Diabetes is associated with increased liver cancer incidence and mortality in adults: A report from Asia Cohort Consortium.

There has been growing evidence suggesting that diabetes may be associated with increased liver cancer risk. However, studies conducted in Asian countries are limited. This project considered data of 968,738 adults pooled from 20 cohort studies of Asia Cohort Consortium to examine the association between baseline diabetes and liver cancer incidence and mortality. Cox proportional hazard model and competing risk approach was used for pooled data. Two-stage meta-analysis across studies was also done. There were 839,194 subjects with valid data regarding liver cancer incidence (5654 liver cancer cases [48.29/100,000 person-years]), follow-up time and baseline diabetes (44,781 with diabetes [5.3%]). There were 747,198 subjects with valid data regarding liver cancer mortality (5020 liver cancer deaths [44.03/100,000 person-years]), follow-up time and baseline diabetes (43,243 with diabetes [5.8%]). Hazard ratio (HR) (95% confidence interval [95%CI]) of liver cancer diagnosis in those with vs. without baseline diabetes was 1.97 (1.79, 2.16) (p < .0001) after adjusting for baseline age, gender, body mass index, tobacco smoking, alcohol use, and heterogeneity across studies (n = 586,072; events = 4620). Baseline diabetes was associated with increased cumulative incidence of death due to liver cancer (adjusted HR (95%CI) = 1.97 (1.79, 2.18); p < .0001) (n = 595,193; events = 4110). A two-stage meta-analytic approach showed similar results. This paper adds important population-based evidence to current literature regarding the increased incidence and mortality of liver cancer in adults with diabetes. The analysis of data pooled from 20 studies of different Asian countries and the meta-analysis across studies with large number of subjects makes the results robust.

Modelling and Optimization of Machined Surface Topography in Ball-End Milling Process.

In order to optimize machined surface topography, this paper presents a novel algorithm for simulating the surface topography and predicting the surface roughness of a ball-end milling process. First, a discrete workpiece model was developed using the Z-map method, and the swept surface of a cutter edge was represented using triangular approximation. The workpiece surface was updated (i.e., material removal process) using the intersection between the vertical reference line and the triangular facet under a cutting judgement. Second, the proposed algorithm was verified by comparing the simulated 3D surface topography as well as 2D surface profile and average roughness (Sa) with experimental measurements. Then, numerical simulation examples planed by the Box-Behnken design methods were carried out to investigate the Sa in the ball-end milling operation. The correlations of Sa and cutting parameters were represented by a response surface reduced quadratic model based on the ANOVA results. Finally, the feed per tooth, radial depth of cut, and tilt and lead angles were optimized for improving the machining efficiency under the Sa constraints. This study presents an effective method for simulating surface topography and predicting the Sa to optimize the cutting parameters during ball-end milling process.

A Pre-Leukemic DNA Methylation Signature in Healthy Individuals at Higher Risk for Developing Myeloid Malignancy.

PURPOSE: DNA methylation alterations are widespread in acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), some of which appear to have evolved independently of somatic mutations in epigenetic regulators. Although the presence of somatic mutations in peripheral blood can predict the risk of development of AML and MDS, its accuracy remains unsatisfactory. EXPERIMENTAL DESIGN: We performed global DNA methylation profiling in a case control study nested within the Singapore Chinese Health Study to evaluate whether DNA methylation alterations were associated with AML/MDS development. Targeted deep sequencing and methylated DNA immunoprecipitation sequencing (MeDIP-seq) were performed on peripheral blood collected a median of 9.9 years before diagnosis of AML or MDS, together with age-matched still-healthy individuals as controls. RESULTS: Sixty-six individuals who developed AML or MDS displayed significant DNA methylation changes in the peripheral blood compared with 167 age- and gender-matched controls who did not develop AML/MDS during the follow-up period. Alterations in methylation in the differentially methylation regions were associated with increased odds of developing AML/MDS. CONCLUSIONS: The epigenetic changes may be acquired independently and before somatic mutations that are relevant for AML/MDS development. The association between methylation changes and the risk of pre-AML/MDS in these individuals was considerably stronger than somatic mutations, suggesting that methylation changes could be used as biomarkers for pre-AML/MDS screening.

Low-Carbohydrate Diet Score and Risk of Hepatocellular Carcinoma: Findings from a Prospective Cohort Study.

Limited data are reported on the association between low-carbohydrate diet (LCD) score, a comprehensive measure of dietary pattern according to sources of carbohydrate, fat and protein, and risk of hepatocellular carcinoma (HCC). We evaluated this score with HCC risk in the Singapore Chinese Health Study, a prospective cohort of 63,275 middle-aged and elderly Chinese living in Singapore and recruited during 1993-1998 period. LCD scores were derived from the semi-quantitative food frequency questionnaire at baseline. A nested case-control study involved 197 HCC cases and 465 controls was also constructed among 28,346 participants who provided blood samples. Cox proportional hazard regression method was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for HCC with different levels of LCD scores. Conditional logistic regression was performed for the case-control study analysis. After 17.6 years of follow-up with 819,573 person-years, 561 participants developed primary HCC. Although there was a null association between total LCD score and HCC risk (HRper-SD increment=1.07, 95% CI: 0.98-1.16; P-trend=0.06), there was a positive association between animal-based LCD and the risk of HCC (HRper-SD increment=1.11, 95% CI: 1.02-1.21; Ptrend=0.01). Furthermore, this association was present in both HBsAg-negative and HBsAg-positive individuals in the case-control study. In stratified analysis for the entire cohort, this positive association was only present in those who consumed alcoholic beverages monthly or less frequent but not in weekly or daily drinker (Pinteraction=0.79). In summary, a diet with lower carbohydrate, higher animal fat and protein was significantly associated with higher risk of HCC among Chinese Singaporeans.

Association between serum uric acid and bone mineral density in males from NHANES 2011-2020.

Currently, the relationship between serum uric acid (SUA) and bone mineral density (BMD) in men remains controversial. This study aims to investigate the relationship between SUA and lumbar spine BMD in American men using data from the National Health and Nutrition Examination Survey (NHANES). A total of 6254 male subjects aged 12-80 years (mean age 35.52 ± 14.84 years) in the NHANES from 2011 to 2020 were analyzed. SUA was measured by DxC using the timed endpoint method, and lumbar spine BMD was measured by dual-energy X-ray absorptiometry (DXA). Multivariate linear regression models were used to explore the relationship between SUA and BMD by adjusting for age, race/Hispanic origin, drinking behavior, smoking behavior, physical activity, body mass index (BMI), poverty-to-income ratio (PIR), total protein, serum calcium, cholesterol, serum phosphorus, and blood urea nitrogen. After correcting for the above confounders, it was found that SUA was positively associated with lumbar spine BMD in the range of SUA < 5 mg/dL (ß = 0.006 95% CI 0.003-0.009, P < 0.001), and BMD of individuals in the highest quartile of SUA was 0.020 g/cm2 higher than those in the lowest quartile of SUA (ß = 0.020 95% CI 0.008-0.032, P = 0.003). This study showed that SUA was positively correlated with lumbar spine BMD in American men within a certain range. This gives clinicians some insight into how to monitor SUA levels to predict BMD levels during adolescence when bone is urgently needed for growth and development and during old age when bone loss is rapid.

Effects of qigong exercise on physical fitness and patient-reported health outcomes in lung cancer survivors.

PURPOSE: The aim of this study was to investigate the effects of a three-month Guolin Qigong (GQ) intervention on physical fitness and patient-reported health outcomes among patients with lung cancer. METHODS: This pilot study was a non-randomized controlled trial. Eligible participants who were over 18 years of age and diagnosed with stage I-IV lung cancer were enrolled in the study and received either the GQ intervention or usual care (UC). Participants in the GQ group performed GQ at least twice a week (one hour per session) for three months. Physical fitness (chair stand, arm curl, sit and reach, back scratch, 8-foot up and go, 6-min walk test) was assessed at baseline, post-intervention, six months, and 12 months. Self-reported quality of life and sleep (European Organization for Research and Treatment of Cancer Quality of Life questionnaire and Pittsburgh Sleep Quality Index) were assessed at baseline, post-intervention, and six months. RESULTS: Forty-nine participants (65% females, 59.1 ± 7.0 years old, ranging from 39 to 71 years old) were enrolled in the study, and 25 participants completed all tests at 12-month follow-up (13 in GQ vs. 12 in UC; 68% females, 59.3 ± 5.5 years old). Compared to the UC group, results for the chair stand and arm curl tests improved significantly in the GQ group from baseline to post-intervention (P = 0.024 and P = 0.041, respectively). Similarly, the 8-foot up and go test improved in the GQ group from baseline to post-intervention and 12 months (P = 0.004 and P = 0.008, respectively) when compared to the UC group. Between-group analyses also revealed a statistically significant improvement in global health status/quality of life from baseline to six months (P = 0.018) and quality of sleep from baseline to post-intervention (P = 0.034) in favor of the GQ group. CONCLUSION: GQ had a beneficial effect on lower and upper body strength, locomotor performance (speed, agility, and balance while moving), quality of sleep, and quality of life among lung cancer survivors, but further randomized controlled trials are warranted to confirm these findings. TRIAL REGISTRATION: The trial has been registered in the Chinese Clinical Trial Registry (ChiCTR2200059145).

Obesity is associated with biliary tract cancer mortality and incidence: A pooled analysis of 21 cohort studies in the Asia Cohort Consortium.

Body fatness is considered a probable risk factor for biliary tract cancer (BTC), whereas cholelithiasis is an established factor. Nevertheless, although obesity is an established risk factor for cholelithiasis, previous studies of the association of body mass index (BMI) and BTC did not take the effect of cholelithiasis fully into account. To better understand the effect of BMI on BTC, we conducted a pooled analysis using population-based cohort studies in Asians. In total, 905 530 subjects from 21 cohort studies participating in the Asia Cohort Consortium were included. BMI was categorized into four groups: underweight (<18.5 kg/m2 ); normal (18.5-22.9 kg/m2 ); overweight (23-24.9 kg/m2 ); and obese (25+ kg/m2 ). The association between BMI and BTC incidence and mortality was assessed using hazard ratios (HR) and 95% confidence intervals (CIs) by Cox regression models with shared frailty. Mediation analysis was used to decompose the association into a direct and an indirect (mediated) effect. Compared to normal BMI, high BMI was associated with BTC mortality (HR 1.19 [CI 1.02-1.38] for males, HR 1.30 [1.14-1.49] for females). Cholelithiasis had significant interaction with BMI on BTC risk. BMI was associated with BTC risk directly and through cholelithiasis in females, whereas the association was unclear in males. When cholelithiasis was present, BMI was not associated with BTC death in either males or females. BMI was associated with BTC death among females without cholelithiasis. This study suggests BMI is associated with BTC mortality in Asians. Cholelithiasis appears to contribute to the association; and moreover, obesity appears to increase BTC risk without cholelithiasis.

Lung Cancer Risk Prediction Models for Asian Ever-Smokers.

INTRODUCTION: Although lung cancer prediction models are widely used to support risk-based screening, their performance outside Western populations remains uncertain. This study aims to evaluate the performance of 11 existing risk prediction models in multiple Asian populations and to refit prediction models for Asians. METHODS: In a pooled analysis of 186,458 Asian ever-smokers from 19 prospective cohorts, we assessed calibration (expected-to-observed ratio) and discrimination (area under the receiver operating characteristic curve [AUC]) for each model. In addition, we developed the "Shanghai models" to better refine risk models for Asians on the basis of two well-characterized population-based prospective cohorts and externally validated them in other Asian cohorts. RESULTS: Among the 11 models, the Lung Cancer Death Risk Assessment Tool yielded the highest AUC (AUC [95% confidence interval (CI)] = 0.71 [0.67-0.74] for lung cancer death and 0.69 [0.67-0.72] for lung cancer incidence) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Model had good calibration overall (expected-to-observed ratio [95% CI] = 1.06 [0.90-1.25]). Nevertheless, these models substantially underestimated lung cancer risk among Asians who reported less than 10 smoking pack-years or stopped smoking more than or equal to 20 years ago. The Shanghai models were found to have marginal improvement overall in discrimination (AUC [95% CI] = 0.72 [0.69-0.74] for lung cancer death and 0.70 [0.67-0.72] for lung cancer incidence) but consistently outperformed the selected Western models among low-intensity smokers and long-term quitters. CONCLUSIONS: The Shanghai models had comparable performance overall to the best existing models, but they improved much in predicting the lung cancer risk of low-intensity smokers and long-term quitters in Asia.

Association of aflatoxin with gallbladder cancer in a case-control study nested within a Chinese cohort.

We evaluated whether aflatoxin B1 (AFB1 ) exposure was associated with later risk of developing gallbladder cancer (GBC). We measured AFB1 -lysine albumin adducts in baseline samples from the Shanghai Cohort Study of 18 244 men aged 45 to 64 years (recruited 1986-1989). We included 84 GBC cases with sufficient serum and 168 controls matched on age at sample collection, date of blood draw and residence. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for detectable vs non-detectable AFB1 -lysine albumin adducts and gallbladder cancer. AFB1 -lysine albumin adducts were detected in 50.0% of GBC cases, and risk of GBC was twice as high in those with detectable vs undetectable levels (OR = 2.0, 95% CI = 1.0-3.9). ORs ranged from 1.8 (95% CI = 0.75-4.3) for 0.5 to <1.75 pg/mg vs undetectable adduct levels to 2.2 (95% CI = 0.91-5.6) for >3.36 pg/mg vs undetectable, suggesting a dose-response (Ptrend = .05). When restricted to cases diagnosed before the median time to diagnosis after blood draw (18.4 years), results were similar (OR = 2.2, 95% CI = 0.80-5.8) to those for the entire follow-up duration. The OR was 9.4 (95% CI = 1.7-51.1) for individuals with detectable AFB1 -lysine albumin adducts and self-reported gallstones compared to individuals with neither. Participants with detectable AFB1 -lysine albumin adducts at baseline had increased risk of developing GBC, replicating the previously observed association between AFB1 exposure and providing the first evidence of temporality.

Pulmonary circulatory system characteristics are associated with future lung cancer risk.

BACKGROUND: Most of the subjects eligible for annual low-dose computed tomography (LDCT) lung screening will not develop lung cancer for their life. It is important to identify novel biomarkers that can help identify those at risk of developing lung cancer and improve the efficiency of LDCT screening programs. OBJECTIVE: This study aims to investigate the association between the morphology of the pulmonary circulatory system (PCS) and lung cancer development using LDCT scans acquired in the screening setting. METHODS: We analyzed the PLuSS cohort of 3635 lung screening patients from 2002 to 2016. Circulatory structures were segmented and quantified from LDCT scans. The time from the baseline CT scan to lung cancer diagnosis, accounting for death, was used to evaluate the prognostic ability (i.e., hazard ratio (HR)) of these structures independently and with demographic factors. Five-fold cross-validation was used to evaluate prognostic scores. RESULTS: Intrapulmonary vein volume had the strongest association with future lung cancer (HR = 0.63, p < 0.001). The joint model of intrapulmonary vein volume, age, smoking status, and clinical emphysema provided the strongest prognostic ability (HR = 2.20, AUC = 0.74). The addition of circulatory structures improved risk stratification, identifying the top 10% with 28% risk of lung cancer within 15 years. CONCLUSION: PCS characteristics, particularly intrapulmonary vein volume, are important predictors of lung cancer development. These factors significantly improve prognostication based on demographic factors and noncirculatory patient characteristics, particularly in the long term. Approximately 10% of the population can be identified with risk several times greater than average.

Incidence of hepatocellular carcinoma in nonalcoholic fatty liver disease without cirrhosis or advanced liver fibrosis.

BACKGROUND: HCC can develop in the absence of cirrhosis in patients with NAFLD. We aimed to estimate the incidence of HCC in patients with NAFLD with and without cirrhosis or advanced liver fibrosis. METHODS: We performed a cohort study to determine the incidence of HCC in patients with NAFLD identified by the International Classification of Diseases 9/10 codes in the electronic health records of a US health care system between 2004 and 2018. The incidence of HCC was stratified by the presence or absence of cirrhosis and by the Fibrosis-4 index (FIB-4) at the time of HCC diagnosis. RESULTS: Of 47,165 patients with NAFLD aged 40-89 years, 981 (2.1%) developed HCC (mean follow-up 3.4 y). Among patients with HCC, 842 (85.8%) had cirrhosis, while 139 (14.2%) did not. Of the 139 patients with HCC without cirrhosis-related diagnostic codes, 26 (2.7%) had FIB-4 >2.67 (advanced fibrosis likely), whereas 43 (4.4%) had FIB-4 < 1.30 (excluding advanced fibrosis). The annual incidence of HCC in patients with NAFLD with and without cirrhosis was 23.6 and 1.1 per 1000 person-years, respectively. Among patients without cirrhosis, the annual incidence of HCC was 2.8 per 1000 person-years with FIB-4 >2.67 and 0.7 per 1000 person-years with FIB-4 <1.30. Patients with NAFLD and cirrhosis were 31.8 times (95% CI, 23.3-43.4) more likely to develop HCC than those without cirrhosis and FIB-4 <1.30, after adjustment for age and sex. CONCLUSIONS: Patients with NAFLD without cirrhosis nor advanced fibrosis have a low incidence of HCC.

The Association Between Serum Riboflavin and Flavin Mononucleotide With Pancreatic Cancer: Findings From a Prospective Cohort Study.

OBJECTIVES: Vitamin B2 (riboflavin) has a prime role in metabolic reactions imperative to cell cycle and proliferation. We investigated the associations between serum concentrations of riboflavin flavin mononucleotide with the risk of pancreatic cancer in a nested case-control study involving 58 cases and 104 matched controls. METHODS: The Singapore Chinese Health Study, an ongoing prospective cohort study of 63,257 Chinese Singaporeans. Conditional logistic regression method was used to evaluate these associations with adjustment for potential confounders including the level of education, body mass index, smoking status, alcohol consumption, history of diabetes, serum cotinine and pyridoxal 5'-phosphate, estimated glomerular filtration rate, and total methyl donors (ie, the sum of serum choline, betaine, and methionine). RESULTS: The risk of pancreatic cancer increased with increasing level of serum riboflavin in a dose-dependent manner, especially in men (Ptrend = 0.003). The odds ratio (95% confidence intervals) of pancreatic cancer for the second and third tertiles of serum riboflavin, compared with the lowest tertile, were 9.92 (1.65-59.77) and 25.59 (3.09-212.00), respectively. This positive association was stronger in individuals with a longer follow-up period (≥7 years). CONCLUSIONS: The findings suggest a potential role of riboflavin in the development of pancreatic cancer, especially in men.

Associations between Ileal Juice Bile Acids and Colorectal Advanced Adenoma.

BACKGROUND: There is an urgent need to identify biomarkers for advanced adenoma, an important precursor of colorectal cancer (CRC). We aimed to determine alterations in ileal juice bile acids associated with colorectal advanced adenoma. METHODS: We quantified a comprehensive panel of primary and secondary bile acids and their conjugates using an ultraperformance liquid chromatography triple-quadrupole mass spectrometric assay in ileal juice collected at colonoscopy from 46 study subjects (i.e., 14 biopsy-confirmed advanced adenomas and 32 controls free of adenoma or cancer). Using analysis of covariance (ANCOVA), we examined the differences in bile acid concentrations by disease status, adjusting for age, sex, body mass index, smoking status and type 2 diabetes. RESULTS: The concentrations of hyodeoxycholic acid (HCA) species in ileal juice of the advanced adenoma patients (geometric mean = 4501.9 nM) were significantly higher than those of controls (geometric mean = 1292.3 nM, p = 0.001). The relative abundance of ursodeoxycholic acid (UDCA) in total bile acids was significantly reduced in cases than controls (0.73% in cases vs. 1.33% in controls; p = 0.046). No significant difference between cases and controls was observed for concentrations of total or specific primary bile acids (i.e., cholic acid (CA), chenodeoxycholic acid (CDCA) and their glycine- and taurine-conjugates) and total and specific major secondary bile acids (i.e., deoxycholic acid and lithocholic acid). CONCLUSIONS: Colorectal advanced adenoma was associated with altered bile acids in ileal juice. The HCA species may promote the development of colorectal advanced adenoma, whereas gut microbiota responsible for the conversion of CDCA to UDCA may protect against it. Our findings have important implications for the use of bile acids as biomarkers in early detection of colorectal cancer.

Lung cancer risk discrimination of prediagnostic proteomics measurements compared with existing prediction tools.

BACKGROUND: We sought to develop a proteomics-based risk model for lung cancer and evaluate its risk-discriminatory performance in comparison with a smoking-based risk model (PLCOm2012) and a commercially available autoantibody biomarker test. METHODS: We designed a case-control study nested in 6 prospective cohorts, including 624 lung cancer participants who donated blood samples at most 3 years prior to lung cancer diagnosis and 624 smoking-matched cancer free participants who were assayed for 302 proteins. We used 470 case-control pairs from 4 cohorts to select proteins and train a protein-based risk model. We subsequently used 154 case-control pairs from 2 cohorts to compare the risk-discriminatory performance of the protein-based model with that of the Early Cancer Detection Test (EarlyCDT)-Lung and the PLCOm2012 model using receiver operating characteristics analysis and by estimating models' sensitivity. All tests were 2-sided. RESULTS: The area under the curve for the protein-based risk model in the validation sample was 0.75 (95% confidence interval [CI] = 0.70 to 0.81) compared with 0.64 (95% CI = 0.57 to 0.70) for the PLCOm2012 model (Pdifference = .001). The EarlyCDT-Lung had a sensitivity of 14% (95% CI = 8.2% to 19%) and a specificity of 86% (95% CI = 81% to 92%) for incident lung cancer. At the same specificity of 86%, the sensitivity for the protein-based risk model was estimated at 49% (95% CI = 41% to 57%) and 30% (95% CI = 23% to 37%) for the PLCOm2012 model. CONCLUSION: Circulating proteins showed promise in predicting incident lung cancer and outperformed a standard risk prediction model and the commercialized EarlyCDT-Lung.

Evaluation of pre-diagnostic blood protein measurements for predicting survival after lung cancer diagnosis.

BACKGROUND: To evaluate whether circulating proteins are associated with survival after lung cancer diagnosis, and whether they can improve prediction of prognosis. METHODS: We measured up to 1159 proteins in blood samples from 708 participants in 6 cohorts. Samples were collected within 3 years prior to lung cancer diagnosis. We used Cox proportional hazards models to identify proteins associated with overall mortality after lung cancer diagnosis. To evaluate model performance, we used a round-robin approach in which models were fit in 5 cohorts and evaluated in the 6th cohort. Specifically, we fit a model including 5 proteins and clinical parameters and compared its performance with clinical parameters only. FINDINGS: There were 86 proteins nominally associated with mortality (p < 0.05), but only CDCP1 remained statistically significant after accounting for multiple testing (hazard ratio per standard deviation: 1.19, 95% CI: 1.10-1.30, unadjusted p = 0.00004). The external C-index for the protein-based model was 0.63 (95% CI: 0.61-0.66), compared with 0.62 (95% CI: 0.59-0.64) for the model with clinical parameters only. Inclusion of proteins did not provide a statistically significant improvement in discrimination (C-index difference: 0.015, 95% CI: -0.003 to 0.035). INTERPRETATION: Blood proteins measured within 3 years prior to lung cancer diagnosis were not strongly associated with lung cancer survival, nor did they importantly improve prediction of prognosis beyond clinical information. FUNDING: No explicit funding for this study. Authors and data collection supported by the US National Cancer Institute (U19CA203654), INCA (France, 2019-1-TABAC-01), Cancer Research Foundation of Northern Sweden (AMP19-962), and Swedish Department of Health Ministry.

High serum magnesium is associated with lower risk of hepatocellular carcinoma among patients with nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a major contributor to the rising incidence of hepatocellular carcinoma (HCC). Magnesium is a major cation in cellular activities. Epidemiological data on magnesium level and its relation to HCC are sparse. This study aimed to examine the associations between serum levels of magnesium and the risk of HCC among patients with NAFLD. METHODS: A total of 26,053 patients with NAFLD were identified in the University of Pittsburgh Medical Center Electronic Health Records from 2004 through 2018. After an average of 5.15 years of follow-up, 395 patients developed HCC after the first measurement of serum magnesium. Cox proportional hazards regression model was used to calculate hazard ratios (HRs) and 95% CIs of HCC incidence associated with quartile levels of serum magnesium after adjustment for age, sex, race, body mass index, diuretics use, history of type 2 diabetes, history of hypertension, history of hyperlipidemia, and tobacco smoking. RESULTS: Patients with NAFLD who developed HCC had a significantly lower mean (± standard deviation) serum magnesium (0.769 ± 0.131 mmol/L) than those who remained free of HCC (0.789 ± 0.125 mmol/L; p = .003). Compared with the lowest quartile, the HRs (95% CIs) of HCC second, third, and fourth quartiles of serum magnesium were 0.87 (0.67-1.12), 0.77 (0.57-1.04), and 0.73 (0.56-0.96), respectively, after adjustment for multiple potential confounders (P trend  = .02). CONCLUSION: This finding suggests higher levels of serum magnesium were significantly associated with decreased risk of HCC among patients with NAFLD.

Soluble CD137 and risk of hepatocellular carcinoma: nested case-control studies in cohorts in Shanghai and Singapore.

BACKGROUND: The majority of hepatocellular carcinoma (HCC) cases occur in the presence of cirrhosis. Biomarkers of cirrhosis-associated immune dysfunction such as CD8+ T cell cytokines could aid HCC risk assessment. METHODS: CD8+ T cell cytokines were determined in pre-diagnostic serum in two studies including 315 HCC case-control pairs in the Shanghai Cohort Study (SCS) and 197 pairs in the Singapore Chinese Health Study (SCHS). Conditional logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) for HCC with levels of five cytokines-soluble CD137 (sCD137), soluble Fas (sFas), perforin, macrophage inflammatory protein 1-beta (MIP-1ß), and tumour necrosis factor alpha (TNF-α). RESULTS: sCD137 levels were significantly higher in HCC cases than controls in both cohorts (Ps < 0.001). Compared with the lowest quartile, multivariable-adjusted ORs (95% CI) of HCC for the highest sCD137 quartile were 3.79 (1.73, 8.30) in the SCS and 3.49 (1.44, 8.48) in the SCHS. The sCD137-HCC association was independent of hepatitis B seropositivity and follow-up time. No other cytokine was consistently associated with HCC risk. CONCLUSION: sCD137 was associated with higher risk of HCC in two studies nested in general population cohorts. sCD137 may be a long-term risk marker of HCC development.

Low-Carbohydrate Diet Score and the Risk of Colorectal Cancer: Findings from the Singapore Chinese Health Study.

BACKGROUND: Colorectal cancer is common cancer with a high mortality rate. Low-carbohydrate diet (LCD) score holistically evaluates the LCD pattern from carbohydrate, protein, and fat intake. Epidemiologic data of LCD-colorectal cancer association are sparse. METHODS: We evaluated the associations between LCD (i.e., total, animal- and plant-based) and colorectal cancer risk in the Singapore Chinese Health Study, a population-based prospective cohort study including 61,321 Chinese in Singapore who were 45 to 74 years old at baseline. Cox proportional hazard regression model was used to determine the HRs and respective 95% confidence intervals (CI) for colorectal cancer associated with LCD after adjusting for potential confounders, including age, sex, BMI, physical activity, family history of colorectal cancer, etc. RESULTS: After an average of 19.5 years of follow-up, 2,520 participants developed colorectal cancer (1,608 colon cancer and 912 rectal cancer). Overall, the association between total or plant-based LCD scores with the risk of colorectal, colon, or rectal cancer was null (all Ptrend ≥ 0.28). The animal-based LCD was modestly associated with colon cancer risk (Ptrend = 0.02), but not with rectal cancer. Compared with the lowest quartile, HRs (95% CIs) of colon cancer for quartiles 2, 3, and 4 of animal-based LCD were 1.12 (0.98-1.29), 1.27 (1.10-1.46), and 1.14 (0.99-1.31), respectively. CONCLUSIONS: A low-level carbohydrate diet with a high level of animal protein and fat was associated with a moderate increase in the risk of colon cancer among Chinese Singaporeans. IMPACT: High consumption of animal protein/fat and low consumption of carbohydrates may increase colon cancer risk.

Quantitation by Liquid Chromatography-Nanoelectrospray Ionization-High-Resolution Tandem Mass Spectrometry of Multiple DNA Adducts Related to Cigarette Smoking in Oral Cells in the Shanghai Cohort Study.

We developed a liquid chromatography-nanoelectrospray ionization-high-resolution tandem mass spectrometry (LC-NSI-HRMS/MS) method for simultaneous quantitative analysis of 5 oral cell DNA adducts associated with cigarette smoking: (8R/S)-3-(2'-deoxyribos-1'-yl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purine-10(3H)-one (γ-OH-Acr-dGuo, 1) from acrolein; (6S,8S and 6R,8R)-3-(2'-deoxyribos-1'-yl)-5,6,7,8-tetrahydro-8-hydroxy-6-methylpyrimido[1,2-a]purine-10(3H)-one [(6S,8S)γ-OH-Cro-dGuo, 2; and (6R,8R)γ-OH-Cro-dGuo, 3] from crotonaldehyde; 1,N6-etheno-dAdo (4) from acrylonitrile, vinyl chloride, lipid peroxidation, and inflammation; and 8-oxo-dGuo (5) from oxidative damage. Oral cell DNA was isolated in the presence of glutathione to prevent artifact formation. Clear LC-NSI-HRMS/MS chromatograms were obtained allowing quantitation of each adduct using the appropriately labeled internal standards. The accuracy and precision of the method were validated, and the assay limit of quantitation was 5 fmol/µmol dGuo for adducts 1-4 and 20 fmol/µmol for adduct 5. The assay was applied to 80 buccal cell samples selected from those collected in the Shanghai Cohort Study: 40 from current smokers and 40 from never smokers. Significant differences were found in all adduct levels between smokers and nonsmokers. Levels of 8-oxo-dGuo (5) were at least 3000 times greater than those of the other adducts in both smokers and nonsmokers, and the difference between amounts of this adduct in smokers versus nonsmokers, while significant (P = 0.013), was not as great as the differences of the other DNA adducts between smokers and nonsmokers (P-values all less than 0.001). No significant relationship of adduct levels to risk of lung cancer incidence was found. This study provides a new LC-NSI-HRMS/MS methodology for the quantitation of diverse DNA adducts resulting from exposure to the α,ß-unsaturated aldehydes acrolein and crotonaldehyde, inflammation, and oxidative damage which are all associated with carcinogenesis. We anticipate application of this assay in ongoing studies of the molecular epidemiology of cancers of the lung and oral cavity related to cigarette smoking.

Globulin and Albumin/Globulin Ratios as Potential Biomarkers for the Diagnosis of Acute and Chronic Peri-Prosthetic Joint Infections: A Retrospective Study.

Background: Peri-prosthetic joint infection (PJI) is the most serious complication after prosthetic joint replacement. However, the diagnosis of PJI remains challenging for clinicians because of the lack of a gold standard. The purpose of this study was to investigate the diagnostic significance of serum globulin, albumin/globulin, and other biomarkers in acute and chronic periprosthetic infections. Patients and Methods: A retrospective study of 162 patients with PJI and aseptic loosening between January 2016 and March 2021 at our institution was performed in three groups. There were 20 patients with acute infection in group A, 36 patients with chronic infection in group B, and 106 patients with aseptic loosening in group C. Globulin, albumin/globulin, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), platelet count (PLT), mean platelet volume (MPV), d-dimer, and platelet count/mean platelet volume ratio (PMR) levels were recorded. The area under the curve (AUC) was used to measure the diagnostic value of globulin and albumin/globulin with other biomarkers for PJI. Results: Compared with the aseptic loosening group, the acute and chronic PJI group had higher levels of CRP, ESR, d-dimer, globulin, PLT, and PMR (p < 0.01) and lower levels of albumin/globulin and MPV (p < 0.01). The optimal cutoff, AUC, sensitivity, and specificity of CRP, albumin/globulin, ESR, and globulin were: CRP, 8.3 mg/L, 0.903, 78.57%, and 88.68%; albumin/globulin, 1.31, 0.899, 91.07%, and 73.58%; ESR, 32 mm/h, 0.888, 75.%, and 85.85%; globulin, 29.5 g/L, 0.880, 91.07%, and 72.64%. Conclusions: Globulin and albumin/globulin have excellent diagnostic value for acute and chronic PJI and are promising potential biomarkers for the diagnosis of PJI. The diagnostic performance of albumin/globulin is superior to that of ESR and similar to that of CRP.