Associations of serum cystatin C concentrations with total mortality and mortality of 12 site-specific cancers.

Purpose: Cystatin C (CysC), beyond its biomarker role of renal function, has been implicated in various physical and pathological activities. However, the impact of serum CysC on cancer mortality in a general population remains unknown. We aimed to examine the associations of serum CysC concentrations with total mortality and mortality of 12 site-specific cancers. Methods: We included 241,008 participants of the UK Biobank cohort with CysC measurements who had normal creatinine-based estimated glomerular filtration rates and were free of cancer and renal diseases at baseline (2006-2010). Death information was obtained from the National Health Service death records through 28 February 2021. Multivariable Cox proportional hazards models were used to compute hazard ratios (HR) per one standard deviation increase in log-transformed CysC concentrations and 95% confidence intervals (95% CI) for mortality. Results: Over a median follow-up of 12.1 (interquartile range, 11.3-12.8) years, 5,744 cancer deaths occurred. We observed a positive association between serum CysC concentrations and total cancer mortality (HR = 1.16, 95% CI: 1.12-1.20). Specifically, participants with higher serum CysC concentrations had increased mortality due to lung cancer (HR = 1.12, 95% CI: 1.05-1.20), blood cancer (HR = 1.29, 95% CI: 1.16-1.44), brain cancer (HR = 1.19, 95% CI: 1.04-1.36), esophageal cancer (HR = 1.20, 95% CI: 1.05-1.37), breast cancer (HR = 1.18, 95% CI: 1.03-1.36), and liver cancer (HR = 1.49, 95% CI: 1.31-1.69). Conclusion: Our findings indicate that higher CysC concentrations are associated with increased mortality due to lung, blood, brain, esophageal, breast, and liver cancers. Future studies are necessary to clarify underlying mechanisms.

Association of ultra-processed food consumption with all cause and cause specific mortality: population based cohort study.

OBJECTIVE: To examine the association of ultra-processed food consumption with all cause mortality and cause specific mortality. DESIGN: Population based cohort study. SETTING: Female registered nurses from 11 US states in the Nurses' Health Study (1984-2018) and male health professionals from all 50 US states in the Health Professionals Follow-up Study (1986-2018). PARTICIPANTS: 74 563 women and 39 501 men with no history of cancer, cardiovascular diseases, or diabetes at baseline. MAIN OUTCOME MEASURES: Multivariable Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals for the association of ultra-processed food intake measured by semiquantitative food frequency questionnaire every four years with all cause mortality and cause specific mortality due to cancer, cardiovascular, and other causes (including respiratory and neurodegenerative causes). RESULTS: 30 188 deaths of women and 18 005 deaths of men were documented during a median of 34 and 31 years of follow-up, respectively. Compared with those in the lowest quarter of ultra-processed food consumption, participants in the highest quarter had a 4% higher all cause mortality (hazard ratio 1.04, 95% confidence interval 1.01 to 1.07) and 9% higher mortality from causes other than cancer or cardiovascular diseases (1.09, 1.05 to 1.13). The all cause mortality rate among participants in the lowest and highest quarter was 1472 and 1536 per 100 000 person years, respectively. No associations were found for cancer or cardiovascular mortality. Meat/poultry/seafood based ready-to-eat products (for example, processed meat) consistently showed strong associations with mortality outcomes (hazard ratios ranged from 1.06 to 1.43). Sugar sweetened and artificially sweetened beverages (1.09, 1.07 to 1.12), dairy based desserts (1.07, 1.04 to 1.10), and ultra-processed breakfast food (1.04, 1.02 to 1.07) were also associated with higher all cause mortality. No consistent associations between ultra-processed foods and mortality were observed within each quarter of dietary quality assessed by the Alternative Healthy Eating Index-2010 score, whereas better dietary quality showed an inverse association with mortality within each quarter of ultra-processed foods. CONCLUSIONS: This study found that a higher intake of ultra-processed foods was associated with slightly higher all cause mortality, driven by causes other than cancer and cardiovascular diseases. The associations varied across subgroups of ultra-processed foods, with meat/poultry/seafood based ready-to-eat products showing particularly strong associations with mortality.

Photocatalytic Bicyclization of Indole-Tethered 1,6-Enynes for Diastereoselective Synthesis of Pyrrolo[3,2,1-jk]carbazoles.

A visible-light-driven photocatalytic protocol is established for the diastereoselective synthesis of pyrrolo[3,2,1-jk]carbazoles via a radical-triggered multicomponent bicyclization reaction starting from readily available indole-tethered 1,6-enynes and α-benzyl-α-bromomalonates under mild conditions. This photocatalytic approach exhibits a wide substrate compatibility and excellent tolerability toward various functional groups and boasts the benefit of efficient ring formation and chemical bond creation.

Photocatalytic Thio/Selenosulfonylation-Bicyclization of Indole-Tethered 1,6-Enynes Leading to Substituted Benzo[c]pyrrolo[1,2,3-lm]carbazoles.

The photocatalyzed radical-triggered thio/selenosulfonylation-bicyclization of indole-tethered 1,6-enynes has been established for the first time, enabling the synthesis of various previously unreported thio/selenosulfonylated benzo[c]pyrrolo[1,2,3-lm]carbazoles with moderate to good yields under mild conditions. The reaction pathway was proposed, consisting of energy transfer, homolytic cleavage, radical addition, 5-exo-dig, radical coupling, and a Mallory reaction cascade. This approach exhibits a wide substrate compatibility and excellent tolerability toward various functional groups and is characterized by its remarkable efficiency in both bond formation and annulation.

Ultra-processed food consumption and mortality among patients with stages I-III colorectal cancer: a prospective cohort study.

Background: Ultra-processed foods (UPFs) are emerging as a risk factor for colorectal cancer (CRC), yet how post-diagnostic UPF intake may impact CRC prognosis remains unexplored. Methods: Data collected from food frequency questionnaires were used to estimate intakes of total UPFs and UPF subgroups (serving/d) at least 6 months but less than 4 years post-diagnosis among 2498 patients diagnosed with stages I-III CRC within the Nurses' Health Study and Health Professionals Follow-up Study during 1980-2016. Hazard ratios (HR) and 95% confidence intervals (CIs) of all-cause, CRC- and cardiovascular disease (CVD)-specific mortality in association with UPF consumption were estimated using an inverse probability weighted multivariable Cox proportional hazards regression model, adjusted for confounders. Findings: The mean (SD) age of patients at diagnosis was 68.5 (9.4) years. A total of 1661 deaths were documented, including 321 from CRC and 335 from CVD. Compared to those in the lowest quintile (median = 3.6 servings/d), patients in the highest quintile (median = 10 servings/d) of post-diagnostic UPF intake had higher CVD mortality (HR = 1.65, 95% CI = 1.13-2.40) but not CRC or all-cause mortality. Among UPF subgroups, higher consumption of fats/condiments/sauces was associated with a higher risk of CVD-specific mortality (highest vs. lowest quintile of intake, HR = 1.96, 95% CI = 1.41-2.73), and higher intake of ice cream/sherbet was associated with an increased risk of CRC-specific mortality (highest vs. lowest quintile, HR = 1.86, 95% CI: 1.33-2.61). No statistically significant association was found between UPF subgroups and overall mortality. Interpretation: Higher post-diagnostic intake of total UPFs and fats/condiments/sauces in CRC survivors is associated with higher CVD mortality, and higher ice cream/sherbet intake is linked to higher CRC mortality. Funding: US National Institutes of Health and the American Cancer Society.

Prognostic value of tumor deposits and positive lymph node ratio in stage III colorectal cancer: a retrospective cohort study.

BACKGROUND: In colorectal cancer (CRC), tumor deposits (TD) have been used to guide the N staging only in node-negative patients. It remains unknown about the prognostic value of TD in combination with positive lymph node ratio (LNR) in stage III CRC. PATIENTS AND METHODS: We analyzed data from 31,139 eligible patients diagnosed with stage III CRC, including 30,230 from the Surveillance, Epidemiology, and End Results (SEER) database as a training set and 909 from two Chinese hospitals as a validation set. The associations of TD and LNR with cancer-specific survival (CSS) and overall survival (OS) were evaluated using the Kaplan-Meier method and Cox regression models. RESULTS: Both TD-positive and high LNR (value≥0.4) were associated with worse CSS in the training (multivariable hazard ratio [HR], 1.50; 95% confidence interval [CI], 1.43-1.58 and HR, 1.74; 95% CI, 1.62-1.86, respectively) and validation sets (HR,1.90; 95%CI, 1.41-2.54 and HR,2.01; 95%CI, 1.29-3.15, respectively). Compared to patients with TD-negative and low LNR (value<0.4), those with TD-positive and high LNR had a 4.09-fold risk of CRC-specific death in the training set (HR, 4.09; 95% CI, 3.54-4.72) and 4.60-fold risk in the validation set (HR, 4.60; 95% CI, 2.88-7.35). Patients with TD-positive/H-LNR CRC on the right side had the worst prognosis (P<0.001). The combined variable of TD and LNR contributed the most to CSS prediction in the training (24.26%) and validation (32.31%) sets. A nomogram including TD and LNR showed satisfactory discriminative ability, and calibration curves indicated favorable consistency in both the training and validation sets. CONCLUSIONS: TD and LNR represent independent prognostic predictors for stage III CRC. A combination of TD and LNR could be used to identify those at high risk of CRC deaths.

Metabolomic signatures of inflammation and metabolic dysregulation in relation to colorectal cancer risk.

BACKGROUND: Inflammation and metabolic dysregulation are associated with increased risk of colorectal cancer (CRC); the underlying mechanisms are not fully understood. We characterized metabolomic signatures of inflammation and metabolic dysregulation and evaluated the association of the signatures and individual metabolites with CRC risk. METHODS: Among 684 incident CRC cases and 684 age-matched controls in the Nurses' Health Study (n = 818 women) and Health Professionals Follow-up Study (n = 550 men), we applied reduced rank and elastic net regression to 277 metabolites for markers of inflammation (CRP, IL6, TNFRSF1B, and GDF15) or metabolic dysregulation (body mass index, waist circumference, C-peptide, and adiponectin) to derive metabolomic signatures. We evaluated the association of the signatures and individual metabolites with CRC using multivariable conditional logistic regression. All statistical tests were 2-sided. RESULTS: We derived a signature of 100 metabolites that explained 24% of variation in markers of inflammation and a signature of 73 metabolites that explained 27% of variation in markers of metabolic dysregulation. Among men, both signatures were associated with CRC (odds ratio per 1-standard deviation increase, inflammation = 1.34, 95% confidence interval 1.07 to 1.68; metabolic dysregulation = 1.25, 1.00 to 1.55); neither signature was associated with CRC in women. Eleven metabolites were individually associated with CRC and biomarkers of inflammation or metabolic dysregulation among either men or women. CONCLUSION: We derived metabolomic signatures and identified individual metabolites associated with inflammation, metabolic dysregulation, and CRC, highlighting several metabolites as promising candidates involved in the inflammatory and metabolic dysregulation pathways for CRC incidence.

Combining fecal immunochemical testing and questionnaire-based risk assessment in selecting participants for colonoscopy screening in the Chinese National Colorectal Cancer Screening Programs: A population-based cohort study.

BACKGROUND: Screening reduces colorectal cancer (CRC) burden by allowing early resection of precancerous and cancerous lesions. An adequate selection of high-risk individuals and a high uptake rate for colonoscopy screening are critical to identifying people more likely to benefit from screening and allocating healthcare resources properly. We evaluated whether combining a questionnaire-based interview for risk factors with fecal immunochemical test (FIT) outcomes for high-risk assessment is more efficient and economical than a questionnaire-based interview-only strategy. METHODS AND FINDINGS: In this multicenter, population-based, prospective cohort study, we enrolled community residents aged 40 to 74 years in 29 provinces across China. From 2016 to 2020, a total of 1,526,824 eligible participants were consecutively enrolled in the Cancer Screening Program in Urban China (CanSPUC) cohort, and 940,605 were enrolled in the Whole Life Cycle of Cancer Screening Program (WHOLE) cohort, with follow-up to December 31, 2022. The mean ages were 56.89 and 58.61 years in CanSPUC and WHOLE, respectively. In the WHOLE cohort, high-risk individuals were identified by combining questionnaire-based interviews to collect data on risk factors (demographics, diet history, family history of CRC, etc.) with FIT outcomes (RF-FIT strategy), whereas in the CanSPUC cohort, high-risk individuals were identified using only interview-based data on risk factors (RF strategy). The primary outcomes were participation rate and yield (detection rate of advanced neoplasm, early-stage detection rate of CRCs [stage I/II], screening yield per 10,000 invitees), which were reported for the entire population and for different gender and age groups. The secondary outcome was the cost per case detected. In total, 71,967 (7.65%) and 281,985 (18.47%) individuals were identified as high-risk and were invited to undergo colonoscopy in the RF-FIT group and RF group, respectively. The colonoscopy participation rate in the RF-FIT group was 26.50% (19,071 of 71,967) and in the RF group was 19.54% (55,106 of 281,985; chi-squared test, p < 0.001). A total of 102 (0.53%) CRCs and 2,074 (10.88%) advanced adenomas were detected by the RF-FIT, versus 90 (0.16%) and 3,593 (6.52%) by the RF strategy (chi-squared test, both p < 0.001). The early-stage detection rate using the RF-FIT strategy was significantly higher than that by the RF strategy (67.05% versus 47.95%, Fisher's exact test, p = 0.016). The cost per CRC detected was $24,849 by the RF-FIT strategy versus $55,846 by the RF strategy. A limitation of the study was lack of balance between groups with regard to family history of CRC (3.5% versus 0.7%). CONCLUSIONS: Colonoscopy participation and screening yield were better with the RF-FIT strategy. The association with CRC incidence and mortality reduction should be evaluated after long-term follow-up.

Grading severity of microscopic vascular invasion was independently associated with recurrence and survival following hepatectomy for solitary hepatocellular carcinoma.

Background: Hepatectomy is the preferred treatment for solitary hepatocellular carcinoma (HCC) without macrovascular invasion and distant metastasis, but long-term survival remains unsatisfactory in certain patients. We sought to identify whether the grading severity of microscopic vascular invasion (MVI) was associated with recurrence and survival among patients with solitary HCC. Methods: Consecutive patients who underwent hepatectomy for solitary HCC were identified from a multicenter prospectively-collected database. Patients were categorized into three groups according to the MVI grading system proposed by the Liver Cancer Pathology Group of China: M0 (no MVI), M1 (1-5 sites of MVI occurring ≤1.0 cm away from the tumor), and M2 (>5 sites occurring ≤1.0 cm or any site occurring >1 cm away from the tumor). Recurrence-free survival (RFS) and overall survival (OS) were compared among the groups. Results: Among 227 patients, 97 (42.7%), 83 (36.6%), and 47 (20.7%) patients had M0, M1, and M2, respectively. Median RFS rates among patients with M0, M1, and M2 were 38.3, 35.1, 11.6 months, respectively, while OS rates were 66.8, 62.3, 30.6 months, respectively (both P<0.001). Multivariate Cox-regression analyses demonstrated that both M1 and M2 were independent risk factors for RFS (hazard ratio 1.20, 95% CI: 1.03-1.89, P=0.040; and hazard ratio 1.67, 95% CI: 1.06-2.64, P=0.027) and OS (hazard ratio 1.28, 95% CI: 1.05-2.07, P=0.035; and hazard ratio 1.97, 95% CI: 1.15-3.38, P=0.013). Conclusions: Grading severity of MVI was independently associated with RFS and OS after hepatectomy for solitary HCC. Enhanced surveillance for recurrence and potentially adjuvant therapy may be considered for patients with MVI, especially individuals with more severe MVI grading (M2).

Serum apolipoproteins and mortality risk: evidence from observational and Mendelian randomization analyses.

BACKGROUND: Apolipoproteins (APOs) have emerged as significant players in lipid metabolism that affects the risk of chronic disease. However, the impact of circulating APO concentrations on premature death remains undetermined. OBJECTIVES: This study aimed to investigate the associations of serum APOs with all-cause, cardiovascular disease (CVD)-related, and cancer-related mortality. METHODS: We included 340,737 participants who had serum APO measurements from the UK Biobank. Restricted cubic splines and multivariable Cox regression models were used to assess the associations between APOs and all-cause and cause-specific mortality by computing hazard ratios (HRs) and 95% confidence intervals (CIs). Based on 1-sample Mendelian randomization (MR) design, including 398,457 participants of White ancestry who had genotyping data from the UK Biobank, we performed instrumental variable analysis with 2-stage least squares regression to assess the association between genetically predicted APOs and mortality. RESULTS: After adjusting for potential confounders including high-density and low-density lipoprotein particles, we observed nonlinear inverse relationships of APOA1 with all-cause, CVD-related, and cancer-related mortality (P-nonlinear < 0.001). By contrast, positive relationships were observed for APOB and all-cause (P-nonlinear < 0.001), CVD-related (P-linear < 0.001), and cancer-related (P-linear = 0.03) mortality. MR analysis showed consistent results, except that the association between APOB and cancer mortality was null. Furthermore, both observational and MR analyses found an inverse association between APOA1 and lung cancer-related mortality (HR comparing extreme deciles: 0.46; 95% CI: 0.26, 0.80; and HR: 0.78; 95% CI: 0.63, 0.97, respectively). CONCLUSIONS: Our findings indicate that circulating APOA1 has potential beneficial effects on all-cause, CVD-related, and lung cancer-related death risk, whereas APOB may confer detrimental effects on all-cause and CVD-related death risk.

Development and validation of a risk prediction model for post-polypectomy colorectal cancer in the USA: a prospective cohort study.

Background: Effective risk stratification tools for post-polypectomy colorectal cancer (PPCRC) are lacking. We aimed to develop an effective risk stratification tool for the prediction of PPCRC in three large population-based cohorts and to validate the tool in a clinical cohort. Methods: Leveraging the integrated endoscopic, histopathologic and epidemiologic data in three U.S population-based cohorts of health professional (the Nurses' Health Study (NHS) I, II and Health Professionals Follow-up Study (HPFS)), we developed a risk score to predict incident PPCRC among 26,741 patients with a polypectomy between 1986 and 2017. We validated the PPCRC score in the Mass General Brigham (MGB) Colonoscopy Cohort (Boston, Massachusetts, U.S) of 76,603 patients with a polypectomy between 2007 and 2018. In all four cohorts, we collected detailed data on patients' demographics, endoscopic history, polyp features, and lifestyle factors at polypectomy. The outcome, incidence of PPCRC, was assessed by biennial follow-up questionnaires in the NHS/HPFS cohorts, and through linkage to the Massachusetts Cancer Registry in the MGB cohort. In all four cohorts, individuals who were diagnosed with CRC or died before baseline or within six months after baseline were excluded. We used Cox regression to calculate the hazard ratio (HR), 95% confidence interval (CI) and assessed the discrimination using C-statistics and reclassification using the Net Reclassification Improvement (NRI). Findings: During a median follow-up of 12.8 years (interquartile range (IQR): 9.3, 16.7) and 5.1 years (IQR: 2.7, 7.8) in the NHS/HPFS and MGB cohorts, we documented 220 and 241 PPCRC cases, respectively. We identified a PPCRC risk score based on 11 predictors. In the validation cohort, the PPCRC risk score showed a strong association with PPCRC risk (HR for high vs. low, 3.55, 95% CI, 2.59-4.88) and demonstrated a C-statistic (95% CI) of 0.75 (0.70-0.79), and was discriminatory even within the low- and high-risk polyp groups (C-statistic, 0.73 and 0.71, respectively) defined by the current colonoscopy surveillance recommendations, leading to a NRI of 45% (95% CI, 36-54%) for patients with PPCRC. Interpretation: We developed and validated a risk stratification model for PPCRC that may be useful to guide tailored colonoscopy surveillance. Further work is needed to determine the optimal surveillance interval and test the added value of other predictors of PPCRC beyond those included in the current study, along with implementation studies. Funding: US National Institutes of Health, the American Cancer Society, the South-Eastern Norway Regional Health Authority, the Deutsche Forschungsgemeinschaft.

Association of Serum Calcium with the Risk of Chronic Obstructive Pulmonary Disease: A Prospective Study from UK Biobank.

BACKGROUND: Although intracellular calcium had been demonstrated to involve in the pathogenesis of chronic obstructive pulmonary disease (COPD), the association between serum calcium and COPD risk remains unclear. METHODS: We included 386,844 participants with serum calcium measurements and without airway obstruction at the baseline from UK Biobank. The restricted cubic splines were used to assess the dose-response relationship. Multivariable cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of albumin-corrected calcium concentrations with the risk of COPD incidence and mortality. RESULTS: During a median of 12.3 years of follow-up, 10,582 incident COPD cases were documented. A linear positive association was observed between serum calcium concentrations and the risk of COPD incidence. Compared to participants with normal serum calcium (2.19-2.56 mmol/L), a 14% higher risk of COPD was observed in hypercalcemic participants (≥2.56 mmol/L, HR = 1.14; 95% CI: 1.02-1.27). No significant effect modifications were observed in stratified variables. In survival analysis, 215 COPD-specific deaths were documented after a median survival time of 3.8 years. Compared to participants with normal serum calcium, hypercalcemic participants had a 109% (HR = 2.09, 95% CI: 1.15-3.81) increased risk for COPD-specific mortality. CONCLUSION: Our study indicated that hypercalcemia was associated with an elevated risk of COPD incidence and mortality in the European population, and suggested that serum calcium may have a potential impact on the progression of COPD.

Association between glycated haemoglobin and the risk of chronic obstructive pulmonary disease: A prospective cohort study in UK biobank.

AIMS: To investigate the association between glycated haemoglobin (HbA1c) levels and chronic obstructive pulmonary disease (COPD) incidents in the general population, and the association between HbA1c levels and mortality in patients with COPD. MATERIALS AND METHODS: We investigated the association of HbA1c levels with COPD risk in the general population in the UK Biobank, using data from 420 065 participants. Survival analysis was conducted for 18 854 patients with COPD. We used restricted cubic spline analysis to assess the dose-response relationship between HbA1c levels and COPD risk and survival. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: During a median follow-up of 12.3 years, 11 556 COPD cases were recorded. HbA1c had a non-linear relationship with COPD risk (p for non-linearity < .05). Compared with the quintile 2 (32.2-<34.3 mmol/mol), those with HbA1c levels above 38.7 mmol/mol (quintile 5) had a 22% (HR, 1.22, 95% CI: 1.15-1.30) higher risk of COPD. Compared with the HbA1c decile 2 (30.5-<32.2 mmol/mol), the HRs (95% CI) of COPD risk were 1.16 (1.03-1.30) and 1.36 (1.24-1.50) in the lowest HbA1c decile (<30.5 mmol/mol) and highest decile (≥41.0 mmol/mol), respectively. The increased COPD risk associated with HbA1c was more pronounced in younger, current smokers, passive smokers, and participants with a higher Townsend deprivation index (all p for interaction < .05). Among patients with COPD, 4569 COPD cases died (488 because of COPD) during a median follow-up of 5.4 years. Regarding COPD survival, HbA1c had a non-linear relationship with all-cause death (p for non-linearity < .05). Those with HbA1c quintile 5 (≥38.7 mmol/mol) had a 23% (HR, 1.23, 95% CI: 1.10-1.37) higher risk of all-cause death compared with the quintile 2 (32.2-<34.3 mmol/mol). Compared with the HbA1c decile 4 (33.3-<34.3 mmol/mol), those in the lowest HbA1c decile (<30.5 mmol/mol) and highest HbA1c decile (≥41.0 mmol/mol) had 22% (HR, 1.22; 95% CI: 1.01-1.47) and 28% (HR, 1.28; 95% CI: 1.11-1.48) higher risk for overall death. However, no significant association was observed between HbA1c levels and the risk of COPD-specific death. CONCLUSIONS: Our findings indicated that lower and higher HbA1c levels were associated with a higher risk of COPD. In COPD cases, lower and higher HbA1c levels were associated with a higher COPD all-cause death risk.

Development and validation of a blood biomarker score for predicting mortality risk in the general population.

BACKGROUND: Blood biomarkers for multiple pathways, such as inflammatory response, lipid metabolism, and hormonal regulation, have been suggested to influence the risk of mortality. However, few studies have systematically evaluated the combined predictive ability of blood biomarkers for mortality risk. METHODS: We included 267,239 participants from the UK Biobank who had measurements of 28 blood biomarkers and were free of cardiovascular disease (CVD) and cancer at baseline (2006-2010). We developed sex-specific blood biomarker scores for predicting all-cause mortality risk in a training set of 247,503 participants from England and Wales, and validated the results in 19,736 participants from Scotland. Cox and LASSO regression analyses were performed to identify independent predictors for men and women separately. Discrimination and calibration were evaluated by C-index and calibration plots, respectively. We also assessed mediating effects of the biomarkers on the association between traditional risk factors (current smoking, obesity, physical inactivity, hypertension, diabetes) and mortality. RESULTS: A total of 13 independent predictive biomarkers for men and 17 for women were identified and included in the score development. Compared to the lowest tertile of the score, the highest tertile showed a hazard ratio of 5.36 (95% confidence interval [CI] 5.04-5.71) in men and 4.23 (95% CI 3.87-4.62) in women for all-cause mortality. In the validation set, the score yielded a C-index of 0.73 (95% CI 0.72-0.75) in men and 0.70 (95% CI 0.68-0.73) in women for all-cause mortality; it was also predictive of CVD (C-index of 0.76 in men and 0.79 in women) and cancer (C-index of 0.70 in men and 0.67 in women) mortality. Moreover, the association between traditional risk factors and all-cause mortality was largely mediated by cystatin C, C-reactive protein, 25-hydroxyvitamin D, and hemoglobin A1c. CONCLUSIONS: We established sex-specific blood biomarker scores for predicting all-cause and cause-specific mortality in the general population, which hold the potential to identify high-risk individuals and improve targeted prevention of premature death.

Vitamin D status and chronic obstructive pulmonary disease risk: a prospective UK Biobank study.

BACKGROUND: Low vitamin D status has been linked to an increased risk for various inflammatory diseases. Conflicting results have been reported regarding chronic obstructive pulmonary disease (COPD). This study aims to investigate the associations of serum 25-hydroxyvitamin D (25(OH)D) concentrations with COPD risk and survival. METHODS: We included 403 648 participants with serum 25(OH)D measurements and free of COPD at baseline from UK Biobank. Follow-up was until 30 September 2021. Multivariable-adjusted cox regression models were applied to estimate HRs and 95% CIs for the associations of season-standardised 25(OH)D concentrations with COPD risk and survival. The restricted cubic splines were used to assess dose-response relationship. Kaplan-Meier estimation was used to create graphs of the survival curves. RESULTS: During a median follow-up of 12.3 (IQR: 11.4-13.2) years, 11 008 cases of COPD were recorded. We observed a non-linear inverse association between 25(OH)D concentrations and COPD risk. Compared with participants in the fourth quintile of 25(OH)D, those in the lowest quintile were associated with a 23% higher risk (HR, 1.23; 95% CI, 1.16 to 1.31). Stronger associations were observed for the risk in men and current smokers (Both p for interaction <0.05). In survival analyses, compared with the fourth quintile, cases in the lowest quintile had a 38% higher risk for overall death (HR, 1.38; 95% CI, 1.22 to 1.56). CONCLUSION: Our findings indicate that serum 25(OH)D concentrations are non-linearly negatively associated with incidence and mortality of COPD, suggesting a potential protective role of vitamin D in the pathogenesis of COPD.

Polygenic risk for termination of the 'healthspan' and its interactions with lifestyle factors: A prospective cohort study based on 288,359 participants.

OBJECTIVES: To investigate whether a polygenic risk score (PRS) and its interactions with lifestyle factors are associated with termination of the 'healthspan' (the number of years living without serious diseases or degeneration). DESIGN, EXPOSURES AND PARTICIPANTS: Death or the incidence of any of seven independent morbidities (cancer, congestive heart failure, myocardial infarction, chronic obstructive pulmonary disease, stroke, dementia, and diabetes) strongly associated with aging were considered to define the termination of the healthspan. A total of 288,359 healthy participants from the UK Biobank were included in this prospective cohort study to evaluate the associations between PRS, lifestyle, and healthspan. The PRS was generated by weighting 12 healthspan-related genetic loci, which and scores were then categorized into three groups in Cox regression models. A lifestyle index was developed that incorporated body mass index (BMI), alcohol consumption, diet, smoking, and physical activity, and these scores were also categorized into three groups. The risk of termination of the healthspan was calculated across the different PRS and lifestyle index groups using Cox regression models. Interactions were estimated with the marginal effect of lifestyle on the risk of termination of healthspan across values of the moderator PRS using kernel estimation. RESULTS: During an average follow-up of 9.83 years, 68,903 healthspan-termination events occurred. It was calculated that people with high polygenic risk could reduce their risk of healthspan termination by 40 % if they maintain a favorable lifestyle. The marginal effect of lifestyle on the risk of healthspan termination increased with growing genetic risk. Smoking and diet showed monotonic changes in opposite directions, while BMI, physical activity, and alcohol had a U-shaped interaction with genetic risk. CONCLUSIONS: Favorable lifestyle can attenuate the risk of termination of the healthspan, especially for people with high genetic risk. The improvement afforded by ideal lifestyle behaviors varies for each individual.

Postoperative infectious complications following laparoscopic versus open hepatectomy for hepatocellular carcinoma: a multicenter propensity score analysis of 3876 patients.

OBJECTIVES: Hepatocellular carcinoma (HCC) is a common indication for hepatectomy that is often complicated by postoperative complication. The authors sought to investigate the relationship between the open with laparoscopic approach of hepatectomy and incidences of postoperative infectious complications. PATIENTS AND METHODS: Using a multicenter database, HCC patients who underwent laparoscopic hepatectomy (LH) or open hepatectomy (OH) were reviewed and analyzed. Propensity score matching (PSM), inverse probability of treatment weight (IPTW), and multivariate logistic regression analyses were utilized to assess the association of the operative approach with postoperative infectious complications, including incisional surgical site infection (SSI), organ/space SSI, and remote infection (RI). RESULTS: Among 3876 patients, 845 (21.8%) and 3031 (78.2%) patients underwent LH and OH, respectively. The overall incidence of infection was 6.9 versus 14.6% among patients who underwent LH versus OH, respectively ( P <0.001). Of note, the incidences of incisional SSI (1.8 vs. 6.3%, P <0.001), organ/space SSI (1.8 vs. 4.6%, P <0.001), and RI (3.8 vs. 9.8%, P <0.001) were all significantly lower among patients who underwent LH versus OH. After PSM (6.9, 1.8, 1.8, and 3.8% vs. 18.5, 8.4, 5.2, and 12.8%, respectively) and IPTW (9.5, 2.3, 2.1, and 5.5% vs. 14.3, 6.3, 4.5, and 9.8%, respectively), LH remained associated with statistically lower incidences of all types of infectious complications. After adjustment for other confounding factors on multivariate analyses, LH remained independently associated with lower incidences of overall infection, incisional SSI, organ/space SSI, and RI in the overall, PSM, and IPTW cohorts, respectively. CONCLUSION: Compared with open approach, laparoscopic approach was independently associated with lower incidences of postoperative infectious complications following hepatectomy for HCC.

The gut microbiome modifies the associations of short- and long-term physical activity with body weight changes.

BACKGROUND: The gut microbiome regulates host energy balance and adiposity-related metabolic consequences, but it remains unknown how the gut microbiome modulates body weight response to physical activity (PA). METHODS: Nested in the Health Professionals Follow-up Study, a subcohort of 307 healthy men (mean[SD] age, 70[4] years) provided stool and blood samples in 2012-2013. Data from cohort long-term follow-ups and from the accelerometer, doubly labeled water, and plasma biomarker measurements during the time of stool collection were used to assess long-term and short-term associations of PA with adiposity. The gut microbiome was profiled by shotgun metagenomics and metatranscriptomics. A subcohort of 209 healthy women from the Nurses' Health Study II was used for validation. RESULTS: The microbial species Alistipes putredinis was found to modify the association between PA and body weight. Specifically, in individuals with higher abundance of A. putredinis, each 15-MET-hour/week increment in long-term PA was associated with 2.26 kg (95% CI, 1.53-2.98 kg) less weight gain from age 21 to the time of stool collection, whereas those with lower abundance of A. putredinis only had 1.01 kg (95% CI, 0.41-1.61 kg) less weight gain (pinteraction = 0.019). Consistent modification associated with A. putredinis was observed for short-term PA in relation to BMI, fat mass%, plasma HbA1c, and 6-month weight change. This modification effect might be partly attributable to four metabolic pathways encoded by A. putredinis, including folate transformation, fatty acid ß-oxidation, gluconeogenesis, and stearate biosynthesis. CONCLUSIONS: A greater abundance of A. putredinis may strengthen the beneficial association of PA with body weight change, suggesting the potential of gut microbial intervention to improve the efficacy of PA in body weight management. Video Abstract.

Associations of diabetes, prediabetes and diabetes duration with the risk of chronic obstructive pulmonary disease: A prospective UK Biobank study.

AIM: To investigate the associations of diabetes, prediabetes and diabetes duration with chronic obstructive pulmonary disease (COPD) risk and survival in the UK Biobank. MATERIALS AND METHODS: We conducted a prospective analysis among 452 680 participants without COPD at baseline using UK Biobank data. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox regression models. The dose-response relationship was explored using restricted cubic splines. A separate survival analysis was conducted for 12 595 patients with incident COPD. RESULTS: Over a median follow-up of 12.3 years, 12 595 cases of COPD were documented. Compared with the reference group, those with prediabetes and diabetes were associated with an 18% (HR 1.18 [95% CI: 1.13-1.24]) and 35% (HR 1.35 [95% CI: 1.24-1.47]) higher risk of COPD, respectively. Diabetes duration was associated with COPD risk, with multivariable HRs (95% CIs) of 1.23 (1.05-1.44), 1.20 (1.04-1.39) and 1.18 (1.01-1.37) for diabetes duration of 7 years or longer, 3 to less than 7 years, and 1 to less than 3 years versus less than 1 year, respectively. Dose-response analysis revealed a non-linear relationship between diabetes duration and COPD risk. Regarding COPD survival, COPD patients with prediabetes and diabetes had a 9% (HR 1.09 [95% CI: 1.00-1.19]) and 21% (HR 1.21 [95% CI: 1.05-1.41]) higher risk of overall death, respectively. Compared with the cases with a diabetes duration of less than 1 year, those with a diabetes duration of 7 years or longer were associated with a 46% higher risk of overall death (HR 1.46 [95% CI: 1.11-1.92]). CONCLUSIONS: Our findings indicate that diabetes, prediabetes and a longer diabetes duration are associated with a higher risk of and worse survival for COPD. Future studies are warranted to determine the optimal way of diabetes control that might reduce COPD risk.