B12 in pre‐diagnostic blood samples from the nested case‐control study, and 8 single nucleotide polymorphisms associated with vitamin B12 concentrations in the MR study.Our main outcome of interest was increased risk for lung cancer, overall and by histological subtype, per increase in circulating vitamin B12 concentrations.We found circulating vitamin B12 to be positively associated with overall lung cancer risk in a dose response fashion (odds ratio for a doubling in B12 [ORlog2B12] = 1.15, 95% confidence interval (95%CI) = 1.06‐1.25). The MR analysis based on 8 genetic variants also indicated that genetically determined higher vitamin B12 concentrations were positively associated with overall lung cancer risk (OR per 150 pmol/L standard deviation increase in B12 [ORSD]= 1.08, 95%CI= 1.00‐1.16).Considering the consistency of these two independent and complementary analyses, these findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer.

Chronic inflammation and oxidative stress play pivotal roles in the pathogenesis of hepatocellular carcinoma (HCC). We conducted a nested case–control study of 347 HCC cases and 691 matched controls within a prospective cohort of 18 244 Chinese men in Shanghai, China. The concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α), a biomarker of oxidative stress, and prostaglandin E2 (PGE2) metabolite (PGE-M), a biomarker of the inflammation mediator PGE2, were determined in baseline urine samples using validated mass spectrometry assays. 8-epi-PGF2α levels were significantly higher in HCC cases than control subjects (geometric means 0.92 versus 0.80 pmol/mg creatinine, P < 0.001). The relative risks of developing HCC for the highest relative to the lowest quartile of 8-epi-PGF2α were 2.55 (95% confidence interval = 1.62–4.01, Ptrend < 0.001). This positive 8-epi-PGF2α–HCC risk association was independent of smoking status, alcohol consumption and hepatitis B or liver cirrhosis and was present 10 years before the clinical manifestation of HCC. This study did not find any significant association between urinary PEG-M and HCC risk. This study provides direct evidence in support of the critical role of oxidative stress in the development of HCC regardless of its underlying causes.

© The Author(s) 2019. A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-Alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2- degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10?6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10?8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models. National Heart, Lung, and Blood Institute; American Heart Association Grant

This study was conducted to investigate the effects of stocking density and dietary nicotinamide (NAM) and butyrate sodium (BA) supplementation on the growth performance, liver mitochondrial function and gut microbiota of broilers at high stocking density. A total of 342, 26-d-old Cobb500 broilers were divided into 5 groups with 6 replicates. Treatments were as follows: (a) Low stocking density (L, 9 birds per cage); (b) High stocking density (H, 12 birds per cage); (c) H + 50 ppm NAM; (d) H + 500 ppm BA; (e) H + 50 ppm NAM + 500 ppm BA (COMB). The results showed that high stocking density significantly reduced the feed intake and body weight gain of broilers, while COMB improved the growth performance at high stocking density. High stocking density significantly reduced the liver metallothionein content, liver mitochondrial membrane potential and the activities of Na+K+-ATPase and Ca2+Mg2+-ATPase. In contrast, the liver metallothionein contents in the NAM, BA and COMB fed group were higher than those in the H group. COMB increased the activity of ATPase as well, but it failed to enhance the mitochondrial membrane potential. Stocking density also affected gut microbiota of broilers. The high-density group increased the relative abundance of Blautia. Supplementation of BA and NAM increased the abundance of Lactobacillus and Bifidobacteria, respectively. In conclusion, a combination of NAM and BA can improve the performance, antioxidant capacity, mitochondrial function and intestinal microbiota of broilers at high stocking density.

While the associations between individual lifestyle factors and risk of pancreatic cancer were studied extensively, their combined impact has not been examined. We evaluated the association of a composite score of healthy lifestyle factors, including body mass index, cigarette smoking, the Alternative Healthy Eating Index-2010 (AHEI-2010), sleep duration, and physical activity with pancreatic cancer risk in the Singapore Chinese Health Study, an ongoing prospective cohort study of 63,257 Chinese aged 45 to 74 years at enrollment in 1993 to 1998 with up to 25 years of follow up. Cox proportional hazard regression method was used to estimate HR and its 95% confidence interval (CI) with adjustment for multiple potential confounders. We identified 316 incident pancreatic cancer cases among the cohort participants after a mean 17 years of follow up. Individuals with higher composite scores representing healthier lifestyle were at significantly lower risk of pancreatic cancer. The multivariate-adjusted HRs (95% CIs) of pancreatic cancer incidence for the composite scores 2, 3, 4, 5, 6 to 7 were 0.60 (0.50–0.91), 0.48 (0.32–0.71), 0.45 (0.31–0.67), 0.41 (0.27–0.62), and 0.38 (0.24–0.62), respectively, compared with the scores 0 to 1 (Ptrend < 0.0001). The inverse association was more apparent among participants without diabetes history and was robust in men and women as well as in alcohol drinkers and nondrinkers. In summary, the association for pancreatic cancer risk was stronger for the aggregated than individual healthy lifestyle factors. These findings suggest that a more comprehensive lifestyle modification strategy would be more effective for prevention of pancreatic cancer than the change of a single lifestyle factor. Prevention Relevance: In this large prospective Asian study, we calculated a composite score of healthy lifestyle factors, including body mass index, cigarette smoking, the Alternative Healthy Eating Index-2010 (AHEI-2010), sleep duration, and physical activity and found this composite score was associated with a significant reduction in pancreatic cancer risk, by as much as 62%. This finding suggests that public health programs emphasizing comprehensive lifestyle modification strategy would be more effective for prevention of pancreatic cancer than the change of a single lifestyle factor.

The role of low frequency variants associated with telomere length homeostasis in chronic diseases and mortalities is relatively understudied in the East-Asian population. Here we evaluated low frequency variants, including 1,915,154 Asian specific variants, for leukocyte telomere length (LTL) associations among 25,533 Singapore Chinese samples. Three East Asian specific variants in/near POT1, TERF1 and STN1 genes are associated with LTL (Meta-analysis P 2.49×10−14–6.94×10−10). Rs79314063, a missense variant (p.Asp410His) at POT1, shows effect 5.3 fold higher and independent of a previous common index SNP. TERF1 (rs79617270) and STN1 (rs139620151) are linked to LTL-associated common index SNPs at these loci. Rs79617270 is associated with cancer mortality [HR95%CI = 1.544 (1.173, 2.032), PAdj = 0.018] and 4.76% of the association between the rs79617270 and colon cancer is mediated through LTL. Overall, genetically determined LTL is particularly associated with lung adenocarcinoma [HR95%CI = 1.123 (1.051, 1.201), Padj = 0.007]. Ethnicity-specific low frequency variants may affect LTL homeostasis and associate with certain cancers., Xuling Chang et al. study whether low frequency variants are associated with leukocyte telomere length and whether these variants predispose to incident cancers and mortalities among East Asians. They find that three East Asian specific variants at POT1, TERF1 and STN1 loci are associated with leukocyte telomere length and report a mechanistic pathway linking TERF1, leukocyte telomere length and incident colon cancer.

Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40–80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was − 0.91 standard-deviations lower in women than men (95%CI − 0.98; − 0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m2 increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p

Marital status has been shown to be associated with mortality, but evidence in Asian populations is limited.To examine the association of marital status with total and cause-specific mortality.This cohort study included individual participant data from 16 prospective studies in the Asia Cohort Consortium conducted between 1963 and 2015. Asian participants with complete information on marital and vital status were included. Study-specific hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards model and then pooled using a random-effects meta-analysis. The analysis began in February 2021 and ended in August 2021.Marital status.All-cause and cause-specific mortality.Of 623 140 participants (326 397 women [52.4%] and 296 743 men [47.6%]; mean [SD] age, 53.7 [10.2] years; mean [SD] follow-up time, 15.5 [6.1] years), 123 264 deaths were ascertained. Compared with married individuals, those who were unmarried had pooled HRs of 1.15 (95% CI, 1.07-1.24) for total mortality, 1.12 (95% CI, 1.03-1.22) for cerebrovascular disease mortality, 1.20 (95% CI, 1.09-1.31) for coronary heart disease mortality, 1.17 (95% CI, 1.07-1.28) for circulatory system diseases mortality, 1.06 (95% CI, 1.01-1.11) for cancer mortality, 1.14 (95% CI, 1.05-1.23) for respiratory diseases mortality, and 1.19 (95% CI, 1.05-1.34) for external causes of death. Positive associations with total mortality were also observed for those who were single (HR, 1.62; 95% CI, 1.41-1.86), separated (HR, 1.35; 95% CI, 1.13-1.61), divorced (HR, 1.38; 95% CI, 1.13-1.69), and widowed (HR, 1.09; 95% CI, 1.04-1.13). In subgroup analyses, the positive association persisted across baseline health conditions, and the risk of death was more pronounced among men or people younger than 65 years.This large pooled cohort study of individual participant data provides strong evidence that being unmarried, as well as belonging to the unmarried subcategories, was positively associated with total and cause-specific mortality. Investment of targeted social support services might need to be considered in light of the mortality differences between married and unmarried individuals.

To investigate therapeutic effect of minimally invasive percutaneous plate internal fixation (MIPPO) through a single incision in treating open distal tibiofibula fractures.From March 2015 to February 2019, 10 patients with open distal tibiofibula fractures were treated with MIPPO technique through single anterolateral incision, including 8 males and 2 females, aged from 31 to 68 years old. According to Gustilo classification, 6 patients were typeⅠ, 3 patients were typeⅡand 1 patient was type ⅢA. Operative time, intraoperative blood loss and fracture healing were observed, Mazur ankle joint scoring was used to evaluate clinical effect.All patients were followed up from 9 to 24 months. Operative time ranged from 85 to 120 min, intraoperative blood loss ranged from 80 to 200 ml, fracture healing time ranged from 18 to 30 weeks. Nine patients with Gustilo typeⅠandⅡachieved satisfactory healing wound, original wound of 1 patient with Gustilo type ⅢA was poor, and healed by skin flap transplantation at stageⅡ. No steel exposed and infection occurred. According to Mazur ankle scoring at the final following-up, total score was from 61 to 97, and 8 patients got excellent result, 1 good and 1 poor.MIPPO technique through anterolateral single incision for the treatment of open distal tibiofibula fractures could protect original medial wound in opertaion, avoid plate exposed through anterolateral extensor tendon to cover internal fixation, and MIPPO technique could protect fracture end blood flow to improve fracture healing rate, and it is a kind of choice.

Background The relation of changes in sleep duration with risk of cognitive impairment are inconclusive. This study evaluated the prospective relationships of changes in sleep duration with risk of cognitive impairment in Singapore Chinese. Methods We used data from 16,948 Chinese men and women who were aged 45-74 years at baseline (1993-1998) during recruitment into the Singapore Chinese Health Study cohort. Daily sleep duration was assessed at baseline, follow-up 2 (2006 to 2010) and follow-up 3 interviews (2014-2016). Cognitive function was evaluated with a Singapore-Modified Mini-Mental State Examination at follow-up 3 interviews when participants were 61–96 years old. Multivariable logistic regression models were used to calculate odd ratios (ORs) and 95% confidence intervals (95% CIs) for cognitive impairment. Results Of the 16,948 participants, 14.4% were defined to have cognitive impairment. Compared with 7 h/day sleep at both baseline and follow-up 2, the OR (95% CI) for cognitive impairment was 1.50 (1.04-2.16) for those who maintained long sleep duration (≥9 h/day), 2.18 (1.37-3.45) for those who prolonged sleep from short duration (≤5 h/day) to long duration (≥9 h/day), and 1.55 (1.20-2.02) for those who prolonged sleep from recommended duration (7 h/day) to long duration. The highest risk was observed in those who shortened sleep from long to short duration (2.93, 1.35-6.34). Limitations Measures of sleep were self-reported. Conclusions Substantial changes in sleep duration over time were associated with higher risks of cognitive impairment. The findings underscore the importance of maintaining optimal sleep duration for the prevention of cognitive impairment.

Food withdrawal is usually used for accurate feed metabolizable energy (ME) assessment in poultry, but its effects on intestinal structure and the absorption of nutrients are unclear. In this study, broilers were fed ad libitum (CT) or withdrew food for 12 (FH12), 24 (FH24), 36 (FH36), or 48 hours (FH48). We showed that food withdrawal increased the energy assimilation when compared with the CT. Food withdrawal improved the digestibility of ether extract and the level of lipid substances and fatty acid-derived β-hydroxybutyrate in serum. Compared to the CT, food withdrawal did not influence the digestibility of starch. Due to 12 hours or longer food withdrawal duration increased glutamate oxidation and uric acid excretion, the analyzed digestibility of crude protein was underestimated, although the upregulated amino acid transporter genes. In addition, histological analysis showed that short-term food withdrawal (12 hours) increased intestinal villus height, crypt depth, and proliferative cell, whereas prolonged food withdrawal (more than 24 hours) impaired villus structure due to the decreased cell proliferation. Moreover, proteomics analysis revealed upregulated pathways in birds withdrawn food for 36 hours involved in nutrient absorption and amino acid oxidation. In conclusion, food withdrawal changes nutrient absorption and utilization, especially for amino acid and ether extract, and results in increased ME. Both glutamate oxidation and fatty acid incomplete oxidation are involved in energy supply after refeeding. In contrast to short-term food withdrawal, prolonged food withdrawal impairs the intestinal structure and villus renewal. Our findings deserve attention from nutritionists who are analyzing food digestibility.

Background: IL27 mRNA is highly enriched in the tissue of hepatocellular carcinoma. Overexpression of IL27 gene has been found to increase T-cell expression of inhibitory receptors, an immunosuppressive feature in tumor microenvironment, that promotes the development of hepatocellular carcinoma. Methods: Two parallel case–control studies of hepatocellular carcinoma, each with 100 case–control pairs were conducted in the Singapore Chinese Health Study and the Shanghai Cohort Study to examine the association between serum IL27 levels and risk of developing hepatocellular carcinoma. Results: The IL27 concentrations were significantly elevated in sera collected from study participants 4 to 5 years prior to the diagnosis of hepatocellular carcinoma in both cohort studies. Compared with the lowest tertile of IL27, odds ratios (OR) of hepatocellular carcinoma for the highest tertile of IL27 was 46.08 [95% confidence interval (CI), 4.68–453.86] in the Singapore Chinese Health Study and 19.09 (95% CI, 3.81–95.57) in the Shanghai Cohort Study (both Ptrend Conclusions: Levels of IL27 in prediagnostic sera were significantly associated with increased risk of hepatocellular carcinoma development. Impact: IL27, through its immunosuppressive property, may play a significant role in the development of hepatocellular carcinoma. Serum levels of IL27 may be used as a biomarker for prediction of hepatocellular carcinoma development.

BACKGROUND: Although adherence to healthful dietary patterns has been associated with a lower risk of kidney function decline in Western populations, evidence in Asian populations remains scanty. OBJECTIVES: We examined predefined dietary patterns, namely, the Alternate Healthy Eating Index-2010 (AHEI-2010), the Dietary Approaches to Stop Hypertension (DASH), and the alternate Mediterranean diet (aMED), in relation to risk of end-stage kidney disease (ESKD). METHODS: We included 56,985 Chinese adults (aged 45–74 y) in the Singapore Chinese Health Study who were free of cancer, stroke, coronary artery disease, and ESKD at recruitment (1993–1998). Dietary pattern scores were calculated based on a validated 165-item FFQ. AHEI-2010 and aMED scores were modified by excluding the alcohol intake component because daily drinking has been associated with a higher risk of ESKD in our study population. We identified 1026 ESKD cases over a median follow-up of 17.5 y via linkage with the nationwide Singapore Renal Registry. Multivariable Cox regression models were used to compute HRs and their 95% CIs. RESULTS: Higher scores of all 3 dietary patterns were associated with lower ESKD risk in a dose-dependent manner. Compared with the lowest quintiles, the multivariable-adjusted HRs (95% CIs) of ESKD were 0.75 (0.61, 0.92) for the highest quintile of AHEI-2010, 0.67 (0.54, 0.84) for DASH, and 0.73 (0.59, 0.91) for aMED (all P-trend ≤ 0.004). These inverse associations were stronger with increasing BMI (in kg/m(2)), and the HRs for the diet–ESKD association were lowest in the obese (BMI ≥ 27.5), followed by the overweight (BMI = 25 to

Asian studies on how physical tests predict short-term mortality in elderly are scarce. We assessed handgrip strength and timed-up-and-go (TUG) as such predictors among elderly Chinese in Singapore. Prospective cohort study. Community-dwelling Chinese elderly in Singapore. We used data from 13,789 subjects in the prospective, population-based Singapore Chinese Health Study, who had a mean age of 74 (range 63 to 97) years at time of measurements. Subjects underwent assessment for handgrip strength and TUG. They were followed for mortality via linkage with nationwide death registry through 2018. In multivariable analyses, handgrip strength was inversely associated with risk of mortality in a dose-dependent manner: the hazard ratio (HR) [95% confidence interval (CI)] comparing extreme quartiles was 2.05 (1.44–2.90) (Ptrend

ObjectiveHemoglobin A1c (HbA1c) accuracy is important for diabetes diagnosis and estimation of overall glycemia. The G6PD-Asahi variant which causes glucose-6-phosphate dehydrogenase (G6PD) deficiency has been shown to lower HbA1c independently of glycemia in African ancestry populations. As different G6PD variants occur in Asian ancestry, we sought to identify Asian-specific G6PD variants associated with HbA1c.Research design and methodsIn eight Asian population-based cohorts, we performed imputation on the X chromosome using the 1000 Genomes reference panel and tested for association with HbA1c (10 005 East Asians and 2051 South Asians). Results were meta-analyzed across studies. We compared the proportion of individuals classified as having diabetes/pre-diabetes by fasting glucose ≥100 mg/dL or HbA1c ≥5.7% units among carriers and non-carriers of HbA1c-associated variants.ResultsThe strongest association was a missense variant (G6PD-Canton, rs72554665, minor allele frequency=2.2%, effect in men=−0.76% unit, 95% CI −0.88 to −0.64, p=1.25×10−27, n=2844). Conditional analyses identified a secondary distinct signal, missense variant (G6PD-Kaiping, rs72554664, minor allele frequency=1.6%, effect in men=−1.12 % unit, 95% CI −1.32 to −0.92, p=3.12×10−15, pconditional_Canton=7.57×10−11). Adjusting for glucose did not attenuate their effects. The proportion of individuals with fasting glucose ≥100 mg/dL did not differ by carrier status of G6PD-Canton (p=0.21). Whereas the proportion of individuals with HbA1c ≥5.7% units was lower in carriers (5%) compared with non-carriers of G6PD-Canton (30%, p=0.03).ConclusionsWe identified two G6PD variants in East Asian men associated with non-glycemic lowering of HbA1c. Carriers of these variants are more likely to be underdiagnosed for diabetes or pre-diabetes than non-carriers if screened by HbA1c without confirmation by direct glucose measurements.

Background Haptoglobin (Hp) is a plasma protein with strong anti‐inflammation and antioxidant activities. Its plasma level is known to be inversely associated with many inflammatory diseases, including cardiovascular diseases. However, the association of HP genetic variants with coronary artery disease (CAD) severity/mortality, and how they interact with common CAD risk factors are largely unknown. Methods We conducted the analysis in a Singaporean Chinese CAD population with Gensini severity scores (N = 582) and subsequently evaluated the significant findings in an independent cohort with cardiovascular mortality (excluding stroke) as outcome (917 cases and 19,093 controls). CAD risk factors were ascertained from questionnaires, and stenosis information from medical records. Mortality was identified through linkage with the nationwide registry of births and deaths in Singapore. Linear regression analysis between HP genetic variant (rs217181) and disease outcome were performed. Interaction analyses were performed by introducing an interaction term in the same regression models. Results Although rs217181 was not significantly associated with CAD severity and cardiovascular mortality (excluding stroke) in all subjects, when stratified by hypertension status, hypertensive individuals with the minor T allele have more severe CAD (β = 0.073, SE = 0.030, p = 0.015) and non‐hypertensive individuals with the T allele have lower risk for mortality (odds ratio = 0.771 (0.607–0.980), p = 0.033). Conclusion HP genetic variant is not associated with CAD severity and mortality in the general population. However, hypertensive individuals with the rs217181 T allele associated with higher Hp levels had more severe CAD while non‐hypertensive individuals with the same allele had lower risk for mortality in the Chinese population., Hp genetic variant is not associated with CAD severity and mortality in the general population. However, hypertensive individuals with the rs217181 T allele which is associated with higher Hp levels had more severe CAD, while non‐hypertensive individuals with the same allele had lower risk for mortality in the Chinese population.

To explore the effect of suture anchor combined with transverse drilling of patella to repair the fracture of the joint of bone and tendon of quadriceps femoris tendon.From April 2016 to January 2018, 6 patients (8 knees) with complete rupture of the joint of the tendon and bone tendon of the quadriceps femoris were treated with the combination of anchor with wire and transverse drilling of the patella, including 5 males (7 knees) and 1 female, aged from 43 to 74 years with an average age of 53 years old. All the patients had pain in knee joint and could not extend the knee actively after trauma. X-ray, CT and MRI were performed on the knee joints, and it was clear that the joint of bone and tendon of quadriceps femoris tendon was completely broken. The X-ray of knee joint was reviewed regularly after operation, and Lysholm score was used to evaluate the function of knee joint.The average operation time of all patients was 60 minutes. Tourniquets were used during the operation, no drainage was placed after the operation, and no blood transfusion was performed in all patients. Six patients were followed up for 15 to 36 months with an average of 26 months. Lysholm score of 6 patients (8 knees) was 79 to 95 in the last follow-up with an average of 89 points. One of the patients with mandatory spondylitis developed infection and healed after 2 debridements.The suture structure of the joint of bone and tendon of quadriceps femoris tendon repaired with suture anchor and lateral drilling of patella is simple, reliable and effective.

Diet and inflammation have been suggested to be important risk factors for lung cancer. We examined the ability of the dietary inflammatory index (DII®) to predict lung cancer in the Singapore Chinese Health Study (SCHS). The DII is a diet quality index based on the literature linking foods and nutrients with inflammatory biomarkers. Using data from the SCHS for 60,232 participants, including 1851 lung cancer cases, we investigated the associations of baseline DII scores calculated from a food frequency questionnaire with risk of developing lung cancer over an average of 17.6 years of follow-up. Hazard ratios (HR) were estimated using Cox regression, adjusting for smoking status and other risk factors. After excluding cancers diagnosed in the first 2 years of follow-up, the DII was non-significantly associated with risk of lung cancer (HRQ5vsQ1 = 1.13; 95% CI 0.94–1.35; P-trend = 0.24) after adjusting for age, dialect group, sex, interview year, education, body mass index, total calorie intake, physical activity and various smoking variables. In stratified analysis, stronger, statistically significant associations were evident in current smokers (HR 1.44; 95% CI 1.11–1.86; Ptrend = 0.03, P for interaction = 0.003) and in male ever-smokers (HRQ5vsQ1 = 1.37; 95% CI 1.07–1.77; P-trend = 0.03). A pro-inflammatory diet, as shown by higher DII scores, is associated with an elevated risk of lung cancer for subjects with a history of smoking. Public health measures should be adopted to promote consumption of a healthy, anti-inflammatory diet to reduce the risk of lung cancer, especially in current and former smokers.

This study was aimed to explore the comparative acidifying properties of 2-hydroxy-4-(methylthio) butanoic acid (HMTBA) and a combination of DL-methionine (DLM) and acidifier in male broiler production. A total of 480 1-day-old broiler chicks were randomly divided into four treatments: A (low HMTBA, 0.057% HMTBA); B (low acidifier, 0.05% DLM + 0.057% acidifier); C (high HMTBA, 0.284% HMTBA); and D (high acidifier, 0.25% DLM + 0.284% acidifier). At 21 d, growth performance, chyme pH, digestive enzyme activities, and intestinal microflora were measured. The pH of crop, gizzard, and ileum contents was higher in the HMTBA treatment group than in DLM + acidifier treatment group. Furthermore, acidifier supplementation promoted growth of butyrate-producing bacteria such as Faecalibacterium, whereas high HMTBA (0.284%) inhibited the proliferation of acid-producing bacteria including Roseburia and Collinsella. The chymotrypsin activity was lower in the HMTBA group than in the DLM + acidifier group. In contrast, high-level HMTBA group showed higher average daily gain and average daily feed intake than the DLM + acidifier group. These results suggested that HMTBA work through different pathways with DLM plus acidifier.